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#### Nanomedicine

By Guizhi Zhu, Lei Mei, and Weihong Tan

From bioimaging to drug delivery and therapeutics, nanotechnology is poised to change the way doctors practice medicine.

In a 1959 lecture at Caltech famously dubbed “There’s Plenty of Room at the Bottom,” American physicist and Nobel laureate–to-be Richard Feynman discussed the idea of manipulating structures at the atomic level. Although the applications he discussed were theoretical at the time, his insights prophesied the discovery of many new properties at the nanometer scale that are not observed in materials at larger scales, paving the way for the ever-expanding field of nanomedicine. These days, the use of nanosize materials, comparable in dimension to some proteins, DNA, RNA, and oligosaccharides, is making waves in diverse biomedical fields, including biosensing, imaging, drug delivery, and even surgery.

Nanomaterials typically have high surface area–to-volume ratios, generating a relatively large substrate for chemical attachment. Scientists have been able to create new surface characteristics for nanomaterials and have manipulated coating molecules to fine-tune the particles’ behaviors. Most nanomaterials can also penetrate living cells, providing the basis for nanocarrier delivery of biosensors or therapeutics. When systemically administered, nanomaterials are small enough that they don’t clog blood vessels, but are larger than many small-molecule drugs, facilitating prolonged retention time in the circulatory system. With the ability to engineer synthetic DNA, scientists can now design and assemble nanostructures that take advantage of ?Watson-Crick base pairing to improve target detection and drug delivery.

Both the academic community and the pharmaceutical industry are making increasing investments of time and money in nanotherapeutics. Nearly 50 biomedical products incorporating nanoparticles are already on the market, and many more are moving through the pipeline, with dozens in Phase 2 or Phase 3 clinical trials. Drugmakers are well on their way to realizing the prediction of Christopher Guiffre, chief business officer at the Cambridge, Massachusetts–based nanotherapeutics company Cerulean Pharma, who last November forecast, “Five years from now every pharma will have a nano program.”

#### Nano-sight

Technologies that enable improved cancer detection are constantly racing against the diseases they aim to diagnose, and when survival depends on early intervention, losing this race can be fatal. While detecting cancer biomarkers is the key to early diagnosis, the number of bona fide biomarkers that reliably reveal the presence of cancerous cells is low. To overcome this challenge, researchers are developing functional nanomaterials for more sensitive detection of intracellular metabolites, tumor cell–membrane proteins, and even cancer cells that are circulating in the bloodstream. (See “Fighting Cancer with Nanomedicine,” The Scientist, April 2014.)

The extreme brightness, excellent photostability, and ready modulation of silica nanopar­ticles, along with other advantages, make them particularly useful for molecular imaging and ultrasensitive detection.

Silica nanoparticles are one promising material for detecting specific molecular targets. Dye-doped silica nanoparticles contain a large quantity of dye molecules housed inside a silica matrix, giving an intense fluorescence signal that is up to 10,000 times greater than that of a single organic fluorophore. Taking advantage of Förster Resonance Energy Transfer (FRET), in which a photon emitted by one fluorophore can excite another nearby fluorophore, researchers can synthesize fluorescent silica nanoparticles with emission wavelengths that span a wide spectrum by simply modulating the ratio of the different dyes—the donor chromophore and the acceptor chromophore. The extreme brightness, excellent photostability, and ready modulation of silica nanoparticles, along with other advantages, make them particularly useful for molecular imaging and ultrasensitive detection.

THE NANOMEDICINE CABINET: Scientists are engineering nanometer-size particles made of diverse materials to aid in patient care. The unique properties of these structures are making waves in biomedical analysis and targeted therapy.
See full infographic: JPG | PDF

Other materials that are under investigation as nanodetectors include graphene oxide (GO), the monolayer of graphite oxide, which has unique electronic, thermal, and mechanical properties. Semiconductor-material quantum dots (QDs), now being developed by Shuming Nie’s group at Emory University, exhibit quantum mechanical properties when covalently coupled to biomolecules and could improve cancer imaging and molecular profiling.1 Spherical nucleic acids (SNAs), in which nucleic acids are oriented in a spherical geometry, scaffolded on a nanoparticle core (which may be retained or dissolved), are also gaining traction by the pioneering work of Chad Mirkin’s group at Northwestern University.2 (Seeillustration.)

