This post is a bit of a long one, so I’m breaking into two sections for readability. Firstly, I’ll discuss how depression affects the brain and how long-term depression I believe it can make it harder to get out of depressive cycles. I mention this not to be a downer and pessimistic; instead, for me knowing this has made it possible to go easier on myself and become somewhat less frustrated through slow/lack of progress. Change takes time along with effort. Secondly, we’ll go into what influences these changes and how we can attempt to take advantage of these mechanisms to benefit us.
“Nothing in the world is worth having or doing unless it means effort, pain and difficulty… I have never in my life envied a human being who led an easy life. I have envied a great many people who led difficult lives and led them well.”
― Theodore Roosevelt
Although the research is in its initial days (although the connection between hippocampal volume and depression has been reported for over 20 years), there’s a growing amount of data pointing to structural changes in the brain due to depression and other mood disorders. “One fMRI study published in The Journal of Neuroscience studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% [some studies indicate up to a 20% loss] smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus.”(1). The hippocampus is an area of the brain responsible for processing long-term memory and recollection. It’s a part of the brain which registers fear from a given situation, the memory of which may affect how you relate and respond to that situation again. How does this occur? Possibly due to long-term stress. Firstly, stress can cause retraction of dendritic processes (a branching extension from the neurone cell body that receives information from other neurones. See figure below.)
in hippocampal neurons. A second adverse effect of stress is the inhibition of neurogenesis in the adult hippocampus. Finally, in some studies, sustained stress can cause loss of preexisting hippocampal neurons (i.e., neurotoxicity)(2)
The amygdala seems to be a bit more tricky when it comes to correlating volume loss and depression. The amygdala, crucial to perception and where emotional memories are retained, is often more active in depressive illness and post-traumatic stress disorder (PTSD). Repeated stressors may enlarge the amygdala. An overactive amygdala, coupled with atypical activity in other brain regions, leads to disturbed patterns of physical activity and sleep. It can also induce abnormal secretion of hormones and other chemicals that affect many systems of the body. A 2008 meta-analysis of magnetic imaging resonance studies wrote:
“Stress-induced glucocorticoid excitotoxicity, which has been postulated to underlie hippocampal atrophy in psychiatric illness, stands as a potential moderator of amygdala volume loss in depression. This is a possible hypothesis given that the amygdala, like the hippocampus, is dense with glucocorticoid receptors. However, if cumulative effects of glucocorticoid exposure are responsible for the volumetric reduction of the amygdala during depression, then we would also predict a negative correlation between amygdala volume and recurrence or level of chronicity of depression, which has been shown in studies of hippocampal volume and depression.”(3)
What was interesting in this particular analysis was that they found unmedicated depressed people showed a reduction in amygdala volume, however, medicated people showed an increase in size.
Drevets et al. using positron emission tomography (PET) imaging reported an increase in amygdala activation and metabolism in depressed patients. The fact that more significant amygdala activity was often observed after negative stimuli would explain the increased ability for depressed people to encode and remember negative rather than positive information, therefore contributing to the negative bias often seen in depressed patients. So the relationship between amygdala size and depression doesn’t seem to be fully elucidated yet.
The prefrontal cortex (PFC), an essential structure in emotional regulation, decision-making and memory, may also shrink with depression. The prefrontal cortex is connected with several brain structures, for processing sensory input and mediating executive motor functions. The ventromedial PFC, located in the frontal lobe and the orbitofrontal cortex, located above the eyes, is involved in the cognitive processing of emotional stimuli originating from the limbic system (e.g., amygdala, ventral striatum, hippocampus, and hypothalamus) and is chiefly engaged in memory consolidation and retrieval. As such, the PFC plays a significant role in regulating appropriate emotional responses, including mood, fear or anxiety. Furthermore, the PFC has been associated with decision-making, personality expression and social behaviour. Neuroimaging studies showed a reduction in the size of multiple areas of the PFC in subjects diagnosed with depression. In line with these studies, post-mortem brain analysis of depressed patients affirmed reduced neural cell size and neural and glial cell densities as well as synapse number in both the dorsolateral and subgenual PFC (4).
Psychology Today summed up these new findings saying;
“[The] evidence is increasingly pointing to the possibility that in addition to being a biological disorder with immediate implications, over time depression may also alter the brain in ways requiring different forms of treatment…”(5).
