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“I travel around the world, eat a lot of shit, and basically do whatever the fuck I want.”  Read our complete Profile of Anthony Bourdain here. 

To keep pain in check, count down

Diverse cognitive strategies affect our perception of pain. Studies by LMU neuroscientist Enrico Schulz and colleagues have linked the phenomenon to the coordinated activity of neural circuits located in different brain areas.

Is the heat still bearable, or should I take my hand off the hotplate? Before the brain can react appropriately to pain, it must evaluate and integrate sensory, cognitive and emotional factors that modulate the perception and processing of the sensation itself. This task requires the exchange of information between different regions of the brain. New studies have confirmed that there is a link between the subjective experience of pain and the relative levels of neural activity in functional structures in various sectors of the brain. However, these investigations have been carried out primarily in contexts in which the perception of pain was intensified either by emotional factors or by consciously focusing attention on the painful stimulus. Now, LMU neuroscientist Enrico Schulz, in collaboration with colleagues at the University of Oxford, has asked how cognitive strategies that affect one’s subjective perception of pain influence the patterns of neural activity in the brain.

In the study, 20 experimental subjects were exposed to a painful cold stimulus. They were asked to adopt one of three approaches to attenuating the pain: (a) counting down from 1000 in steps of 7, (b) thinking of something pleasant or beautiful, and (c) persuading themselves – by means of autosuggestion – that the stimulus was not really that bad. During the experimental sessions, the subjects were hooked up to a 7T magnetic resonance imaging (MRI) scanner to visualise the patterns of neural activity in the brain, which were later analysed in detail.

In order to assess the efficacy of the different coping strategies, participants were also asked to evaluate the subjective intensity of the pain on a scale of 0 to 100. The results revealed that the countdown strategy was the most effective of the three methods. “This task obviously requires such a high level of concentration that it distracts the subject’s attention significantly from the sensation of pain. In fact some of our subjects managed to reduce the perceived intensity of pain by 50%,” says Schulz. “One participant later reported that she had successfully adopted the strategy during the most painful phase of childbirth.”

In a previous paper published in the journal Cortex in 2019, the same team had already shown that all three strategies help to attenuate the perception of pain, and that each strategy evoked a different pattern of neural activity. In the new study, Schulz and his collaborators carried out a more detailed analysis of the MRI scans, for which they divided the brain into 360 regions. “Our aim was to determine which areas in the brain must work together in order to successfully reduce the perceived intensity of the pain,” Schulz explains. “Interestingly, no single region or network that is activated by all three strategies could be identified. Instead, under each experimental condition, neural circuits in different brain regions act in concert to varying extents.”

The attenuation of pain is clearly a highly complex process, which requires a cooperative response that involves many regions distributed throughout the brain. Analysis of the response to the countdown technique revealed close coordination between different parts of the insular cortex, among other patterns. The imaginal distraction method, i.e. calling something picturesque or otherwise pleasing to mind, works only when it evokes intensive flows of information between the frontal lobes. Since these structures are known to be important control centres in the brain, the authors believe that engagement of the imaginative faculty may require a greater degree of control, because the brain needs to search through more ‘compartments’ – to find the right memory traces, for instance. Comparatively speaking, counting backwards stepwise – even in such awkward steps – is likely to be a more highly constrained task. “To cope with pain, the brain makes use of a recipe that also works well in other contexts,” says Anne Stankewitz, a co-author of the new paper: “success depends on effective teamwork.” Her team now plans to test whether their latest results can be usefully applied to patients with chronic pain.

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How to Make a Motor Neuron

A team of scientists has uncovered details of the cellular mechanisms that control the direct programming of stem cells into motor neurons. The scientists analyzed changes that occur in the cells over the course of the reprogramming process. They discovered a dynamic, multi-step process in which multiple independent changes eventually converge to change the stem cells into motor neurons.

“There is a lot of interest in generating motor neurons to study basic developmental processes as well as human diseases like ALS and spinal muscular atrophy,” said Shaun Mahony, assistant professor of biochemistry and molecular biology at Penn State and one of the lead authors of the paper. “By detailing the mechanisms underlying the direct programing of motor neurons from stem cells, our study not only informs the study of motor neuron development and its associated diseases, but also informs our understanding of the direct programming process and may help with the development of techniques to generate other cell types.”

The direct programming technique could eventually be used to regenerate missing or damaged cells by converting other cell types into the missing one. The research findings, which appear online in the journal Cell Stem Cell on December 8, 2016, show the challenges facing current cell-replacement technology, but they also outline a potential pathway to the creation of more viable methods.

“Despite having a great therapeutic potential, direct programming is generally inefficient and doesn’t fully take into account molecular complexity,” said Esteban Mazzoni, an assistant professor in New York University’s Department of Biology and one of the lead authors of the study. “However, our findings point to possible new avenues for enhanced gene-therapy methods.”

The researchers had shown previously that they can transform mouse embryonic stem cells into motor neurons by expressing three transcription factors – genes that control the expression of other genes – in the stem cells. The transformation takes about two days. In order to better understand the cellular and genetic mechanisms responsible for the transformation, the researchers analyzed how the transcription factors bound to the genome, changes in gene expression, and modifications to chromatin at 6-hour intervals during the transformation.

“We have a very efficient system in which we can transform stem cells into motor neurons with something like a 90 to 95 percent success rate by adding the cocktail of transcription factors,” said Mahony. “Because of that efficiency, we were able to use our system to tease out the details of what actually happens in the cell during this transformation.”

“A cell in an embryo develops by passing through several intermediate stages,” noted Uwe Ohler, senior researcher at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin and one of the lead authors of the work. “But in direct programming we don’t have that: we replace the gene transcription network of the cell with a completely new one at once, without the progression through intermediate stages. We asked, what are the timing and kinetics of chromatin changes and transcription events that directly lead to the final cell fate?“

The research team found surprising complexity – programming of these stem cells into neurons is the result of two independent transcriptional processes that eventually converge. Early on in the process, two of the transcription factors – Isl1 and Lhx3 – work in tandem, binding to the genome and beginning a cascade of events including changes to chromatin structure and gene expression in the cells. The third transcription factor, Ngn2, acts independently making additional changes to gene expression. Later in the transformation process, Isl1 and Lhx3 rely on changes in the cell initiated by Ngn2 to help complete the transformation. In order for direct programming to successfully achieve cellular conversion, it must coordinate the activity of the two processes.

“Many have found direct programming to be a potentially attractive method as it can be performed either in vitro – outside of a living organism – or in vivo – inside the body and, importantly, at the site of cellular damage,” said Mazzoni. “However, questions remain about its viability to repair cells – especially given the complex nature of the biological process. Looking ahead, we think it’s reasonable to use this newly gained knowledge to, for instance, manipulate cells in the spinal cord to replace the neurons required for voluntary movement that are destroyed by afflictions such as ALS.”

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