The Healthy Brain at Rest
Like everything else we experience, emotions, thoughts, and behaviour arise from the activity of neurons in the brain. Over the last 25 years, neuroimaging technologies like MRI and PET scans have allowed scientists to explore the structure and function of the human brain in unprecedented detail. We are now able to identify over 20 different networks of regions at work in the brain, even when a person is simply resting quietly in the scanner. Each of these networks serves a slightly different purpose: from sensations like vision and hearing, to actions like moving or speaking, to more complex functions like recollection and self-reflection, problem-solving, emotion regulation, and impulse control.
The brain’s activity is constantly shifting amongst these networks, depending on what it is doing at any given moment. Using new image-analysis techniques, we can actually reconstruct functional MRI scans into movie-like images that show the ebb and flow of neural activity between the many different networks of the brain. Watching these networks communicate with one another is something like listening in on a conversation in a crowded, intimate room. In this case, the speakers are distinct networks of brain regions for vision, hearing, movement, recollection and self-reflection, inner speech, planning and goal-setting, and the generation of the inner bodily sensations that are the “feelings” of emotions.
As in polite human conversation, these different participants normally take their turns to speak. Depending on the task at hand, some groups leading the conversation for a time, while others hang back. In a healthy mental life, the brain retains the flexibility to shift its mental conversation smoothly from one network to the next, according to the needs of the moment. Desires and goals unpack themselves neatly into plans, strategies, and actions. The healthy mind immerses itself in its surroundings, getting on with the business of the day, riding steadily through the many stresses of everyday life, and able to experience emotions as helpful navigational markers rather than a confounding, paralyzing fog.
The Brain in Depression
In depression, the brain loses the flexibility of healthy mental life. Instead, its conversation become mired in a vicious and descending spiral of hopelessly tangled negative thoughts, emotions, behaviours, and gut feelings. The entire force of its motivation shifts away from plans and actions in the external world, and instead becomes locked into internal self-reflection, recollection, rumination, and retreat. The idea of remaining in this hopeless state becomes intolerable, but escape appears impossible. This state is no longer one of mere passing sadness, but one of enduring despair. Paralyzed by an intolerable present and a hopeless-looking future, the mind is now stuck in the mode of depression.
If we peer into the depressed brain with the help of a PET scanner, we can see a one-hour snapshot of this mode of mental paralysis: in general terms, an excess of activity in the lower limbic structures of the brain, which generate emotional states and recollections, and a lack of activity in more recently-evolved regions of the prefrontal cortex, which are capable of regulating thoughts, emotions, and behavior based on the context of a situation.
If we use a functional MRI scan, we can follow the activity of the individual networks second-by-second as the mind wanders from thought to thought. In depression, what we see is that three networks in particular seem to take over the mental conversation:
The first network is involved in recollection, rumination, self-reflection, and thinking about scenarios from the past and future. This network is often called the default mode network because the brain spends so much more time in this mode than any other. Whenever our attention wanders away from the present moment, this network is likely to be dominating the mental conversation of the brain.
The second network, which we’ll call the somatic marker network, is involved in generating the internal bodily (or “somatic”) sensations that accompany emotions — in short, the feel of our feelings. These are the lump in the throat that goes with sadness, the butterflies in the stomach that go with anxiety, the racing heart that goes with excitement, or the leaden heaviness that goes with despair.
The brain needs the somatic marker network to translate the complexities of everyday life back into our basic emotional and motivational needs. Through its activity, a sheet of paper with ink saying “Thank you” can generate the same rosy inner glow as the smile of a friend. An ordinary brown envelope labelled “Canada Revenue Agency” can spark the same shiver of fear as a stranger appearing in the window at night.
Somatic markers are like emotional signposts that can help to guide us towards what we need and away from what may harm us. Though their functions are essential to our survival, they can also go awry. When the brain is stuck in depression, the colourful signage of our somatic markers feels as if painted over in black, leaving all courses of action equally unappealing.
The third network, which we’ll call the cognitive control network, is involved in the thought processes behind reasoning, logic, intellectual problem-solving, and the performance of complex tasks. This network is sometimes called the task-positive network because it is active during a wide variety of activities. It tends to compete with the default-mode network, so that rumination ceases when we are being active, and activity ceases when we are ruminating.
Three Networks Entangled
These three networks are able to share information with one another, and so they should. In healthy life, communication between these networks is a useful feature of the brain — one that allows thoughts and memories to take on some emotional significance, and long-term plans to guide our short-term thoughts and activities. However, this needs to happen in a regulated fashion if it is going to help us through the world.
In a state of health, we should be able to reflect upon a negative event in the past without being overwhelmed by sadness in the present. We should be able to have a negative thought, such as “I’m such a scatterbrain”, without feeling a sinking sensation of worthlessness and despair. We should be able to have an emotion, as when watching a film or hearing a story, without triggering a flood of memories of every rejection or defeat we have ever suffered. Yet in depression, each kind of thinking feeds the others, leaving the brain stuck in a downward spiral of negative thought and rumination — all at the expense of purposeful action.
The Dorsal Nexus: A Crossroads of Brain Activity in Depression
In a relatively recent discovery, neuroscientists have identified a specific region of the brain that serves as a crossroads for the three different networks. This region is known as the dorsal nexus, and it lies in an area tucked between the two hemispheres of the brain, a few centimetres underneath the hairline of the scalp. In technical terms, this area is called the dorsomedial prefrontal cortex: the part of the frontal lobes that is both dorsal (near the top) and medial (near the middle).