So what do we do with all this information and how does it help us with treatment?
Adult neurogenesis was first proposed in the 1960s; however, it wasn’t until the 1990s that the theory became widely accepted and that neurogenesis could play a substantial role in brain function. Although the functional significance of adult neurogenesis in humans — due to the difficulty in studying observing it, remains to be established, increasing evidence has implicated compromised neurogenesis as a possible contributor in the development of mental illnesses; one of which being major depressive disorder (MDD). Neurogenesis has been shown to occur in the hippocampi of adult humans, and more recently it has been accepted to occur in the amygdala, both of which we’ve established could become altered due to long-term depression.
The neurogenic niche, which is characterised by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid is a specialised microenvironment that has a significant role in maintaining and regulating neural stem cells (NSC) proliferation. Neural stem cells in the adult brain continuously supply new neurons to the hippocampal dentate gyrus(6). The dentate gyrus (DG) are thought to contribute to the formation of new episodic memories, the impromptu exploration of new environments, and other functions. Many intrinsic factors, such as hormones, trophic factors, glia (non-neuronal cells), and vasculature (the vascular system of a part of the body), contribute to the neurogenic niche.
Hormones and neurogenesis
Hormones are signalling factors of the neuroendocrine system with essential functions in regulating human physiology and behaviour. The hippocampus shows a high degree of plasticity when exposed to gonadal hormones and stress hormones. The hippocampus regulates the hypothalamic-pituitary-adrenal (HPA) axis through a negative feedback mechanism via mineralocorticoid (MR) and glucocorticoid (GR) receptors, both of which are expressed highly in the DG. Interestingly, newly-generated neurons in the DG may be particularly crucial in the HPA negative-feedback mechanism. Depressed patients show abnormal HPA function such as abnormal day secretion of cortisol, which results in an abnormal circadian rhythm, and the hypersecretion of cortisol. There may also be a significant difference in how hormones act in females and males. For example, peak levels of ovarian hormones during cycle is correlated with increased levels of proliferation; conversely, it has been noted in some animals less testosterone is associated with a reduction of new neurons. Given the dysregulation of HPA negative-feedback in depression, normalising the HPA axis is one of the leading targets of recent psychiatric interventions.
“The removal of testicular hormones through castration increases HPA activity in males, whereas testosterone replacement reverses this effect, acting to reduce corticosteroid levels. Conversely, ovariectomy results in decreased HPA activity, whereas oestradiol replacement reverses this effect through the enhancement of corticosteroid output in females…These findings suggest a causal relationship between gonadal hormones and HPA output, albeit in different directions in males and females. Given the apparent roles of testosterone and oestradiol in reducing and enhancing glucocorticoid release, respectively, both hormones have been implicated in depression and antidepressant treatment.”(7).
“To contrast estrogen, the depletion of androgens by castration in adult male rats didn’t impact proliferation in the hippocampus but reduced the survival rate of new neurons…However, androgen-receptors are absent from the dentate gyrus, which suggests that testosterone effects on new neuron survival may have indirect mechanisms.”(8)
“The chronic administration of corticosterone…reduced cell proliferation and the density of immature neurons in the adult hippocampus in both male and female rats. Furthermore, the depletion of glucocorticoids, through the removal of the adrenal gland, resulted in an increase in adult hippocampal neurogenesis and removed stress-induced suppression of cell proliferation in the hippocampus.”(8)
Neurotrophic growth factors
Endogenous neurotrophic growth factors, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived nerve factor (GDNF), vascular endothelial growth factor (VEGF) and insulin-like growth factor-one (IGF-1), have integral roles in stimulating neural stem cells proliferation, differentiation and central nervous system development. While it’s been established neurotrophic factors maintain the survival and function of cholinergic and dopaminergic neurons(9), there are emerging roles for neurotrophic factors, such as BDNF and NGF, in maintaining neurogenesis in the adult brain.
