Complex regional pain syndrome

Doctors Struggle to Treat Mysterious and Unbearable Pain – New York Times

Hadn’t heard about this before:

[…] she felt a sudden pop in her hamstring. “It felt like a guitar string had been plucked and it had broken,” said Ms. Toussaint, who is now 45.

An intense burning sensation followed; it felt as if her leg had been doused in gasoline and set on fire, she said. The next day, the college athletics trainer determined that she had pulled her hamstring. But even years later, the pain would not subside. It migrated to her other leg, leaving her bedridden for nearly a decade, and overtook her vocal cords, leaving her temporarily mute.

All the while, doctors puzzled over and even doubted her mysterious condition.

Ms. Toussaint now knows that she is among an estimated one million Americans living with complex regional pain syndrome, a nerve disorder formerly known as reflex sympathetic dystrophy syndrome. For patients with the disorder, a trauma as mild as a fractured wrist or a twisted ankle can cause the nerves to misfire, so much so that intense pain messages are constantly sent to the brain.

Interestingly, neural stimulation only provides a short-term benefit with eventual adaptation. In some cases, ketamine administration (enough to put the patients in a temporary coma) has completely stopped the pain. Ketamine is an anesthetic (although it has been known to actually stimulate circulation at certain doses) with well-known psychedelic properties. It is also a non-competitive NMDA antagonist that is often used in conjunction with traditional opiods for an analgesic effect.

I wonder if this effect is simply due to the interaction with the NMDA receptor or is something more complex. (For example, the analgesic effects of ketamine when combined with a opiods seem unrelated.)

Here’s a link to the original paper in the journal Pain, which suggests that CRPS patients have suffered damage to small-diameter PNS nociceptive fibers.

Uncertainty, Neuromodulation, and Attention

Neuron : Uncertainty, Neuromodulation, and Attention

Haven’t read this article from Peter Dayan’s lab yet but some interesting Bayesian modeling implicating acetylcholine as a signal of expected uncertainty and norepinephrine as a signal of unexpected uncertainty.

Abstract:

Uncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain’s implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Maybe we should call it gliascience instead?

Cell : Astrocytes Put down the Broom and Pick up the Baton [N&V summary]

Some beautiful work [original article] by Oliet’s lab in a recent issue of Cell demonstrates the importance of glia in synaptic plasticity. The show a system where D-serine and not glycine controls the NMDA receptor in a coagonist role (or perhaps glutamate is really the coagonist…) and show how similar pairing protocols can have opposite effects (LTD vs. LTP) depending on D-serine modulation by astrocytes. Yet more hidden factors in plasticity are being revealed!

Here’s the key figure:

More details from the News & Views summary after the jump. Continue reading

CX717: Preventing sleep deprivation trauma

Intelligent Life 2006 | From A to Zzzzz

Introducing CX717, a drug being developed by Cortex Pharmaceuticals of Irvine, California. It’s the first of what promises to be many aimed at detaching people from the daily routine of eight hours each for work, rest and play.

Tests conducted on rhesus monkeys last year suggest that CX717 can wire users to remain awake for 36 hours without the jitters, euphoria and eventual crash that come after mega-doses of caffeine or amphetamines. Further down the line are even more radical compounds—stimulants that can wipe out sleep for several days at a stretch, and pills that deliver a whole night’s shut-eye in two hours.

More information about the ampakine CX717 can be found here. We previously mentioned the delay match-to-sample performance improvement of monkeys on CX717.

Synaptic tuning : Nature Reviews Neuroscience

Synaptic tuning : Nature Reviews Neuroscience

For those interested in neuromodulators:

Treatment of striatal neurons with a D1 receptor agonist led to an increase in the dendritic staining intensity of NMDA receptor NR2B subunits. There was also an increase in the association of NR2B subunits with PSD-95 — a scaffold protein required for the assembly of NMDA receptors — and in the surface localization of NR2B-containing receptors.

Original article in J. Neurosci. from Dunah and colleagues. An excerpt from the original aricle of a neat application of FRET continues after the jump.
Continue reading

TR: Future of Neurotechnology

Technology Review: Emerging Technologies and their Impact

I don’t know too much about Zach Lynch, other than that he has a blog and refers to his company as the “neurotechnology market authority”, but there are some interesting tidbits from the TR interview:

TR: Research suggests that antidepressants are effective partly because they stimulate neurogenesis. So companies such as BrainCells, based in San Diego, CA, are screening compounds that promote growth of neural stem cells in the brain. They say these drugs could bring new therapies for depression and, eventually, neurodegenerative diseases.

ZL: It’s an exciting area, and the investment community is certainly interested. But the jury is still out.

TR: We’re also starting to see a new kind of therapy for brain-related illnesses — electrical stimulation. Various types of stimulation devices are now on the market to treat epilepsy, depression, and Parkinson’s disease. What are some of the near- and far-term technologies we’ll see with this kind of device?

ZL: We’re seeing explosive growth in this area because scientists are overcoming many of the hurdles in this area. One example is longer battery life, so devices don’t have to be surgically implanted every five years. Researchers are also developing much smaller devices. Advanced Bionics, for example, has a next-generation stimulator in trials for migraines.

In the neurodevice space, the obesity market is coming on strong. Several companies are working on this, including Medtronics and Leptos Biomedical. In obesity, even a small benefit is a breakthrough, because gastric bypass surgery [one of the most common treatments for morbid obesity] is so invasive.