Nanoparticles are also proving their worth as probes for various types of bioimaging, including fluorescence, magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). For instance, Xiaoyuan Chen, now at the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering, and Hongjie Dai of Stanford University have developed carbon nanotubes for performing PET scans in mice. When modified with the macromolecule polyethylene glycol to improve biocompatibility, the nanotubes were very stable and remained in circulation for days, far longer than the few hours typical of many molecular imaging agents.3 Further modification with a short-peptide targeting ligand called RGD caused the nanotubes to selectively accumulate in tumors that overexpressed integrin, the molecular target of RGD, enabling precise tumor imaging.

To further increase the specificity of nanodetectors, researchers can add recognition probes such as aptamers—short synthetic nucleic acid strands that bind target molecules. For example, we conjugated gold nanoparticles with aptamers that had been identified through iteratively screening DNA probes using living cancer cells.4 Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors and provide a potential target for early cancer diagnosis. However, CTCs are rare, with blood concentrations of typically fewer than 10 cells per milliliter of blood. Collaborating with physicians to profile samples from leukemia patients, we demonstrated that aptamers are capable of differentiating among different subtypes of leukemia, as well as among patient samples before and after chemotherapy (unpublished data). In addition to leukemia, we have selected aptamers specific to cancers of the lung, liver, ovaries, colon, brain, breast, and pancreas, as well as to bacterial cells. Other researchers have developed nanoparticles with numerous and diverse surface aptamers, enabling them to bind their targets more efficiently and securely.

#### Eye on the target

The prototype of targeted drug delivery can be traced back to the concept of a “magic bullet,” proposed by chemotherapy pioneer and 1908 Nobel laureate Paul Ehrlich. Ehrlich envisioned a drug that could selectively target a disease-causing organism or diseased cells, leaving healthy tissue unharmed. A century later, researchers are developing many types of nanoscale “magic bullets” that can specifically deliver drugs into target cells or tissues.

NANOCAPSULES: A false-color transmission electron micrograph of liposomes, spherical particles composed of a lipid bilayer around a central cavity that can be engineered to deliver both hydrophobic and hydrophilic drugs to specific cells in the body ©DAVID MCCARTHY/SCIENCE SOURCE

Doxil, the first nanotherapeutic approved by the US Food and Drug Administration, is a liposome (~100 nm in diameter) containing the widely used anticancer drug doxorubicin. The therapy takes advantage of the leaky blood vasculature and poor lymphatic drainage in tumor tissues that allow the nanoparticles to squeeze from blood vessels into a tumor and stay there for hours or days. Scientists have also been developing nanotherapeutics capable of targeting specific cell types by binding to surface biomarkers on diseased cells. Targeting ligands range from macromolecules, such as antibodies and aptamers, to small molecules, such as folate, that bind to receptors overexpressed in many types of cancers.

Aptamers in particular are a popular tool for targeting specific cells. Aptamer development is efficient and cost-effective, as automated nucleic acid synthesis allows easy, affordable chemical synthesis and modification of functional moieties. Other advantages include high stability and long shelf life, rapid tissue penetration based on the relatively small molecular weights, low immunogenicity, and ease of antidote development in the case of an adverse reaction to therapy by simply administering an aptamer’s complementary DNA. We have demonstrated the principle of modifying aptamers on the surfaces of doxorubicin-containing liposomes, which then selectively delivered the drug to cultured cancer cells.5

Recent advances in predicting the secondary structures of a DNA fragment or interactions between multiple DNA strands, as well as in technologies to automatically synthesize predesigned DNA sequences, has opened the door to more advanced applications of aptamers and other DNA structures in nanomedicine. For instance, we have developed aptamer-tethered DNA nanotrains, assembled from multiple copies of short DNA building blocks. On one end, an aptamer moiety allows specific target cell recognition during drug delivery, and a long double-stranded DNA section on the other end forms the “boxcars” for drug loading. The nanotrains, which can hold a high drug payload and specifically deliver anticancer drugs into target cancer cells in culture and animal models,6 could reduce drug side effects while inhibiting tumor growth. Alternatively, Daniel Anderson of MIT engineered a tetrahedral cage of DNA, often called “DNA origami,” for folate-mediated targeted delivery of small interfering RNAs (siRNAs) to silence some tumor genes.7 And Mirkin’s SNAs can similarly transport siRNAs as “guided missiles” to knock out overexpressed genes in cancer cells. Mirkin’s group also recently demonstrated that the SNAs were able to penetrate the blood-brain barrier and specifically target genes in the brains of glioblastoma animal models.2 Peng Yin of Harvard Medical School and the Wyss Institute and others are now building even more complex DNA nanostructures with refined functions, such as smart biomedical analysis.8

Conventional assembly of such DNA nanostructures exploits the hybridization of a DNA strand to part of its complementary strand. In addition, we have discovered that DNA nanostructures called nanoflowers because they resemble a ring of nanosize petals, can be self-assembled through liquid crystallization of DNA, which typically occurs at high concentrations of the nucleic acid.9 Importantly, these DNA nanostructures can be readily incorporated with components possessing multiple functionalities, such as aptamers for specific recognition, fluorophores for molecular imaging, and DNA therapeutics for disease therapy.

