Treating unto others

From Dr. David Clark, a parable about the Golden Rule in dementia treatment:

The Identity Function

Weekend BioRxiv Preprint Review: Modulation of Body Mass Composition using Vestibular Nerve Stimulation

The "set point" theory of hunger, eating and body weight maintains that everyone has a "normal" body weight as set by the brain's hypothalamus. Weight loss medications sometimes have been suggested in an attempt to affect this "set point" for weight control.

The paper below asserts that stimulation of the vestibular system of the inner ear with an externally applied current may lower the body weight "set point." If so this might mean that galvanic stimulation of points behind the external ear may result in weight loss in obese humans.

This shows promise, but any future study will need to take the nausea which may result from vestibular signal excess or imbalance into account.

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ABSTRACT

Modulation of Body Mass Composition using Vestibular Nerve Stimulation.

Paul D. McGeoch, Jason McKeown, Vilayanur S. Ramachandran

doi: http://dx.doi.org/10.1101/087692

Abstract

There is increasing evidence of a set-point for body weight in the brain, that is regulated by the hypothalamus. This system modifies feeding behavior and metabolic rate, to keep body fat within predetermined parameters. It is also known that animals subjected to chronic centrifugation show a reduction in body fat. Experiments with mutant mice found that this loss of fat appears to be mediated by a vestibulo-hypothalamic pathway. Vestibular nerve stimulation (VeNS), also known as galvanic vestibular stimulation, involves non-invasively stimulating the vestibular system by applying a small electrical current between two electrodes placed over the mastoid processes. We suggest that any means of repeatedly stimulating the otolith organs in humans would cause a reduction in total body fat, and that VeNS would be a useful technique to use in this regard. Below we provide pilot data to support this idea.

Happy Thanksgiving

In this old political cartoon, the nations of old Europe and Asia sit at the Thanksgiving feast while posturing in attitudes of hostility. Hawaii (still a nation at the time the cartoon was published) is pictured as the youth with the maile lei sitting third from the left in the foreground. Hawaii seems attentive, if bemused by the Old World's circus of conflicts.

Why the Eastern pundits failed to call the 2016 US Presidential election.

Steinberg's comic map should have warned them. That tiny area of US countryside in the drawing has more electoral votes per pixel than NY and CA combined.

Brain Area Activation May Reproducibly Predict Placebo Pain Effect Via fMRI: an fMRI Study Done RIght

One of my criticisms in past years of fMRI has been the lack of reproducibility of most published fMRI studies. The excessive type I statistical errors (false positives) in the fMRI literature may reflect the fact that the statistical N in such studies usually is linked to the number of voxels on the fMRI software used in such studies (often tens of thousands) rather than the number of subjects studied (generally less than 20, sometimes less than 5). Similar concerns come up with EEG analysis, where the N may reflect thousands of individual voltage measures over time in a few subjects, whereas the proper N should be the number of persons studied, often less than 10.

The study below, published in Plos One Biology, may have accomplished a rare confirmation of their hypothesis, one that might, if done consistently, remove most of the remaining type I errors from fMRI studies yet to be published: they looked at one group of placebo responders, got their data on which part of the brain changed with placebo pain relief, and then verified that area on another subject pool.

If a separate group of researchers verify the same area as correlated with placebo pain relief, this would be very strong evidence that the placebo response in pain correlates with activation of the right midfrontal gyrus. This is an area previously linked to executive function. What does executive function have to do with pain? That is unclear. According to Japee et al at the NIH, "The right middle frontal gyrus (MFG) has been proposed to be a site of convergence of the dorsal and ventral attention networks, by serving as a circuit-breaker to interrupt ongoing endogenous attentional processes in the dorsal network and reorient attention to an exogenous stimulus." So, perhaps this part of the brain can under some circumstances prevent us from paying attention to our pains.

Note that although the brain region (the right mid-frontal cortex) involved in placebo pain response seems to have been confirmed on the second study, the effects of duloxetine being different in the different study subjects would have to be verified in a third, still not done study.

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ABSTRACT

Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials

Pascal Tétreault, Ali Mansour, Etienne Vachon-Presseau, Thomas J. Schnitzer, A. Vania Apkarian , Marwan N. Baliki

Published: October 27, 2016http://dx.doi.org/10.1371/journal.pbio.1002570

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia.

Trial Registration ClinicalTrials.gov NCT02903238

Send in the clowns?

According to the sensationalist press, no, don't send them in, this coming evening on October 31. In memorial to the clowns, then, a video:

Weekend BioRxiv Preprint Review: The Neural Correlates of Dreaming

Not long after the development of the electoencephalogram (EEG) it was found that the EEG during sleep shows more synchronized and slower activity most of the time compared to our waking EEG. This was termed "slow wave sleep." These predominating slow wave sleep periods are interrupted by briefer periods of desynchronized, faster EEG activity, during which there are rapid movements of the eyes: this is termed REM sleep.

Most, but not all, dreams occur during REM sleep. This makes sense if faster and desynchronous brain activity is present when the brain is actively processing experiences, since dreams seem to be a kind of experience the brain can process. The rapid eye movements are similar to those we use when looking around us when awake, and it is likely that visual imagery during REM sleep is accompanied by the dreamer moving the eyes in a similar way they would if the dream images were actually in their waking vision. Other muscles of the body are quite relaxed during dreams: if they are not, a sleep disturbance ("REM behavior disorder") in which dream actions are accompanied by body movement may occur.

What of the dreams during slow wave (non-REM, or NREM) sleep? The study below suggests that even though much of the brain during such dreams shows slow activity, there is still a small area of the posterior brain which shows faster, desynchronized activity during dreams that occur during non-REM sleep. The area of the brain which has such faster activity during NREM dreaming is the same area activated by visual imagery during wakefulness, suggesting that, philosophically speaking, visual qualia are being generated during such dreams.

Studies such as this are difficult, time consuming, and expensive to do well, since one must, for each data point, have subjects sleep in the lab with an investigator or well trained tech able to wake the subjects at the right moment to ask if the subject was indeed dreaming when awakened. The investigators are to be complimented for their work.

One quibble: the investigators say at the end of their paper that "our findings indicate that the neural correlate of consciousness, rather than involving the broad lateral fronto-parietal network, is restricted to a posterior hot zone." This would be true if having visual imagery means we must be conscious. But are we really conscious while dreaming? Certainly we are not conscious in the same way we are when awake.

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ABSTRACT

The neural correlates of dreaming

Francesca Siclari, Benjamin Baird, Lampros Perogamvros, Giulio Bernardi, Joshua J LaRocque, Brady Riedner, Melanie Boly, Bradley R Postle, Giulio Tononi

doi: http://dx.doi.org/10.1101/012443

Consciousness never fades during wake. However, if awakened from sleep, sometimes we report dreams and sometimes no experiences. Traditionally, dreaming has been identified with REM sleep, characterized by a wake-like, globally ‘activated’, high-frequency EEG. However, dreaming also occurs in NREM sleep, characterized by prominent low-frequency activity. This challenges our understanding of the neural correlates of conscious experiences in sleep. Using high-density EEG, we contrasted the presence and absence of dreaming within NREM and REM sleep. In both NREM and REM sleep, the presence of dreaming was associated with a local decrease in low-frequency activity in posterior cortical regions. High-frequency activity within these regions correlated with specific dream contents. Monitoring this posterior ‘hot zone’ predicted the presence/absence of dreaming during NREM sleep in real time, suggesting that it may constitute a core correlate of conscious experiences in sleep