Nerve Growth Factor, NGF
Rita Levi-Montalcini discovered Nerve Growth Factor in the 1940s and pioneered the field of growth factor research. She identified NGF as a substance secreted from mouse sarcoma (cancerous, malignant tumours of the connective tissues) tissue that stimulated neuronal survival and neurite outgrowth from chicken ganglia (nerve clusters). This provided some of the first evidence of paracrine signalling, whereby cells in one tissue secreted a protein which readily diffused to another tissue to elicit cellular changes in the target tissue. NGF has been shown to promote the survival and differentiation of neurons, an outgrowth of neurites. NGF appears to play a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis-mediated stress response. The non-neural activity of NGF has also gained significant attention in recent years, and NGF has been shown to have roles in the development of the male and female reproductive systems, the endocrine, cardiovascular and immune systems(10).
“NGF levels were significantly reduced in depressed patients (p = 0.002) as compared with healthy elderly controls. Elderly control subjects [n=77] with previous depressive episode also showed a significant reduction in NGF levels as compared with controls (p <0.01); NGF levels were similar between patients with a current depressive episode and previous depressive episode (p = 0.2).”(11)
“Our study [n=40] showed a significant reduction in hippocampal NGF and [Tropomyosin receptor kinase A] TrkA and [messenger RNA] mRNA expression among the individuals who died by suicide compared to normal controls agree with the observations of Dwivedi et al.18 The results of the present study indicate significant insufficient brain neurotrophin environments in suicide victims, strengthening the role of neurotrophins in the pathophysiology of suicide.”
However, additional nerve growth factor isn’t always a good thing, unfortunately. Because NGF increases the growth of neurons, it can contribute to more pain, exacerbating arthritis, psoriasis, and chronic injuries.
In some reports, NGF can increase the spread and life of some tumour cells as well. Unfortunately, NGF has a hard time picking which cells to maintain and protect versus the ones that it should not. In the case of some tumours, nerve growth factor helps increase the health of malignant cells.
Generally, NGF has a protective effect though, at times, it should be approached with caution(12).
Brain-derived neurotrophic factor, BDNF
BDNF is a neurotrophin involved in the production, differentiation, and survival of neurons and has also been shown to represent a vital factor in the regulation of neurogenesis and synaptic plasticity. It exerts its neurotrophic effects by stimulating the tropomyosin-related kinase receptor B (TrkB). An in-depth meta-analysis by Molendijk et al. showed that, despite study heterogeneity, serum BDNF levels are overall lowered in patients with depression(13). Also, a reduction in BDNF and TrkB expression in the hippocampus and prefrontal cortex has been reported in post-mortem brain examinations of teenagers who committed suicide [n=29](14).
“Studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect.”(15)
“Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants.”(16)
“There is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression.”(17)
Glial cell line-derived neurotrophic factor, GDNF
GDNF was first discovered in a glial cell line but is expressed in many parts of the brain. It is a member of the transforming growth factor β (TGF-β) superfamily and is essential for neuronal survival, especially for dopaminergic and serotonergic neurons. Thus far, the exact involvement of GDNF in the biology of depression is not entirely understood, but its neuroprotective ability might make it an attractive future target for antidepressant treatment.
“Patients [n=34] with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 [Hamilton Depression Rating Scale] scores (r = -0.343, p = 0.003).”(18)
“Serum GDNF was significantly lower in MDD patients [n=76] before treatment than in control subjects. From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant. The present study suggests that lowered serum GDNF might be involved in the pathophysiology of MDD, and antidepressant treatment increases the GDNF in MDD.”(19)
Vascular endothelial growth factor, VEGF
VEGF is primarily known for its induction of angiogenesis (the process through which new blood vessels form from pre-existing vessels) and modulation of vascular permeability during embryogenesis and growth, as well as pathological events such as in tumorigenesis. “Chronic stress in rats decreased the expression of VEGF and its receptor in the hippocampus (Heine et al. 2005). Further, VEGF is required for the proliferation of neural stem-like cells in the hippocampus following [electroconvulsive treatment] ECT.”(4). Along with this VEGF is involved in increased learning, neuroprotective in cases of hypoxia, and it also has been shown to increase expression of other neurotrophic growth factors. However, current research seems to be mixed with many studies showing increased expression of VEGF in depressed patients. The hypothesis then contrasts this that some anti-depressants may elicit their clinical benefits via an increase in VEGF.