Another example of novel nanoparticles is DNA micelles, three-dimensional nanostructures that can be readily modified to include aptamers for specific cell-type recognition, or DNA antisense for gene silencing. The lipid core and sphere of projecting nucleic acids can enter cells without any transfection agents and have high resistance to nuclease digestion, making them ideal candidates for drug delivery and cancer therapy.

Researchers are developing many types of nanoscale “magic bul­lets” that can specifically deliver drugs into target cells or tissues.

Such advances in targeting are now making it possible to deliver combinations of drugs and ensure that they reach target cells simultaneously. Paula Hammond and Michael Yaffe of MIT recently reported a liposome-based combination chemotherapy delivery system that can simultaneously deliver two synergistic chemotherapeutic drugs, erlotinib and doxorubicin, for enhanced tumor killing.10Erlotinib, an inhibitor of epidermal growth factor receptor (EGFR), promotes the dynamic rewiring of apoptotic pathways, which then sensitizes cancer cells to subsequent exposure to the DNA-damaging agent doxorubicin. By incorporating erlotinib, a hydrophobic molecule, into the lipid bilayer shell while packaging the hydrophilic doxorubicin inside of the liposomes, the researchers achieved the desired time sequence of drug release—first erlotinib, then doxorubicin—in a one-two punch against the cancer. They also demonstrated that the efficiency of drug delivery to cancer cells was enhanced by coating the liposomes with folate.

Scientists are also engineering “smart” nanoparticles, which activate only in the disease microenvironment. For example, George Church of Harvard Medical School and the Wyss Institute and colleagues invented a logic-gated DNA nanocapsule that they programmed to deliver drugs inside cells only when a specific panel of disease biomarkers is overexpressed on the cell surface.11And Donald Ingber’s group, also at Harvard Medical School and the Wyss Institute, developed microscale aggregates of thrombolytic-drug-coated nanoparticles that break apart under the abnormally high fluid shear stress of narrowed blood vessels and then bind and dissolve the problematic clot.12

With these and other nanoplatforms for targeted drug delivery being tested in animal models, medicine is now approaching the prototypic magic bullet, sparing healthy tissue while exterminating disease.

#### Nano-fighters

In addition to serving as mere drug carriers that deliver the toxic payload to target cells, nanomaterials can themselves function as therapeutics. For example, thermal energy is emerging as an important means of therapy, and many gold nanomaterials can convert photons into thermal energy for targeted photothermal therapy. Taking advantage of these properties, we conjugated aptamers onto the surfaces of gold-silver nanorods, which efficiently absorb near-infrared light and convert energy from photons to heat. These aptamer-conjugated nanorods were capable of selectively binding to target cells in culture and inducing dramatic cytotoxicity by converting laser light to heat.13

Magnetic nanoparticles are also attractive for their ability to mediate heat induction. Jinwoo Cheon of Yonsei University in Korea developed core–shell magnetic nanoparticles, which efficiently generated thermal energy by a magnetization-reversal process as these nanoparticles returned to their relaxed states under an external, alternating-current magnetic field.14 Using this technology, Cheon and his colleagues saw dramatic tumor regression in a mouse model.
A third type of nanosize therapeutic involves cytotoxic polymers. For example, we synthesized a nucleotide-like molecule called an acrydite with an attached DNA aptamer that specifically binds to and enters target cancer cells.15 The acrydite molecules in the resultant acrydite-aptamer conjugates polymerized with each other to form an aptamer-decorated molecular string that led to cytotoxicity in target cancer cells, including those exhibiting multidrug resistance, a common challenge in cancer chemotherapy.

Many other subfields have been advanced by recent developments in nanomedicine, including tissue engineering and regenerative medicine, medical devices, and vaccines. We must proceed with caution until these different technologies prove safe in patients, but nanomedicine is now poised to make a tremendous impact on health care and the practice of clinical medicine.

