Foolproof method for succeeding in modern neurochemistry

Neurochemistry Post-Docs! Looking to publish interesting and important papers on the neurochemistry of reward but don't know what to study? Then Dr. Swenson's Revolutionary Topic Selection Method is for you!

For centuries, western philosophers have thought carefully about the nature and kinds of pleasure.* You too can benefit from their efforts!

Here's the key to Dr. Swenson's Revolutionary Topic Selection Method: These philosophers have been studying mental phenomena. You study neural phenomena. And mental phenomena are ultimately neural phenomena!

Other inferior neuropsychological research programs have tried using philosophical claims to select topics. But they would have you try to prove or disprove philosophical claims with neuroscience. That may win you friends amongst philosophers. But you don't want philosopher friends!** You want prestigious publications and lucrative grants!

That's where Dr. Swenson's Revolutionary Topic Selection Method can help! You needn't worry about proving or disproving philosophical claims. With Dr. Swenson's Revolutionary Topic Selection Method, you will use writers ranging from the ancient Greeks to the modern utilitarians to help you design experimental paradigms that are the key to scientific fame.

Here's just one taste of what the system has to offer. Philosophers have, in various guises, debated whether some pleasures are better than others by virtue of being more refined and intellectually infused.

Now a lesser program might have you consider whether opera or pop music produces greater activity in dopaminergic pathways in subjects with past exposure to both. But that will impress only philosophers.

With Dr. Swenson's Revolutionary Topic Selection Method you will instead find in these disputes some promising leads for experimentation. You may, for example, design your experiments to investigate connections between the reward pathway activity, memories, and higher order processes. You don't care whether the refined music elicits more apparent reward. You care about whether pop music and opera elicit systematically different connections throughout the brain.***

Now, it is true that Dr. Swenson's Revolutionary Topic Selection Method can't promise experimental results that will woo philosophers.**** But Dr. Swenson's Revolutionary Topic Selection Method can help you select topics which will uncover processes which underlie our complex mental lives. And that's what you want.

And lucrative grants!

Act now and Dr. Swenson's Revolutionary Topic Selection Method can be yours for a pathetically small amount of money. First 10 callers get a free T-shirt and Shamwow.


*Yes, this comes dangerously close to 'since the dawn of time'. I cringe too.

**I'm serious.

***I know, music isn't the best example. But it's easy to set out. Thanks a lotOliver Sacks.

****Philosophers will nonetheless distort your results and woo themselves.

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This post was inspired by

Heterogenerity of Reward Mechanisms

SpringerLink - Neurochemical Research, Volume 35, Number 6: "The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms. The system is variable, is changed during development, is sex-dependent, and is influenced by genetic differences. Not all of the elements participate in the reward of all stimuli. Different set of mechanisms are involved in the reward of different drugs of abuse, yet different mechanisms in the reward of natural stimuli such as food or sexual activity; thus there are different systems that distinguish different stimuli. Separate functions of the reward system such as anticipation, evaluation, consummation and identification; all contain function-specific elements. The level of the stimulus also influences the participation of the elements of the reward system, there are possible reactions to even below threshold stimuli, and excessive stimuli can change reward to aversion involving parts of the system. Learning and memory of past reward is an important integral element of reward and addictive behavior. Many of the reward elements are altered by repeated or chronic stimuli, and chronic exposure to one drug is likely to alter the response to another stimulus. To evaluate and identify the reward stimulus thus requires heterogeneity of the reward components in the brain. "

(Via http://mindhacks.com/.)

Mutations in the SCN9A gene and pain sensitivity

The article emphasizes the genetics, but I'm more interested in the implication that the heightened sensitivity relates to the speed at which sodium channels close in nociceptive neurons.

Gene Linked To Pain Perception - Science News: "Gene linked to pain perception
Common genetic variant makes some people more sensitive
By Laura Sanders
Web edition : Monday, March 8th, 2010

[....]
The team found that people who reported higher levels of pain were more likely to carry a particular DNA base, an A instead of a G, at a certain location in the gene SCN9A. The A version is found in an estimated 10 to 30 percent of people, Woods says, though its presence varies in populations of different ancestries.

[....]
The same trend — higher pain levels reported by people who carried the A — held true in cohorts of people with other painful conditions including sciatica, phantom limb syndrome and lumbar discectomy.
[....]

The genetic variation affects the structure of a protein that sits on the outside of nerve cells and allows sodium to enter upon painful stimuli. The sodium influx then spurs the nerve cell to send a pain message to the brain.

This channel protein is a promising target for extremely specific and effective pain drugs, Waxman says: ‘Given that this channel has been indicted, it would be nice if we could develop therapeutic handles that turn it off or down.’

