The Man With Half A Brain

A lovely new paper reports in fascinating detail on a man who lost a uniquely large portion of his brain: Bilateral limbic system destruction in man.

The authors, Feinstein et al from Iowa City, have studied the patient, "Roger", for 14 years. Roger was born in 1952, and lived a fairly uneventful life until he contracted herpes simplex encephalitis (HSE) at the age of 28.

HSE is an extremely rare condition in which the herpes virus infects the central nervous system. Untreated, it is fatal in 70% of people. Survivors suffer varying degrees of neurological damage. Roger suffered more than most - his is the worst case of herpes encephalitis damage among patients currently alive, and there are only three recorded cases of similarly extensive lesions. Roger lost almost his entire "limbic system":

The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral.

"Limbic system" is an old, vague, but still popular term for a collection of brain structures located deep in the centre of the brain (but not to be confused with the basal ganglia). It's often thought of as the "primitive", "emotional" part of the brain, and there is some truth to this. Roger's limbic system was profoundly damaged on both sides; on the right side, the lesion included the whole temporal lobe and most of the ventral prefrontal cortex as well.

What happened to Roger's mind when his brain suffered such injury? In many ways, remarkably little. His only major impairment is profound anterograde amnesia: he is unable to remember anything that has happened since the infection, which was 28 years ago.

For Roger, not much has changed over the past 28 years. He has virtually no episodic memories for any events that have transpired over the past three decades. For example, he has no recollection of 9/11, and when shown pictures of the planes crashing into the World Trade Center he often responds with bewilderment, speculating that Russia must be attacking America.

This is, obviously, a disabling deficit: Roger cannot lead a normal life. But in other areas of mental functioning, he is quite normal. His IQ is above average; his speech and language abilities are excellent; his vision and hearing are normal, although he has no sense of taste or smell. His short term (working) memory, attention, and reasoning abilities are unimpaired. His motor abilities are fine - he is reportedly an excellent bowler - and he is able to improve motor skills through practice. And his recall of things which happened before the infection is largely preserved, although the few years just before the infection are partially lost.

Fascinatingly, Roger's personality and emotional life seems to have been changed by the infection as well, but in a rather fortunate way -

Roger appears remarkably unconcerned by his condition. He hardly ever complains and, in general, shows little worry for anything in life. Both of his parents and his sister fervently claim that “Roger is always happy,” an observation that is consistent with our own impression. Moreover, based on his family’s report, Roger is paradoxically happier now than he was before his brain damage. ... His premorbid disposition of being somewhat reserved and introverted has shifted to being outgoing and extroverted...

Most conversations with Roger involve animated speech that is replete with prosody, gesture, and, often times, laughing. He readily displays signs of positive emotion including happiness, amusement, interest, and excitement. As previously noted, Roger’s positive mood has remained essentially unchanged over nearly three decades.

His only other reported quirks are an insatiable appetite, and a habit of collecting and holding onto everyday items.

What does all this mean? Neuroscientists will find little about the case surprising. No textbooks are going to have to be rewritten. Roger's inability to form new memories, combined with preserved memory of events up to the few years before the damage, is similar to that seen in other cases of bilateral hippocampus damage. The most famous being the sadly recently deceased patient "H. M.", but there have been plenty of others. The hippocampus seems to be necessarily for forming new long term memories, but the memories themselves are stored elsewhere.

Roger's happy-go-lucky disposition is also not too unexpected, given that he suffered bilateral damage to the ventromedial prefrontal cortex (vmPFC). Last year I wrote about a study from the same Iowa team finding that damage to this area seems to protect against depression. And this is the same region which was targeted by the infamous prefrontal lobotomies of the 40s and 50s - which, for all their ethical shortcomings, sometimes did seem to relieve people of mental anguish.

For me, Roger provides two main lessons, both rather satisfying ones. Firstly, even after losing large parts of the brain, life goes on. The brain is modular, and we can live without many of the modules. And secondly, if our emotional circuitry is damaged, we generally feel better, rather than worse. To put it another way, perhaps, happiness is our default state, and emotions just have a habit of getting in the way.

Feinstein, J., Rudrauf, D., Khalsa, S., Cassell, M., Bruss, J., Grabowski, T., & Tranel, D. (2009). Bilateral limbic system destruction in man Journal of Clinical and Experimental Neuropsychology, 1-19 DOI: 10.1080/13803390903066873

The Man With Half A Brain

A lovely new paper reports in fascinating detail on a man who lost a uniquely large portion of his brain: Bilateral limbic system destruction in man.