Guizhi Zhu is a postdoctoral associate in the Department of Chemistry and at the Health Cancer Center of the University of Florida. Weihong Tan is a professor and associate director of the Center for Research at the Bio/Nano Interface at the University of Florida. He also serves as the director of the Molecular Science and Biomedicine Laboratory at Hunan University in China, where Lei Mei is a graduate student.

#### References

1. W.C.W. Chan, S. Nie, “Quantum dot bioconjugates for ultrasensitive nonisotopic detection,”Science, 281:2016-18, 1998.
2. J.I. Cutler et al., “Spherical nucleic acids,” J Am Chem Soc, 134:1376-91, 2012.
3. Z. Liu et al., “In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice,” Nat Nano, 2:47-52, 2007.
4. K. Sefah et al., “Development of DNA aptamers using Cell-SELEX,” Nat Protoc, 5:1169-85, 2010.
5. H. Kang et al., “A liposome-based nanostructure for aptamer directed delivery,” Chem Commun, 46:249-51, 2010.
6. G. Zhu et al., “Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics,” PNAS, 110:7998-8003, 2013.
7. H. Lee et al., “Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery,” Nat Nano, 7:389-93, 2012.
8. Y. Ke et al., “Three-dimensional structures self-assembled from DNA bricks,” Science, 338:1177-83, 2012.
9. G. Zhu et al. “Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications,” J Am Chem Soc, 135:16438-45, 2013.
10. S.W. Morton et al., “A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways,” Sci Signal, 7:ra44, 2014.
11. S.M. Douglas et al., “A logic-gated nanorobot for targeted transport of molecular payloads,”Science, 335:831-34, 2012.
12. N. Korin et al., “Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels,” Science, 337:738-42, 2012.
13. Y.-F. Huang et al., “Selective photothermal therapy for mixed cancer cells using aptamer-conjugated nanorods,” Langmuir, 24:11860-65, 2008.
14. J.-H. Lee et al., “Exchange-coupled magnetic nanoparticles for efficient heat induction,” Nat Nano, 6:418-22, 2011.
15. L. Yang et al., “Engineering polymeric aptamers for selective cytotoxicity,” J Am Chem Soc, 133:13380-86, 2011.

 Palabra(s) clave: Nanomedicine

### Naughty or Nice? One Brain Scan Is Now All It Takes to Find Out

With a simple scan of your brain at rest, scientists can now guess whether — on average — you are naughty or nice.

“We have now begun to see really strong evidence of a connection between measures of brain function, connectivity and many aspects of people’s lives and personality,” says lead author Dr. Stephen Smith, a biomedical engineer at the University of Oxford.

The surprisingly strong correlations, published last week in Nature Neuroscience, are the first to emerge from the ambitious Human Connectome Project (HCP), a global effort that seeks to map all the pathways between the brain’s hundreds of regions and millions of neurons, and then to relate those connectivity patterns to personality and behavior.

#### “I am my connectome”

The brain's complex wiring: The corpus callosum bridges the left and right hemispheres with some 200 million connections. Each wire pair here would represent approximately 1 million nerves.

So stated Dr. Sebastian Seung, a computational neuroscientist at MIT, in a 2010 TED talk that propelled the nascent field of connectomics into the public limelight. In one sentence, Seung touched on two provocative ideas.

One was philosophical: that people’s self-identity — our personality, habits, lifestyles, memories and experiences — are stored in functional connections in our brains. Disrupt the connectome (as in cases like schizophrenia), and we lose our core identity.

The other idea was more of a scientific prophecy: by advancing brain-imaging technologies, we may be able to map out the wiring of our brains in unprecedented detail. Similar to geographical maps, which allowed explorers to venture to the edge of the world, a brain atlas may push the frontier of neuroscience forward by offering an in-depth visualization of the inner workings of our minds.

“The days of just looking at one part of the brain are waning,” says Dr. Arthur Toga at the University of Southern California, a lead scientist in the HPC project.