In depression, but not in healthy mood, the dorsal nexus serves as a point of intersection where the default mode, cognitive control, and somatic marker networks all overlap. In depression, this intersection has effectively lost its traffic light. Information begins to flow unchecked between the three networks, so that thoughts, feelings, and emotions all drive one another in an uncontrolled fashion. In a healthy brain, the neurons of the dorsal nexus can act to shut down these intrusive thought processes. However, when this area is underactive, we find ourselves unable to act on the simple-sounding advice to just “stop thinking about it and move on”, no matter how useful it would be to do so.
Many lines of evidence point to the importance of the dorsal nexus for healthy mood. For example, there are patients who have suffered head injuries in which the dorsal nexus is damaged. Such patients are at extremely high risk of suffering from depression. The opposite is also true: in large studies of hundreds of patients with depression, it is possible to find a subtle thinning of the brain’s grey matter in the dorsomedial prefrontal cortex. The same is true in bipolar disorder, although in this illness other areas are also involved.
There are also cases of patients in whom the dorsal nexus has been accidentally turned off by deep brain stimulation electrodes that were implanted just a few millimetres off the target. When the electrodes are activated, severe and crushing depression sets in — within a matter of seconds. Fortunately, the depression resolves almost as quickly when the electrodes are turned off again, and when they are repositioned, they assume their proper function.
For some patients with depression, the key to getting better may be restoring the activity of the dorsal nexus, or at least rebalancing the activity of the three networks that intersect there. Once the brain’s networks are unstuck from the mode of depression, the full range of its abilities can come back into play once again.
Getting the Brain Unstuck
One way to reactivate the dorsal nexus is to use medications that alter neurotransmitter levels. The brain uses a wide variety of neurotransmitters, such as serotonin, norepinephrine, and dopamine, to make subtle changes in the ongoing activity of its neurons. Depending on their levels, these kinds of neurotransmitters can cause important changes in the flow of information between the various nodes in the brain’s networks. For example, increased serotonin levels can reduce the connectivity between the dorsal nexus and the hippocampus, a brain structure that is important for recalling memories of life events, and is overactive in depression.
Antidepressant medications act by increasing the levels of serotonin (for example, SSRIs like escitalopram) and often norepinephrine (for example, SNRIs like duloxetine), and occasionally dopamine (for example, bupropion). For some people, adjusting the levels of these neurotransmitters is enough to get the brain’s networks back into their normal pattern of activity. The tangled, vicious circles of conversation that accompany depression resolve, and the brain regains its ability to move flexibly among thought processes once again.
Psychotherapy can accomplish a similar effect. Many current therapies against depression work by teaching the brain a new set of cognitive and behavioral skills to replace the ingrained, dysfunctional habits of thought that lead the brain back into depression. For example, cognitive behavioral therapy (CBT) involves building a habit of detecting the automatic thought patterns that provoke negative emotional states, and then challenging those thoughts by considering the evidence for and against them. Mindfulness-based cognitive therapy (MBCT) involves learning to attending to the sensations and thoughts of the present moment, on purpose and without judgment. With practice, mindfulness helps us to notice when the mind wanders off into rumination and habitual negative thinking. By merely observing these mental activities rather than being carried away with them, the brain avoids getting stuck in the mode of depression.
CBT, MBCT, and other forms of therapy for depression all cause lasting changes in the patterns of communication between the brain’s many networks. These changes in network activity can be seen on MRI or PET scans, and reflect a fundamental shift in the character of the brain’s ongoing conversation. Toxic alliances of brain regions dissolve, and more resilient patterns of mental activity begin to flourish. Of course, therapy is hard work: changing our old habits takes a lot of mental effort, and a mind too badly mired in depression mode may not be up to the job. If depression is too overpowering, and neither medications nor therapy can tease the tangled networks apart, there is a third option: going after the networks themselves, with direct stimulation of the brain.
Brain stimulation can often succeed in altering the activity patterns of the brain, even if medications or therapy have failed. Techniques like repetitive transcranial magnetic stimulation (rTMS) are capable of strengthening or weakening the connections between neurons, and increasing or decreasing the activity of target brain regions.
The most common target brain region for rTMS in depression is the dorsolateral prefrontal cortex (DLPFC), which is a key node in thecognitive control network. This region is typically underactive in depression, so the conventional approach is to apply high-frequency, excitatory stimulation, usually on the left side of the brain. However, low-frequency stimulation of the right side is also effective, and low-frequency stimulation of the left side has also worked well for some patients in some studies.
Another potential target for rTMS in depression is the dorsomedial prefrontal cortex (DMPFC), which is the location of the dorsal nexus itself. Since this region lies deeper in the brain than the DLPFC, it is harder to reach with the shallow magnetic fields of typical flat butterfly rTMS coils. However, deeper-penetrating coils are capable of stimulating this region. Some studies have found that stimulating the DMPFC is useful in treating the impulsive food binges and purges of bulimia nervosa, or the cravings of alcohol dependence. Our clinic has also found this region to be an effective target for major depression, much like the DLPFC. However, it is still unclear whether one target is more effective than the other, or whether the most effective target and type of stimulation is different from person to person, as seems tobe the case with medication.
The frontopolar cortex (FPC) and ventromedial prefrontal cortex (VMPFC) are also nodes in the three networks. Tucked between the two hemispheres just above eyebrow level, the FPC is one of the major nodes of the default mode network, which is central to rumination and self-reflection. Other brain stimulation treatments, like ECT and DBS, seem to work in part by decreasing the activity of the FPC and VMPFC. Rare patients who have survived damage to the FPC, from surgery or injury, sometimes show dramatic resolution in their symptoms of depression. Findings like these suggest that the FPC and VMPFC might turn out to be very powerful targets for stimulation with inhibitory forms of rTMS. Studies are now underway to see if this is the case. However, this issue is still unclear for the time being.