Researchers already knew that people with mutations in SCN9A can have extreme pain syndromes. Genetic changes that render the protein completely inactive can leave a person impervious to pain, although otherwise healthy. Other mutations can lead to conditions such as ‘man on fire’ syndrome, in which people experience relentless, searing pain.
[....]
In additional laboratory studies, the researchers found that nerve cells carrying the A variant of the gene took longer to close their sodium gates, allowing a stronger pain signal to be sent to the brain. Nerve cells carrying the more common G version of the gene snapped shut faster, stopping the pain signal sooner. "

TENS confusion

Given that TENS was part of the discovery of the gate-control theory 40 years ago, it really would be nice if its implications for the distinction between nociception and pain had seeped in. This is from a press release on Science Daily:

Widely used device for pain therapy not recommended for chronic low back pain A new guideline issued by the American Academy of Neurology finds that transcutaneous electric nerve stimulation (TENS), a widely used pain therapy involving a portable device, is not recommended to treat chronic low-back pain that has persisted for three months or longer because research shows it is not effective.... TENS can be effective in treating diabetic nerve pain, also called diabetic neuropathy, but more and better research is needed to compare TENS to other treatments for this type of pain. Research on TENS for chronic low-back pain has produced conflicting results. For the guideline, the authors reviewed all of the evidence for low-back pain lasting three months or longer. Acute low-back pain was not studied. The studies to date show that TENS does not help with chronic low-back pain.

So far so good. But then in the nickel summary of what TENS is they write:

With TENS, a portable, pocket-sized unit applies a mild electrical current to the nerves through electrodes. TENS has been used for pain relief in various disorders for years. Researchers do not know how TENS may provide relief for pain. One theory is that nerves can only carry one signal at a time. The TENS stimulation may confuse the brain and block the real pain signal from getting through.

How about:

Neural signals reporting injury have to pass through a gate in the spine in order to be transmitted to the brain and cause pain. The electric impulse from TENS closes the gate.

That's still inaccurate. But it at least avoids framing the phenomenon as the system stopping the pain before it gets to the brain. Getting people used to distinguishing between nociception and pain is a small but important step in a better public understanding of analgesia and chronic pain conditions.

Why papercuts hurt so damn much

During my bimonthly rereading of Price's Psychological Mechanisms of Pain and Analgesia, I ran across this in the middle of a discussion of the relationship between tissue damage and pain intensity:

the rate of tissue damage is a direct function of protein in activation that, in turn, is a function of temperature. However, the amount of tissue damage is a function of both skin temperature and duration of stimulation. Since heat-induced pain depends only on the temperature attained by the cells of the skin and on duration of stimulation, pain intensity follows the rate of tissue damage and not its total amount. One consequence of this phenomenon is that some extensive wounds may be less painful than slight wounds. Pain from tissues that have suddenly become inflamed, such as a toothache, is an example." [Page 11; italics original]

A role for glial cell-targeting treatments for pain?

The Psychology of Pain blog links to an interesting new study from CU-Boulder. I don't want to steal too much of his post, so here's a tease:

Under normal circumstances glial cells are thought to be like housekeepers, said Watkins. They essentially clean up debris and provide support for neurons.

But, like Gremlins, they have a nasty side too

[the researchers] believe they have figured out how morphine affects glial cells and neurons. 'We've found that different receptors are involved in how morphine suppresses pain through its actions on neurons versus how morphine activates glial cells,' Watkins said. 'What this means is that you should be able to separate the suppressive effects of morphine -- its pain-reducing effects through its action on neurons -- from all of its bad effects when it excites glial cells.'

(Via Psychology of Pain.)

Redheads need more drugs

Huh.

The Pain of Being a Redhead - Well Blog - NYTimes.com:
A growing body of research shows that people with red hair need larger doses of anesthesia and often are resistant to local pain blockers like Novocaine. As a result, redheads tend to be particularly nervous about dental procedures and are twice as likely to avoid going to the dentist as people with other hair colors, according to new research published in The Journal of the American Dental Association.

Researchers believe redheads are more sensitive to pain because of a mutation in a gene that affects hair color. In people with brown, black and blond hair, the gene, for the melanocortin-1 receptor, produces melanin. But a mutation in the MC1R gene results in the production of a substance called pheomelanin that results in red hair and fair skin.

The MC1R gene belongs to a family of receptors that include pain receptors in the brain, and as a result, a mutation in the gene appears to influence the body’s sensitivity to pain. A 2004 study showed that redheads require, on average, about 20 percent more general anesthesia than people with dark hair or blond coloring. And in 2005, researchers found that redheads are more resistant to the effects of local anesthesia, such as the numbing drugs used by dentists.
[....]

It's also nice to hear that the research came from taking this sort of common experience seriously, rather than simply dismissing it:

Dr. Daniel I. Sessler, an anesthesiologist and chairman of the department of outcomes research at the Cleveland Clinic, said he began studying hair color after hearing so many colleagues speculate about redheads requiring more anesthesia.

