Encephalon 19 at Peripersonal Space

Encephalon 19: Emotion vs. Reason (a false dichotomy) and a hidden emotion quote embedded in the text appear at Peripersonal Space. Can you solve the mystery?

Among the included posts are two from Neurophilosophy and (of course) The Phineas Gage Fan Club about the widely-covered Nature paper, Damage to the prefrontal cortex increases utilitarian moral judgements (Koenigs et al., 2007). Can I say anything new about it? [Can I ever finish reading the paper without getting too annoyed? Stay tuned...] Now everyone knows about the "trolley problem" and the "fat man" thought experiments in ethics.

Oh, and don't forget this fun one, "smother for dollars" (Greene et al., 2001):

You are in hospital lounge waiting to visit a sick friend. A young man sitting next to you explains that his father is very ill. The doctors believe that he has a week to live at most. He explains further that his father has a substantial life insurance policy that expires at midnight.

If his father dies before midnight, this young man will receive a very large sum of money. He says that the money would mean a great deal to him and that no good will come from his father's living a few more days. He offers you half a million dollars to go up to his father's room and smother his father with a pillow.

Is it appropriate for you to kill this man's father in order to get money for yourself and this young man?

In unrelated news, the figure below is from a cool article that presents four alternative hypotheses regarding the effects of tool-use on the visuotactile representation of peripersonal space (Fig 1., Holmes et al. 2004).



Holmes NP, Calvert GA, Spence C. (2004). Extending or projecting peripersonal space with tools? Multisensory interactions highlight only the distal and proximal ends of tools. Neurosci Lett. 372:62-7.

The effects of tool-use on the brain’s representation of the body and of the space surrounding the body (‘peripersonal space’) has recently been studied within a number of disciplines in cognitive neuroscience, and is also of great interest to philosophers and behavioural ecologists. To date, most experimental findings suggest that tool-use extends the boundary of peripersonal space – visual stimuli presented at the tips of tools interact more with simultaneous tactile stimuli presented at the hands than visual stimuli presented at the same distance, but not associated with the tools. We studied the proposed extension of peripersonal space by tool-use by measuring the effects of three different tool-use tasks on the integration of visual and tactile stimuli at three distances from participants’ hands along two hand-held tools. When the tool-use task required using the shafts or the tips of the tools, visuotactile interactions were stronger at the tips of the tools than in the middle of the shaft. When the handles of the tools were used, however, visuotactile interactions were strongest near the hands and decreased with distance along the tools. These results suggest that tools do not simply ‘extend’ peripersonal space, but that just the tips of tools actively manipulated in extrapersonal space are incorporated into the brain’s visuotactile representations of the body and of peripersonal space.

Garry Trudeau on Female Soldiers and PTSD

Doonsbury, by Garry Trudeau (3/27/07)

Female Soldiers, PTSD, and Norepinephrine

Francisco Goya, The Disasters of War
[idea for using this image stolen from Mixing Memory's latest post on mirror neurons]

The 4th anniversary of the Iraq war was on Sunday, and some news outlets ran an obvious (but highly neglected) story: Violence takes severe mental toll on Iraqis.

Much more common are stories on the psychological toll of war in U.S. military personnel. There's a depressing article in the New York Times Magazine about post-traumatic stress disorder in women soldiers stationed in Iraq.

The Women’s War

By SARA CORBETT

Many female soldiers have lived through the terrible violence of the war in Iraq. Others have experienced sexual assault — or worse, a combination of the two. They have found themselves struggling to cope with their lives.

Among other examples, the article recounts the ordeal of Suzanne Swift, a 21-year-old Army specialist, who went AWOL rather than return to a second tour of duty in Iraq:

Despite the fact that military procedure for dealing with AWOL soldiers is well established - most are promptly court-martialed and, if convicted, reduced in rank and jailed in a military prison - Suzanne Swift's situation raised a seemingly unusual set of issues. She told Army investigators that the reason she did not report for deployment was that she had been sexually harassed repeatedly by three of her supervisors throughout her military service: beginning in Kuwait; through much of her time in Iraq; and following her return to Fort Lewis. She claimed too to be suffering from post-traumatic stress disorder, or PTSD, a highly debilitating condition brought on by an abnormal amount of stress. According to the most recent edition of The Diagnostic and Statistical Manual of Mental Disorders, used by mental-health professionals to establish diagnostic criteria, PTSD symptoms can include, among other things, depression, insomnia or "feeling constantly threatened." It is common for those afflicted to "re-experience" traumatic moments through intrusive, graphic memories and nightmares.

