No ventral prefrontal cortex? No problem!

Brain damage - it's not much fun when it's your brain, but for science, it's often good news. While neuroimaging can find the neural correlates of mental processes - areas of the brain which become active during the experience of an emotion, say - lesion studies are often necessary to establish the direction of causality. Just because somewhere in the brain is activated during the experience of fear, for example, doesn't mean that this area is responsible for our feelings of fright; it might just happen to be lighting up as a side effect. Neuroimaging can't tell the difference, but if someone suffers damage to some part of the brain and then becomes fearless, it becomes possible to establish which parts do what. Localizing a function to a certain region of the brain is not the same as understanding it, of course, but it's a start.

The main problem with lesion studies is that there aren't enough of them. Because of those pesky ethical considerations, you can't just go around poking holes in people's brains - you have to wait until damage occurs naturally. In many interesting parts of the brain, localized damage is frustratingly uncommon.

Yet good things come to those who wait. The Journal of Neuroscience have just published a landmark lesion study by Koenigs et. al.(*) who studied two separate, large groups of people who had suffered brain damage to a range of areas - Vietnam veterans with combat head injuries, and Iowa citizens who had suffered tumors, strokes, and other medical conditions. In both samples they measured symptoms of depression and attempted to correlate them with the location of the lesions.

They succeeded. In both samples, patients who had suffered damage to the ventro-medial prefrontal cortex (vmPFC), which sits a few inches behind the center of the forehead, seemed to be protected against depression. Compared to people who had suffered lesions to all of the other parts of the brain, people with vmPFC damage on both sides of the brain were rated as having fewer depressive symptoms, both according to their own report and the observations of the experimenters. In particular, they reported being almost completely free of emotional or subjective symptoms such as feelings of guilt, sadness, or self-dislike. For illustration, they describe the incredible (and ironic) case of a woman with a self-inflicted vmPFC lesion:

We identified one patient in the Iowa registry who represents an intriguing case of an apparent alleviation of severe depression after a bilateral vmPFC lesion. ... per secondary report the patient was being treated for depression when she attempted suicide 11 years ago by means of a gunshot to the head. The gunshot destroyed most of ventral PFC, including vmPFC bilaterally, but left intact most of dorsal PFC. The patient’s neuropsychologist, neurosurgeon, and long-term boyfriend all remarked that her depression was markedly diminished after the brain injury (boyfriend, speaking 16 months after the injury: “no sign of depression whatsoever since the accident”; neuropsychologist: “she never shows distress, worry, or anger”).

Overall, these results are exciting, but unsurprising - the vmPFC is commonly thought of as being involved in emotion and emotional decision making; Antonio Damasio famously inferred this from the case of Phineas Gage, who after losing his medial prefrontal cortex to an iron rod, became impulsive, reckless, and unconcerned for himself or others. It's not difficult to see that someone with such characteristics might be resistant to such emotional difficulties as depression, or, say, post-traumatic stress - and indeed Koenigs et. al. previously reported that such lesions also protect against PTSD in combat veterans.

Fascinatingly, old-fashioned psychosurgery frequently ended up destroying much the same areas of the brain; the desired result, sometimes achieved, was a patient who no longer cared or worried about anything - which was thought preferable to someone paralyzed by despair or anxiety. The point is that the vmPFC is not specifically a "depression area of the brain" - although these results suggest that it is necessary for the experience of depression, it is probably also responsible for a broad range of other emotions, and patients lacking a vmPFC clearly lack more than just sadness. (If there is a "depression area", which is possible, my money's on the subgenual cingulate cortex.)

The paper also reported that damage to another part of the brain, the dorsal prefrontal cortex (bilateral), seemed to cause depression - however, there were only 5 patients with this kind of damage, of whom 2 were clinically depressed, so it's harder to interpret this result:

The proportion of individuals meeting DSM-IV criteria for "current" MDD was significantly greater for the dorsal PFC lesion group (2 of 5) than for the non-PFC lesion group (1 of 101; p = 0.005) or non-brain-damaged group (0 of 54; p = 0.006). Thus, bilateral dorsal PFC lesions were associated with a relatively high prevalence of subsequent major depression.

A few things to note: Case histories are anecdotes, not data - and the brain of the woman described above is extensively abnormal; CT scans, not for the squeamish. The total number of vmPFC patients here was just twenty. This is the largest group of these patients studied so far, because this kind of injury is very rare, but this is still a smallish sample. Most importantly, levels of depression in the control groups in this study were fairly low. The vmPFC group showed essentially zero depressive symptoms, but even the control patients only showed mild symptoms on average, and only a couple of them were diagnosed with actual clinical depression. So the between-group differences were, while statistically significant, modest.

(*) Annoyingly, pretty much every paper from Mike Koenigs is a landmark lesion study. It's always the same lesion patients. Not that this is a major problem, I'm just annoyed that he gets to study them and not me.

M. Koenigs, E. D. Huey, M. Calamia, V. Raymont, D. Tranel, J. Grafman (2008). Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression Journal of Neuroscience, 28 (47), 12341-12348 DOI: 10.1523/JNEUROSCI.2324-08.2008