‘The reason we studied redheads in the beginning, it was essentially an urban legend in the anesthesia community saying redheads were difficult to anesthetize,’ Dr. Sessler said. ‘This was so intriguing we went ahead and studied it. Redheads really do require more anesthesia, and by a clinically important amount.’

If I had red hair, I would bring a copy of the paper with me to the dentist/doctor to help them take my needs seriously.*

*Just as I would, for example, show literature on the usefulness of pre-incision lidocaine in lowering post-surgicial pain to my surgeon.

I might also post articles on the problems with using morphine in patients with kidney problems on the wall by an elderly relative's hospital bed.

Online introduction to pain processes

The-New-Science-of-Pain-Relief has a nice introductory walkthrough of the basic neurology of pain here.

Philosophers will, of course, carefully take note the role of C nociceptive afferents.

Medical News Today News Article

Medical News Today News Article: "Stroking The Skin Sends Signals Direct To The Brain, Deadens Pain Impulses

16 Apr 2009   

The specialised nerve fibres in the skin are called CT nerves (C-tactile) and they travel directly to the areas in the brain that are important in the emergence of feelings.

'Basically the signals that tell the brain that we are being stroked on the skin have their own direct route to the brain, and are not blocked even if the brain is receiving pain impulses from the same area. In fact it's more the opposite, that the stroking impulses are able to deaden the pain impulses,' says Line Löken, postgraduate student in neurophysiology at the Sahlgrenska Academy.
[....]
Each individual nerve fibre is responsible for touch signals from roughly a square centimetre of skin. The research team used a specially-designed robot, which brushed over the exact area of skin for which a particular nerve fibre is responsible. The subjects were also asked to rate how pleasant or unpleasant they found the brushing.

'As the nerve signals that were sent in the CT nerves became more frequent, the subjects reported the experience as being increasingly pleasant. Of the skin nerves that we studied, it was only the CT nerves that had this strong link between the frequency of the signals and how pleasant it felt,' says researcher Johan Wessberg.

Notes:

Journal: Nature Neuroscience
Title of the article: Coding of pleasant touch by unmyelinated afferents in humans
Authors: Line S. Löken, Johan Wessberg, India Morrisson, Francis McGlone, Håkan Olausson
The full text article is available on Nature Neuroscience's web page: http://www.nature.com/neuro/journal/vaop/ncurrent/abs/nn.2312.html

By: Elin Lindström Claessen
"

Translating nociceptive processing into human pain models.

Limits on pain models:

Translating nociceptive processing into human pain models.: "

Exp Brain Res. 2009 Apr 29;
Schmelz M

As volunteers can easily communicate quality and intensity of painful stimuli, human pain models appear to be ideally suited to test analgesic compounds, but also to study pain mechanisms. Acute stimulation of nociceptors under physiologic conditions has proven not to be of particular use as an experimental pain model. In contrast, if the experimental models include sensitization of the peripheral or central pain processing they may indeed mimic certain aspects of chronic pain conditions. Peripheral inflammatory conditions can be induced experimentally with sensitization patterns correlating to clinical inflammatory pain. There are also well-characterized models of central sensitization, which mimic aspects of neuropathic pain patients such as touch evoked allodynia and punctate hyperalgesia. The main complaint of chronic pain patients, however, is spontaneous pain, but currently there is no human model available that would mimic chronic inflammatory or neuropathic pain. Thus, although being helpful for proof of concept studies and dose finding, current human pain models cannot replace patient studies for testing efficacy of analgesic compounds."

(Via HubMed - pain.)

Trying to control pain

Interesting.

Trying To Control Pain Can Be A Double-edged Sword, Say Scientists

ScienceDaily (Nov. 2, 2006) — Scientists have shown for the first time why a feeling of control helps us reduce pain.....Using fMRI scanners, which allow scientists to examine how the brain operates, the research, led by Dr Katja Wiech and Dr Raffael Kalisch, showed that when people feel that they can control their pain, an area of their prefrontal cortex associated with a feeling of security is activated. The findings are published in the Journal of Neuroscience today and have been welcomed by the Expert Patients Programme.

More significantly, the team went on to show that when faced with pain beyond their control, people who tend to feel more in control of their own lives show a lower response in the prefrontal cortex, indicating that they are less effective in coping with pain than those who don't expect to have control.

"Patients with persistent pain report that often it is not the pain itself that makes their situation unbearable, but the fact that there is nothing they can do against it which makes them feel helpless," explains Dr Wiech. "Unfortunately, this feeling of uncontrollability in turn tends to worsen the pain. On the other hand, teaching persistent pain patients psychological coping strategies to handle their pain usually does help reduce its effects."