In the next 10 years, I think we’ll start to see a combination of technologies, like maybe a brain stimulator that releases L-dopa [a treatment for Parkinson’s disease]. Whether that’s viable is a whole other question, but that possibility is there because of the microelectronics revolution.

The real breakthrough will come from work on new electrodes. This will transform neurostimulator applications. With these technologies, you can create noninvasive devices and target very specific parts of the brain. It’s like going from a Model T to a Ferrari. Those technologies will present the real competition for drugs.

New stable genetically-encoded Ca sensor

A FRET-Based Calcium Biosensor with Fast Signal Kinetics and High Fluorescence Change — Mank et al. 90 (5): 1790 — Biophysical Journal

Relevant details (from the discussion):

Above we reported the generation of a FRET-based calcium biosensor employing TnC as calcium-binding moiety that is fast, is stable in imaging experiments, and shows a significantly enhanced fluorescence change. Its off-rate is significantly faster than those of previous double chromophore sensors and even outmatches the fastest single fluorophore sensors to date.

Although it is faster than what was previously available, it would be nice if the off-rate was even faster:

Its off-rate was extremely fast, optimally fitted with a double exponential with a dominating {tau} of 142 ms (A1 = 0.63) and a minor {tau} of 867 ms (A2 = 0.06) (Fig. 2 D). Mutation of the N-cap residue 131 of helix G within TnC from isoleucine to threonine (35Go) yielded an indicator of higher calcium affinity with a Kd of 1.7 µM (Fig. 2 B) and shifted the Hill slope to 1.1, although at reduced maximal fluorescence change of 270%. TN-XL expressed well in primary hippocampal neurons at 37°C. Fluorescence was evenly distributed, filling all neuronal processes, with no signs of aggregation. The nucleus was devoid of fluorescence. Repeated stimulations with high potassium followed by repeated washouts demonstrated stable baselines over long recording sessions and reproducible signals after stimulation. Moreover the signals induced by high potassium were more than doubled compared to TN-L15.

Hippocampus response to KCl application

Maybe junk DNA is not junk?

Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes — Rigoutsos et al. 103 (17): 6605 — Proceedings of the National Academy of Sciences

Not directly neuroscience-related but this is a pretty cool paper nonetheless. Basically, the authors use automated pattern recognition to pick out small strings in the “non-coding” regions of the human genome. They show that these pyknons are found at regular distances within coding regions and UTRs. Even more intriguing is that

approx. 40% of the known microRNAs are similar to 689 pyknons and that the pyknons subsume 56 of the 72 recently reported 3′ UTR motifs, lending further support to the possibility of a connection between the pyknons and RNAi/PTGS.

Both RNAi (RNA interference) and PTGS (post-transcriptional gene silencing) have recently been found to be major regulatory mechanisms for endogenous gene silencing and regulation. Here’s a link to a primer on PTGS and RNAi.

NMDA receptor might not be coincidence detector for LTD side of STDP

Two Coincidence Detectors for Spike Timing-Dependent Plasticity in Somatosensory Cortex — Bender et al. 26 (16): 4166 — Journal of Neuroscience

Dan Feldman’s group at UCSD has found that different “sides” of STDP (ie. LTP vs. LTD) at cortical synapses might be mediated through distinct signalling pathways. The major finding was that LTD was induced independent of NMDA receptors. Rather, LTD required mGluRs and VGCCs.

There are many questions here. The most interesting to think about is, Are we going to find different STDP rules all over the brain? And, if so, what will be the commond ground between them?

Here’s the abstract:

Many cortical synapses exhibit spike timing-dependent plasticity (STDP) in which the precise timing of presynaptic and postsynaptic spikes induces synaptic strengthening [long-term potentiation (LTP)] or weakening [long-term depression (LTD)]. Standard models posit a single, postsynaptic, NMDA receptor-based coincidence detector for LTP and LTD components of STDP. We show instead that STDP at layer 4 to layer 2/3 synapses in somatosensory (S1) cortex involves separate calcium sources and coincidence detection mechanisms for LTP and LTD. LTP showed classical NMDA receptor dependence. LTD was independent of postsynaptic NMDA receptors and instead required group I metabotropic glutamate receptors and calcium from voltage-sensitive channels and IP3 receptor-gated stores. Downstream of postsynaptic calcium, LTD required retrograde endocannabinoid signaling, leading to presynaptic LTD expression, and also required activation of apparently presynaptic NMDA receptors. These LTP and LTD mechanisms detected firing coincidence on ~25 and ~125 ms time scales, respectively, and combined to implement the overall STDP rule. These findings indicate that STDP is not a unitary process and suggest that endocannabinoid-dependent LTD may be relevant to cortical map plasticity.

Inferring network activity on a MEA from pairwise correlations

Weak pairwise correlations imply strongly correlated network states in a neural population : Nature

Very few MEA studies make it into Nature, so this definitely got my attention.

Often in neuroscience we are confronted with a small sample measurement of a few neurons from a large population. Although many have assumed, few have actually asked: What are we missing here? What does recording a few neurons really tell you about the entire network?

Using an elegant prep (retina on a MEA viewing defined scenes/stimuli), Segev, Bialek, and students show that statistical physics models that assume pairwise correlations (but disregard any higher order phenomena) perform very well in modeling the data. This indicates a certain redundancy exists in the neural code. The results are also replicated with cultured cortical neurons on a MEA.

Some key ideas from the paper are presented after the jump. Continue reading