What Depression Looks Like in the Brain

Chronic depression, over time, can produce marked changes in brain structures that are heavily involved in regulating our emotional stability. Two critical players, the amygdala and the hippocampus, are a pair of small brain structures that work in tandem to generate emotions, attach emotions to memories, and store and index those memories.

The Amygdala

The almond-shaped amygdala is the brain’s emotion factory, Alert Central, the “gut feeling” center. It alerts you to events in your environment, directs your evaluation of those events and signals the hippocampus to store and map your feelings to memories of the events.

The Hippocampus

The seahorse-shaped hippocampus is a core region in the limbic (emotional) system that also has widespread connections to regions that comprise the neuroanatomical network of mood regulation (e.g., the prefrontal cortex, anterior thalamic nuclei, basal ganglia and hypothalamus).

Major depression has been associated with decreased density and volume in the hippocampus.

fMRI (Functional Magnetic Resonance Imaging) studies have shown that the hippocampi of people with Major Depression are smaller than those of individuals with no history of depression (Videbech, Ravnkilde, 2004; Frodl, T., et al, 2006), possibly caused by repeated episodes of Major Depression. A smaller hippocampus supports fewer feel-good serotonin receptors.

Serotonin imbalances can trigger depression.

Some researchers believe that people with depression may simply be born with smaller hippocampi, predisposing them to depression. Others believe that reduced volume is the result of neuroplastic changes caused by depression. Severe stress, for example, impedes our ability to properly form memories. So do traumatic events. Extended release of the stress hormone cortisol has been found to be toxic to the hippocampus’ ability to form memories (WebMD, 2006). Extended release of other stress hormones, such as glucocorticoids, actually cause nerve cells in the hippocampus to atrophy.

But on the bright side, hippocampal atrophy is reversible, if the stress ends.

Developing emotional resilience can mitigate structural damage and allow for repair.

They Hypothalamus

Another brain structure that plays a critical role in contributing to depression include the hypothalamus, which is highly sensitive to internal and external changes that affect emotional equilibrium. The hypothalamus plays a critical role in controlling the autonomic nervous system, which controls automatic or spontaneous internal processes such as maintaining homeostasis and vegetative functions — temperature regulation, metabolism. The hypothalamus receives input from noradrenergic (involving noradrenaline or norepinephrine) and serotonergic (involving serotonin) neural pathways that modulate appetite and vegetative functions, as well as from the mesolimbic dopamine pathway, which helps regulate pleasure. This is how serotonin and noradrenaline (norepinephrine) levels influence appetite, energy, motivation and your overall sense of well-being.

In people with depression who are agitated or demonstrate symptoms of anxiety, the hypothalamus is stimulating the adrenal medulla to increase adrenaline (epinephine) output, which increases anxiety. Increased adrenaline prevents the hypothalamus from creating peace and tranquility. So, in mind-body illnesses such as depression and anxiety, our nervous system responses to stressors are actually pathological reactions that result in the physical symptoms often experienced during depression (e.g., fatigue, lethargy, psychomotor agitation, problems sleeping and eating).

Changes in brain chemistry influence our mood and thought processes. Depression can be triggered by fluctuations in the levels of brain chemicals such as neurotransmitters and neurohormones.

Neurotransmitters act as chemical messengers that send signals from one nerve cell to another, facilitating communication between the brain and the rest of the body.

Neurohormones are substances, such as peptides or steroids, produced by one tissue and conveyed via the bloodstream to act on a part of the nervous system.

Neurotransmitters

For many people with depression, quantities of the neurotransmitter serotonin are significantly reduced or may fluctuate wildly. Serotonin elevates mood, promotes social confidence and a feeling of well-being. If serotonin levels are high, your confidence soars, and you feel less vulnerable. If serotonin levels are low, you may feel helpless, become defensive and less willing to take risks. Serotonin also plays a key role in helping us maintain a proper perspective of events; for example, serotonin modulates rejection sensitivity. Low serotonin levels can cause depressed people to be acutely sensitive to rejection.

GABA

Gamma-aminobutyric acid (GABA), a neurotransmitter that regulates other neurotransmitters such as serotonin, epinephrine and norepinephrine, is thought to play a role in causing depression. GABA, working in tandem with serotonin, acts as an inhibitory neurotransmitter that quiets the stress response when a person thinks about stressful events.

Dopamine

Altered dopamine pathways have been associated with depressive behaviors. Dopamine is involved in the release of our natural feel-good endorphins, which act as natural mood lifters and have a calming effect on us. Dopamine also modulates feelings of pleasure and reward and is the primary neurotransmitter involved in attention, learning, memory and motivating behavior and motor activity (motion).

HVA

Clinical investigations have found that depressed patients have reduced cerebrospinal levels of homovanillic acid (HVA), which is the major metabolite of dopamine in the central nervous system. Neuroimaging studies have confirmed a deficiency of synaptic dopamine in depressed patients. They were found to have problems with dopamine transport and binding at synapses (junctions) between neurons or nerve cells in the brain (Meyer, J.H., et al, 2006).