Given their current track record of providing adequate medical care to returning veterans, will the current administration find the funds to improve the standard of care not only for the physically wounded (see the Walter Reed debacle), but also for the astonishingly large number of vets (33%) diagnosed with mental illnesses?

The V.A. notes that as of last November, [almost] one-third [see Seal et al., 2007] of the veterans of Iraq and Afghanistan treated at its facilities were given diagnoses of a mental-health disorder, with PTSD being the most common. So far, the V.A. has diagnosed possible PTSD in some 34,000 Iraq and Afghanistan veterans; nearly 3,800 of them are women. Given that PTSD sometimes takes years to surface in a veteran, these numbers are almost assuredly going to grow.

What are the appropriate treatments for women with PTSD? Surely not this one:

While serving in a mostly male reserve unit in Kuwait, [another soldier] was sexually assaulted. After returning home to Michigan, she began exhibiting symptoms of PTSD - jumpiness, intrusive thoughts and nightmares - and promptly went to her local V.A. hospital for help. She was then put into group therapy - which has long been shown to be an economical and reasonably effective way of helping trauma survivors process their experiences - but her "group" was made up entirely of male Vietnam vets, some of whom were trying to work through sex crimes they committed during military service. Others came home from war and beat their wives. "I freaked out," the female reservist told me. "It sent me into a complete tailspin."

In addition to psychotherapy (including Exposure Therapy (Jaycox et al., 2002; Schnurr et al., 2007) -- a Cognitive Behavioral intervention -- and Eye Movement Desensitization and Reprocessing (Rothbaum et al., 2005; van der Kolk et al., 2007)) for those with PTSD, drugs that affect the neurotransmitter norepinephrine have been tested. A recent clinical trial of guanfacine was a complete failure (Neylan et al., 2006):

Neylan TC, Lenoci M, Samuelson KW, Metzler TJ, Henn-Haase C, Hierholzer RW, Lindley SE, Otte C, Schoenfeld FB, Yesavage JA, Marmar CR. (2006). No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. Am J Psychiatry 163: 2186-8.

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Guanfacine is an antihypertensive drug and an alpha-2 adrenergic agoninst that binds to autoreceptors on locus coeruleus (Berridge & Waterhouse, 2003) neurons [when administered at high doses¹], thereby inhibiting their activity and hence, the release of norepinephrine. When administered at low doses, guanfacine binds to post-synaptic alpha-2 receptors in places like the prefrontal cortex (Arnsten et al., 1988).

Another blood pressure medication, propranolol (a beta blocker), has been more widely used as a potential treatment for anxiety disorders and PTSD (e.g., Strawn & Geracioti, 2007). Similar to the use of alpha-2 agents, the idea behind propranolol is to normalize the hyperactive noradrenegic system in PTSD (a state produced by exposure to extreme levels of stress). Excessive norepinephrine (and the associated signal transduction activity) is thought to result in a trauma-induced enhancement of memory encoding for the harrowing event (Debiec & LeDoux, 2006).

Animal models of fear conditioning have been used to assess possible pharmacological treatments targeting the amygdala, a critical region for fear learning (Debiec & LeDoux, 2006). These treatments aim to impair memory consolidation and reconsolidation (reactivating a memory by retrieving it):

...propranolol, injected either systemically or directly into LA [lateral amygdala] lastingly impaired fear memory. Postreactivation propranolol significantly weakened fear responses measured 48 h later. ... Interestingly, our published findings indicate that propranolol disrupts reconsolidation of a memory 2 months after training. Therefore, even well-consolidated old fear memories undergo reconsolidation and may be disrupted by means of pharmacological manipulation.

For a more selective approach to PTSD, is it possible to

Wipe out a single memory (original source: Nature news) [??]

A single, specific memory has been wiped from the brains of rats, leaving other recollections intact.

The study adds to our understanding of how memories are made and altered in the brain, and could help to relieve sufferers of post-traumatic stress disorder (PTSD) of the fearful memories that disrupt their lives.