The authors, Feinstein et al from Iowa City, have studied the patient, "Roger", for 14 years. Roger was born in 1952, and lived a fairly uneventful life until he contracted herpes simplex encephalitis (HSE) at the age of 28.

HSE is an extremely rare condition in which the herpes virus infects the central nervous system. Untreated, it is fatal in 70% of people. Survivors suffer varying degrees of neurological damage. Roger suffered more than most - his is the worst case of herpes encephalitis damage among patients currently alive, and there are only three recorded cases of similarly extensive lesions. Roger lost almost his entire "limbic system":

The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral.

"Limbic system" is an old, vague, but still popular term for a collection of brain structures located deep in the centre of the brain (but not to be confused with the basal ganglia). It's often thought of as the "primitive", "emotional" part of the brain, and there is some truth to this. Roger's limbic system was profoundly damaged on both sides; on the right side, the lesion included the whole temporal lobe and most of the ventral prefrontal cortex as well.

What happened to Roger's mind when his brain suffered such injury? In many ways, remarkably little. His only major impairment is profound anterograde amnesia: he is unable to remember anything that has happened since the infection, which was 28 years ago.

For Roger, not much has changed over the past 28 years. He has virtually no episodic memories for any events that have transpired over the past three decades. For example, he has no recollection of 9/11, and when shown pictures of the planes crashing into the World Trade Center he often responds with bewilderment, speculating that Russia must be attacking America.

This is, obviously, a disabling deficit: Roger cannot lead a normal life. But in other areas of mental functioning, he is quite normal. His IQ is above average; his speech and language abilities are excellent; his vision and hearing are normal, although he has no sense of taste or smell. His short term (working) memory, attention, and reasoning abilities are unimpaired. His motor abilities are fine - he is reportedly an excellent bowler - and he is able to improve motor skills through practice. And his recall of things which happened before the infection is largely preserved, although the few years just before the infection are partially lost.

Fascinatingly, Roger's personality and emotional life seems to have been changed by the infection as well, but in a rather fortunate way -

Roger appears remarkably unconcerned by his condition. He hardly ever complains and, in general, shows little worry for anything in life. Both of his parents and his sister fervently claim that “Roger is always happy,” an observation that is consistent with our own impression. Moreover, based on his family’s report, Roger is paradoxically happier now than he was before his brain damage. ... His premorbid disposition of being somewhat reserved and introverted has shifted to being outgoing and extroverted...

Most conversations with Roger involve animated speech that is replete with prosody, gesture, and, often times, laughing. He readily displays signs of positive emotion including happiness, amusement, interest, and excitement. As previously noted, Roger’s positive mood has remained essentially unchanged over nearly three decades.

His only other reported quirks are an insatiable appetite, and a habit of collecting and holding onto everyday items.

What does all this mean? Neuroscientists will find little about the case surprising. No textbooks are going to have to be rewritten. Roger's inability to form new memories, combined with preserved memory of events up to the few years before the damage, is similar to that seen in other cases of bilateral hippocampus damage. The most famous being the sadly recently deceased patient "H. M.", but there have been plenty of others. The hippocampus seems to be necessarily for forming new long term memories, but the memories themselves are stored elsewhere.

Roger's happy-go-lucky disposition is also not too unexpected, given that he suffered bilateral damage to the ventromedial prefrontal cortex (vmPFC). Last year I wrote about a study from the same Iowa team finding that damage to this area seems to protect against depression. And this is the same region which was targeted by the infamous prefrontal lobotomies of the 40s and 50s - which, for all their ethical shortcomings, sometimes did seem to relieve people of mental anguish.

For me, Roger provides two main lessons, both rather satisfying ones. Firstly, even after losing large parts of the brain, life goes on. The brain is modular, and we can live without many of the modules. And secondly, if our emotional circuitry is damaged, we generally feel better, rather than worse. To put it another way, perhaps, happiness is our default state, and emotions just have a habit of getting in the way.

Feinstein, J., Rudrauf, D., Khalsa, S., Cassell, M., Bruss, J., Grabowski, T., & Tranel, D. (2009). Bilateral limbic system destruction in man Journal of Clinical and Experimental Neuropsychology, 1-19 DOI: 10.1080/13803390903066873

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

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