Dr Wiech and her team set up an experiment to investigate how people cope with pain. In the first stage, volunteers were given an electric stimulus to the backs of their hands and told that they could stop the pain at any point. In the second stage, they were told that the decision to stop the pain was out of their control and could only be stopped by a person or computer outside the room.

Using one of the centre's fMRI scanners, the researchers were able to show that a number of areas of the brain were activated according to whether the volunteer felt in control of the pain. Most important was the anterolateral prefrontal cortex, which is associated with successful coping with feelings of anxiety.

The findings may have implications for future therapeutics, believes Dr Wiech.

"If we were able to stimulate the prefrontal cortex through psychological intervention, medication or some other stimulus, we could help reduce the pain felt by a patient," she says. "However, we are still some way of this."

The team also analysed the subjects' outlook on life, examining whether they felt in control of their own lives. They found that whilst the subjects' outlook did not affect the anterolateral prefrontal cortex when they controlled the stimulus, when they were not able to stop the painful stimulation subjects with no control expectations were better at activating this brain region than those with a strong control belief.

The findings support the practice of "acceptance-based therapy" whereby doctors focus on training patients to cope with the pain rather than attempting to make the pain go away.

"Throughout our lives, we are taught that we should aim to take control of our lives, to get the best job, find the best partner," says Dr Wiech. "But sometimes we should accept what we have and make the most of it. Rather than constantly battling pain, our research supports the view that it is better to provide a patient with the tools to cope with his or her persistent pain."

The findings are welcomed by Pete Moore, lead trainer in pain management for the Expert Patients Programme Community Interest Company.

"This is interesting work by UCL. We have found that many people with pain are over achievers and tend to do more than they have to. This is why when people with persistent pain attend an Expert Patients Programme they are provided with a toolbox of self-management skills to support them to manage their day-to-day pain."

Wellcome Trust (2006, November 2). Trying To Control Pain Can Be A Double-edged Sword, Say Scientists. ScienceDaily. Retrieved March 19, 2008, from http://www.sciencedaily.com­ /releases/2006/10/061031191327.htm

The subjective experience of punishment

Friend of PFP has an intriguing article on sensitivity to punishment and punitive practices here.

Abstract:
Suppose two people commit the same crime and are sentenced to equal terms in the same prison facility. I argue that they have identical punishments in name only. One may experience incarceration as challenging but tolerable while the other is thoroughly tormented by it. Our sentencing policies seek to equalize the duration of their incarceration, yet largely ignore the differences in their experiences of isolation, stigma, and confinement. In this article, I argue that, according to our prevailing theories of punishment, the subjective experience of punishment matters. There is, therefore, a disconnect between our punishment practices and our best attempts to justify those practices.

There are three possible responses. First, we could try to modify or expand our theories to avoid the obligation to calibrate punishment. I show why this approach is unlikely to succeed. Second, we could conclude that, even though we ought to calibrate our punishments, doing so would be too costly or difficult to administer. This response is too hasty. In civil litigation, we do make subjective assessments of damages. Advances in neuroscience may someday make these assessments more accurate and less expensive. Even if we cannot individually calibrate punishments, we can surely enact sentencing policies that are more subjectively-sensitive than the policies we have now. We are left, then, with only the third response: to recognize that subjective experience matters in assessments of punishment severity and to take at least modest steps toward calibrating punishment, either through individual measurement or, more feasibly, by enacting punishment policies that are subjectively sensitive.

Mirror-touch synethesia

From The Week (not online so no link)

They feel your pain
Some people can feel others' pain --literally. When those with a rare condition called mirror-touch synethesia see another person being touched or hurt, they actually feel the sensation themselves. There are several types of synesthesia, a neurological syndrome that causes senses to cross paths in the brain. For some synesthetes, for instance, specific colors create distinctive sounds in their head. Experts had heard only ancedotal accounts of mirror-touch synethesia until neuroscientist Sarah-Jayne Blakemore discussed the phenomenon at a seminar in 2003. "There was a woman in the audience who asked 'doesn't everyone experience that? Isn't that completely normal?" Blakemore tells Nature. Since then, Blakemore has studied 10 other mirror-touch synesthetes. All of them have overactive mirror neurons, which are the brain cells that allow us to see an action and comprehend it enough to be able to mimic it. "I have never been able to understand how people can enjoy looking at bloodthirsty films," says Alice, one of Blakemore's study subjects. "I can feel it."

Two comments:
(1) To some extent all of us do this. For example, one of my students tells me that once her boyfriend accidentally pulled her hair and yipped 'Ouch!' before she said anything. He claimed that it actually hurt him when he did it (I'm presuming that he doesn't have this condition).

(2) In general, I've always thought synesthesia is one of the coolest neurological conditions. A friend with perfect pitch tells me that he can tell if a note is off by its color --for example, A 440 seems red to him. That sounds very cool (though I'm not sure how much I'd like to have the version discussed here).