Depression and the excited brain
From the outside depression appears to be a deficit state. That is, people with depression seem to lack something, to have a sense of absence. From the inside though, this is often far from the case: the mind is described as churning; as being beset by ruminative thoughts, dread, and anguish. Evidence from brain imaging studies mostly support this second view. Many studies show increased activity in the ventral (or lower) regions of the brain, which are implicated in the experience of emotion. Related to this, they are also strongly connected with the body’s regulatory systems — systems that control sleep, appetite, and sexual function, all of which can be disturbed in depression. Many studies also report that depressed patients show decreased activity in dorsal (or upper) brain regions that support cognitive processes, forming a pattern of disturbance that has been described by American neurologist Helen Mayberg as the “limbic-cortical dysregulation” model of depression.
A just-published article in JAMA Psychiatry by Miller and colleagues adds more evidence to support this view. It reports a meta-analysis of 14 functional MRI studies of youth depression (including the paper derived from my PhD.) While I have some problem with combining studies with such different methodologies in the same analysis, there are a couple of things I like about this paper. The first, and most important, is its support of the emerging picture of depression as an illness of brain excitability, centred on regions that support emotional and somatic processes. These regions of increased activity contrast with the meta-analysis’s reports of decreased activity in regions associated with more abstract cognitive processes, fitting symptoms of depression such as difficulty concentrating and making decisions. The results are broadly consistent with Mayberg’s model.
Second, I like that the paper accepts the argument — which I am often forced to defend — that we should include young people up to the age of 25 in studies of youth depression. It seems odd to choose 18 as a cut-off on the basis (I assume, it is always unstated) that this when we get the vote. It has no foundation in biology. Brain developmental processes proceed in a continuous way from puberty until a person is about 25 — not coincidentally, over the same period that the incidence of mental illness peaks. If a study purports to examine mental illness in the context of brain developmental processes, then it really must, as this study does, include young people up to their mid-twenties. (And not include pre-pubertal children in the same analyses: puberty marks a clear disjunction in brain developmental processes, suggesting that pre-pubertal children should be analysed separately. The Miller meta-analysis, to its detriment, includes studies with children as young as 4.)
Newer treatments for depression are responding directly to this theory of ventral brain excitability. Ketamine blocks the brain’s main excitatory neurotransmitter — glutamate — and more evidence is emerging that it provides rapid relief from depression. Anti-inflammatory medications might also have a role in treatment. Increased activity in ventral brain regions is associated with an inflammatory state, and although it isn’t clear whether depression causes inflammation or inflammation causes depression — or likely the causal influence works both ways — it is clear that inflammation plays a role in depression for some people, and that anti-inflammatory medications might help. Helen Mayberg has championed deep brain stimulation as a treatment for chronic treatment-resistant depression. DBS responds directly to imaging evidence of increased ventral brain activity: electrodes are implanted in ventral brain regions to interrupt the abnormally elevated activity. Early studies showed promise, though recent trials have proved disappointing.
Still, for the skeptics who claim that brain imaging has never done anything to help anyone with mental illness — which has a kernel of truth — I believe it is helping us to sketch a picture of the brain basis of depression. Depression is a complicated illness that has effects from the social-cultural to the synapse, and brain imaging will never tell us the whole story. It can help though to clarify fundamental aspects of it: to provide targets for therapeutic intervention, and to aid our understanding of how treatments such as the psychotherapies work.