All very Lacuna Inc. (as other observers have noted). Original paper:

Doyere V, Debiec J, Monfils MH, Schafe GE, Ledoux JE. (2007). Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala. Nat Neurosci. Mar 11; [Epub ahead of print].

When reactivated, memories enter a labile, protein synthesis–dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

In that experiment (and others like it), rats were treated with the MEK Inhibitor, U0126 [which inhibits the kinase activity of MAP kinase kinase, or MEK -- aka MKK or MAP2K²], not propranolol. U0126 is not exactly approved for human use³.

So what about propranolol for PTSD? According to Strawn & Geracioti (2007),

The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Footnotes

¹ Or so the story went, a story that motivated the idea of guanfacine treatment in the first place. However, recent work (Ramos & Arnsten, 2005; Arnsten & Li, 2007) has shown that alpha-2 receptors are much more prominent post-synaptically, and guanfacine is more selective for those than for pre-synaptic autoreceptors (and is selective to a greater extent than clonidine, another alpha-2 blood pressure med known to produce sedation).

² Also see the fun MAP Kinase Signal Transduction Animation by Dr. Vic Lemas.

³ We're getting way out of my league here, but apparently U0126 is in the very "early clinical phase" for cancer treatment (a "Target for the Future") and is viewed as a "radical approach to stroke therapy." The only published studies have been done with cell cultures, with a few in live rodents.


References

Arnsten AF, Cai JX, Goldman-Rakic PS. (1988). The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 8:4287-98.

Arnsten AF, Li BM. (2005). Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377-84.

Berridge CW, Waterhouse BD. (2003). The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev. 42:33-84.

Debiec J, LeDoux JE. (2006). Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann NY Acad Sci. 1071:521-4.

Jaycox LH, Zoellner L, Foa EB. (2002). Cognitive-behavior therapy for PTSD in rape survivors. J Clin Psychol. 58:891-906.

Ramos BP, Arnsten AF. (2007). Adrenergic pharmacology and cognition: Focus on the prefrontal cortex. Pharmacol Ther. 113:523-36.

Rothbaum BO, Astin MC, Marsteller F. (2005). Prolonged Exposure versus Eye Movement Desensitization and Reprocessing (EMDR) for PTSD rape victims. J Trauma Stress. 18:607-16.

Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA, Thurston V, Orsillo SM, Haug R, Turner C, Bernardy N. (2007). Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297:820-30.

Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. (2007). Bringing the war back home: mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities. Arch Intern Med. 167:476-82.

Strawn JR, Geracioti TD Jr. (2007). Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety Mar 12; [Epub ahead of print].

van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper EK, Korn DL, Simpson WB. (2007). A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: treatment effects and long-term maintenance. J Clin Psychiatry 68:37-46.

A Thinking Blogger?

While we're on the topic of being a snarky cranky critic...


...Shelley at Retrospectacle has kindly nominated me for a Thinking Blogger Award!

1. Not much is known about the author of The Neurocritic blog, but he's funny, snarky, and blogs neuro-stuff awesomely.

[It's nearly as prestigious as being on the C-List!!]

This is clearly one of those meme thingys on teh intarwub, but I'm not blogging about it!

Spindle Neurons and Science Writing

In the wake of a hyperbolic new article (Freedberg & Gallese, 2007) on trendoid mirror neurons, Neurobloggy Land has noted that spindle neurons (aka von Economo neurons) are competing for attention.

In Neuroscience and Science Writing, Jonah at The Frontal Cortex argues that colorful, metaphoric language is suitable for popular science writing, even though it may lack precision (and may even be scientifically inaccurate, as I shall argue below). The case in point here is a post claiming that spindle neurons "convey our social emotions across the entire brain." Natasha commented on the use of language, saying:

But this doesn't as a statement make any sense "their antenna-like cell body is able to convey our social emotions across the entire brain". Neurons fire action potentials and the best they can conduct is patterns of firing or epsps/ipsps. They can't convey something as complex as 'social emotions'! That sounds like very sloppy thinking, even if they conduct something, some pattern, some information, to other brain regions its not 'saturating other brain regions with the same feeling'.

Jonah responded to this criticism:

The comment, of course, is true. Neurons traffic in electricity and neurotransmitter. A squirt of dopamine isn't a feeling; it's just a squirt of dopamine.

. . .