“Fourteen studies met our eligibility criteria [n=1633]. VEGF was significantly elevated in individuals with MDD when compared to healthy controls. Funnel plot inspection and the Egger’s test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, a sample for the assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender, emerged as significant sources of heterogeneity…Taken together, existing data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.”(20)
“Antidepressant drugs were shown to induce hippocampal expression of VEGF. Also, the experiments in animals models of depression have demonstrated that VEGFR2 signalling is indispensable for the cellular and behavioural response to antidepressant drugs.”(21)
“VEGF levels were increased in the plasma or serum of depressed patients versus controls in eight studies…On the other hand, two studies demonstrated decreased plasma or serum VEGF levels in depressed patients compared to healthy individuals. No significant difference in VEGF levels between cases and controls were reported in three studies”(22)
Insulin-like growth factor, IGF-1
IGF-1 and its receptor IGF-1R are produced in the liver but are found in many tissues, including the brain and influences growth and differentiation processes. IGF-1 has been proposed as a potential therapeutic target for neurodegenerative diseases such as MDD (23). Various effects have been attributed to IGF-1 in terms of its role in neural signalling, neurotrophic mechanisms, and neuroprotection in pro-neuroinflammatory conditions. Intranasal administration has been proposed to provide a shorter path for IGF-1 to enter the brain, avoiding unwanted effects of IGF-1 in peripheral tissues. As with VEGF, the association between IGF and depression appears to be a complex one, where more or less, isn’t always better.
“The results from both the cross-sectional and longitudinal analyses revealed a ‘U’-shaped [n=6017 mean age 65] pattern of association, such that lower and higher levels of IGF-1 were associated with a slightly elevated risk of depression, whereas the lowest risk was seen around the median levels.”(24)
“Most data are very consistent and show that IGF-1 treatment exerts antidepressant like-activity by normalization of behavioural disturbances in various animal models of depression…Furthermore, the antidepressant-like effects of IGF-1 were often associated with an increase in cell proliferation in the hippocampus.”(23)
Neuroinflammation and adult neurogenesis
Neuroinflammation is comprised of biochemical and cellular responses of the nervous system to infection, neurodegenerative diseases and injury. These responses are directed at alleviating the triggering factors by involving the central nervous system (CNS) immunity to defend against potential harm. Responses are complex and include the activation of glia, release of inflammatory mediators; such as cytokines (small proteins) including chemokines, and generation of reactive oxygen and nitrogen species. The innate immune response of the CNS can be both protective and toxic; abnormal microglial activation, mitochondrial dysfunction, and protein aggregation can trigger an acute inflammatory response that, if unresolved, becomes chronic and damaging (25,26). Interestingly, the impact of pro-inflammatory cytokines on neurogenesis is not confined to proliferation, cell death, and neuronal differentiation, but may also be double-edged by impacting the integration of newly generated neurons in the adult brain. At present, the effect of neuroinflammation on neurogenesis remains controversial; however, based on studies in neurodegenerative disorders, it appears that in general, chronic neuroinflammation negatively regulates neurogenesis(25).
“These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of the biological mechanisms underlying depression induced by neuroinflammation.”(27)
“Iptakalim (Ipt), an ATP-sensitive potassium (K-ATP) channel opener that can cross the blood-brain barrier freely, has been demonstrated to inhibit neuroinflammation and enhance adult hippocampal neurogenesis….treatment with Ipt (10 mg/kg/day, i.p [intraperitoneal injection]) for 4 weeks restored the decrease of sucrose preference and shortened the immobile time in forced swimming tests and tail suspension tests in mice. Further, we found that Ipt reversed the induced reduction of the adult hippocampal neurogenesis and improved cerebral insulin signalling in the CMS mice. Furthermore, Ipt negatively regulated nod-like receptor protein 3 (NLRP3) expression and, in turn, inhibited microglia-mediated neuroinflammation by suppressing the activation of the NLRP3-inflammasome/caspase-1/interleukin 1β axis in the hippocampus of CMS mice.”(28)
“…mounting evidence suggests that neuroinflammation affects both embryonic and adult neurogenesis, contributing to the pathogenesis of numerous neurodevelopmental, neuropsychiatric, and neurological disorders.”(25)
This concludes part one, and part two will deal with neurotransmitters, turning all this into actionable information and the full list of references.
I’m not a doctor etc. no medical body or the like has evaluated this information. Information is shared for educational purposes only and acquired through studying for myself. You should consult your primary care doctor before acting on any content, especially if you are taking medication, or have a medical condition/s.
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