Historically, most of the depression research and pharmacological treatments focused on the neurotransmitter serotonin (5-HT). But we now know that it’s not that simple. Modern antidepressant drugs that target serotonin reuptake or reabsorption  (e.g., Selective Serotonin Reuptake Inhibitors or SSRIs) often fail to fully relieve symptoms related to drive and motivation, such as loss of pleasure, loss of interest, fatigue and loss of energy.

Beyond serotonin, dopamine and noradrenaline also strongly influence the feelings associated with depression.

In many cases, dopamine and norepinephrine (noradrenaline), which is both a neurotransmitter and a neurohormone, are heavy contributors to the affective aspects of depression. Affect refers to the experience of feeling emotions — the emotional feeling, tone and mood attached to our thoughts and the resulting behaviors or external manifestations — which is why disorders such as depression, bipolar disorders and anxiety are often referred to as affective disorders.

Positive affect includes a broad range of positive mood states, including feelings of happiness or joy, interest, energy, enthusiasm, alertness and self-confidence. Negative affect may be thought of as general distress that includes a broad range of negative mood states, such as fear, anxiety, irritability, loneliness, guilt, disgust and hostility (Clark and Watson, 1991). Negative affect is common to both mood and anxiety disorders.

People suffering from depression often have a negative affect as well as a decrease in positive affect, such as a loss of interest in something they once enjoyed.

There’s a difference between “negative affect” and “decreased positive affect.” People with Major Depression commonly experience loss of interest, energy, motivation and loss of pleasure (referred to as anhedonia) — all core symptoms of depression that are thought of as “decreased positive affect.” These symptoms, which are all related to drive, motivation and energy, are thought to result from dysregulation of dopamine and norepinephrine, which heavily influence the brain’s pleasure and reward-motivation circuitry.

Negative affect is associated with serotonin dysregulation.

But depressive symptoms associated with negative affect, such as fear, anxiety and irritability — symptoms that are predominant in people who have both depression and anxiety — are thought to result from serotonin dysregulation (Nutt, D., Demyttenaere, K., et al, 2006).

Stress Hormones

Cortisol is a stress hormone that can trigger depressed mood. In people who are depressed, cortisol is produced in excess, and it’s responsible for much of the physiological damage caused by long-term stress.

Sometimes depressives aren’t aware of what triggers their depression.

They may feel that “depression just came out of the blue,” but that’s not true. It never “just comes out of the blue.” It only seems like it because they’re experiencing psychological discontinuity between feeling and thought. When a memory or live event triggers depression, feeling is separated from thought. The person with depressioloses the thought, but the feeling keeps on churning.

Here’s how this happens neurolochemically…

Your conscious, second-by-second processing of verbal conversation happens in one part of your brain (the prefrontal lobes of the neocortex), while your emotional evaluations are happening in another part of the brain, the limbic system, which is a network of brain structures involved in learning, memory, motivation and producing emotions.

When you face a stress-inducing event, two things happen: (1) Your language and working memory centers decode the meaning and insert the meaning into your conscious mind; (2) A subcortical system triggers a stress response — your limbic system launches a cascade of events that sends stress hormones — including cortisol — racing throughout your body. Stressors spike cortisol surges.

Prefrontal lobe activity — conscious, rational processing of the event — happens in nanoseconds. But your emotional system lags behind for seconds, even minutes. So, cortisol is still floating in your bloodstream thirty seconds after the news vanishes from working memory, yet you no longer remember what triggered the depressed mood. For example, let’s say that you hear a song on the radio that was playing in the background five years ago in the same moment that bad news was delivered to you, such as the death a loved one. You unconsciously associate the memory of your past traumatic experience with the song playing in the present, triggering a depressed mood.

Because a trigger is closely tied to a meaningful event in the past, it can be relatively easy for something in the present to set off depression.

When respiration and heart rates increase, activity increases in brain areas that secrete norepinephrine (noradrenaline). Increased norepinephrine ultimately increases stimulation of the hypothalamus, which, in turn, increases the stress-related production of stress hormones like cortisol and ACTH (adrenocorticotropic hormone).

When a stressful event occurs, or we are triggered by something associated with our past, the neurochemicals responsible for our fight-or-flight response are activated.

Norepinephrine and epinephrine (adrenaline) are also part of our fight-or-flight response. They are both stress hormones and neurotransmitters that stimulate the sympathetic nervous system, causing increased heart rate, increased blood glucose and increased blood flow to the muscles — all conditions that prepare us to respond to imminent danger.

The fight-flight response is not all bad, of course. It’s the instinct that motivates you to start running immediately if a big black bear is chasing you. It’s only when these brain chemicals become imbalanced that they threaten our emotional stability.