And yet, I'm also not planning on abandoning my "reification" of brain cells anytime soon. I still think it's acceptable to refer to spindle cells as conveyors of social emotion, or to allude to dopamine neurons as representing feelings of pleasure. Although no subjective experience - like a feeling - can be literally reduced into a discrete neural circuit, I think such writerly approximations are acceptable. ... It's a necessary inaccuracy, a way of collapsing different levels of scientific description.

He went on to suggest that

a significant and growing body of evidence suggesting that our spindle neurons are involved in the transmission of social emotion and social intuition.

Not to be a snarky cranky critic or anything, but I disagree about the strength of that evidence (and responded thusly)...

Based on the cited comments from Allman et al. (2005), I can see why you might think that spindle neurons transmit social emotions. However, their Trends in Cognitive Sciences article was categorized under the Opinion section with the title, "Intuition and autism: a possible role for Von Economo neurons" [my emphasis]. The article is highly speculative. No neurophysiological studies of spindle cells have ever been conducted, for obvious reasons (no single-unit recording in chimps or humans or humpback whales). So nothing is known about their physiological properties. Nothing is even known about their target projection sites (Allman et al., 2005): "However, it is not known where the VENs ultimately project."

Neuroanatomical data suggest that the dendritic structure of VENs (von Economo neurons) makes them "computationally simple compared with pyramidal neurons" (Watson et al., 2006), at least for their inputs.

Finally, humpback whales have many spindle cells (Hof et al., 2006), but they're largely solitary creatures (Valsecchi et al., 2002):

"These findings suggest that, if any social organization does exist, it is formed transiently when needed rather than being a constant feature of the population, and hence is more likely based on reciprocal altruism than kin selection."

...with all due respect to science writers (outside the blog format) who are faced with inadequate space, editors who push to simplify, and deadlines.

Oh, and Patrick Hof, another expert spindle cell neuroanatomist who is not John Allman, is more circumspect about their functional significance.

And while we're at it, check out the neurocritical comment by tfman on the study that sparked the debate, a recent article about spindle cells and humor (Watson et al., 2007):

Hey.. I read this paper, and for what its worth, seems to me the entire bloody brain is sensitive to humor (green in Figure 4), including the (unsexy) temporal cortex. bilateral inferior frontal gyri and more.

But wait, activity that correlates with subjective feeling of funniness (fig 2,3) is also found in white matter (!!) and the ventricles (!) so how much can we trust the rest of the data? (and SPM has the unsettling tendency to project both sulcal and gyral activity to the surface of the cortex in their graphical displays, which is misleading)

So lets put some of this in context: Von Economo cells are part of a larger system (just like mirror neurons are part of larger systems), and possible involved in the integration of information that is needed to 'get' jokes (especially verbal ones). Focusing on them, for whatever reason, in this article is likely to be as an arbitrary political decision akin to those papers that focus on "mirror neuron areas" when its clear the entire brain is involved in imitation.

. . .

References

Allman JM, Watson KK, Tetreault NA, Hakeem AY. (2005). Intuition and autism: a possible role for Von Economo neurons. Trends Cog Sci. 9:367-73.

Freedberg D, Gallese V. (2007). Motion, emotion and empathy in esthetic experience. Trends Cog Sci. Mar 6; [Epub ahead of print]

Hof PR, Chanis R, Marino L. (2005).Cortical complexity in cetacean brains. Anat Rec A Discov Mol Cell Evol Biol. 287:1142-52.

Valsecchi E, Hale P, Corkeron P, Amos W. (2002). Social structure in migrating humpback whales (Megaptera novaeangliae). Mol Ecol. 11:507-18.

Watson KK, Jones TK, Allman JM. (2006). Dendritic architecture of the von Economo neurons. Neuroscience 141: 1107-12.

Watson KK, Matthews BJ, Allman JM. (2007). Brain activation during sight gags and language-dependent humor. Cereb Cortex 17:314-24.

Mirror Neurons Control The Universe

Chris at Mixing Memory has a piece on the latest paper (Freedberg & Gallese, TICS 2007) to describe mirror neurons as accounting for empathy, art, aesthetics, and all forms of nonverbal communication (and and peace, love, and understanding. What's so funny?).

Mirror neurons are indeed neat, but many observers think the whole craze is an overhyped meme.

And Your BRRAAAAIINNNSS!!!

from The Invisible Library

Head on over to that godless liberal at Pharyngula for Encephalon #18.