Launched six years ago with an initial fund of 40 million, the HPC is scanning the brains of 1,200 adults with fMRI. A major branch of the project focuses on the brain at rest — that is, when it’s not concentrating on a specific task but rather allowed to wander. These “resting state connectomes” are thought to reflect how different areas of the brain are hooked up in a “locked and loaded” state, in case a sudden future task requires them to efficiently fire together. (This video a brain's connectome with diffusion MRI.) But there’s more: each brain scan is linked to reams of demographic and personality data summarized by hundreds of different traits. These range from objective measures such IQ test scores, attention span and socioeconomic status, to self-reported factors like life satisfaction, personality, and whether they had used drugs or shown physical aggression in the past. It’s a treasure trove ripe for data mining. Smith and his team dug deep. #### Good brains, bad brains The team wasn’t simply interested in relating one personality or success factor to another. From the onset, explained Smith, we wanted to use a single integrated analysis, and see whether specific brain connectivity patterns are associated with specific sets of correlated traits, either good or bad. The team took the data from 461 scans and ran a massive computer program to create an average map of the brain’s resting state across 200 different regions. Then in every participant, the scientists looked at how much those regions talked to each other, effectively charting out where the strongest links lie and what the strength of the connections are. Connectome extraction procedure: Scientists partition a brain scan into hundreds of regions, and use a technique called tractography to extract out functional connections. Finally, in a computational tour-de-force, the team added 280 different traits to the pool of brain scan data, and for each participant performed canonical correlation analysis — a type of statistical wizardry that helps unearth relationships between datasets with hundreds of complex variables. The result was stark and stunning: the brain connectivity patterns could be aligned in a single axis, where one end was associated with positive traits — such as more education, better memory and physical performance — whereas the other with negative ones, such as rule-breaking and poor sleep quality. People on the “positive” side of the axis also had stronger connectivity between brain networks associated with higher cognitive functions, including memory, language, introspection and imagination. It’s incredibly impressive, says Dr. Marcus Raichle, a neuroscientist at Washington University, that scans of the brain at rest were sufficient to condense vastly variable life experiences into a single, simple axis. With one scan, you can distinguish people with successful traits, leading successful lives versus those who don’t, he says. Obviously for each person there’s going to be an error bar in guessing who they are as a person by just looking at their brain connectivity, stressed Smith, but overall the association is very strong. #### Building a good connectome The study begs the obvious question: which way does the influence go? Are our brains’ wiring patterns leading us to success or failure in life, or are life experiences shaping the connections in our brains? For now, says Smith, we don’t know the answer, and it’s very likely that the direction of causality goes both ways. To test causality, we would need intervention studies that impose positive traits — say, enforced education — and see whether that imprints a “good” connectome on the brain. That’s in the future, but for now we can look for traits that correlate with positive brain connections, and tweak them in a way that pulls the brain towards the “positive” end of the axis. Marijuana use in recent weeks, for example, was one of the factors that drove a brain more towards the “bad” end of the axis. This suggests that pot is a negative life trait that should be prioritized for further study. But scientists caution that “good” and “bad” are relative, and must be placed into social context — is it fair to consider marijuana use for medical reasons as negative? A person’s placement on the positive-negative scale also isn’t a proxy for general intelligence. For example, people with good hand-eye coordination tended to slide towards the “bad” side of the axis. There’s so much that we still need to sort out, says Van Wedeen, a neuroscientist at the Massachusetts General Hospital. This is just a taste of what’s to come — with the HCP in full swing, it’s likely that a further deluge of data — how we develop as kids, how our brains age in health and disease — will provoke more questions than answers. But it’s a good place to start. Image Credit: Shutterstock.com; brewbooks/FlickrHagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al/Wikimedia Commons  Palabra(s) clave: Arthur Togabig databrain imagingbrain scanconnectomefmriHuman Connectome ProjectMarcus RaichleNature NeuroscienceSebastian SeungStephen SmithUniversity of OxfordUniversity of Southern California #### Neural fundamentals: Sex differences in the nervous system [1261] Male, female symbols artwork. Credit: Benita Denny / Wellcome Images ### Neural fundamentals: Sex differences in the nervous system by Laura Suen The brain is an intricate, plastic organ and scientists are only beginning to understand that differences between male and female brains are extremely complex and influenced by genetics, physiology, experience, and learning. Neuroscience research in the early 1990s focused on sexual dimorphism of the central nervous system (CNS) in terms of developmental sensitivity to hormones like estrogen, testosterone, and progesterone. This work found that during the process of sexual differentiation, regions of the brain are influenced by their hormonal environment, including their concentrations and metabolism in the CNS.1 Follow up research showed that genetic mechanisms, rather than strictly steroid-dependent ones,2 may trigger sexual differentiation of the brain.1 Approximately a decade ago, researchers Michael Rhodes and Robert Rubin realized in the course of studying the nervous system that differences between the sexes went further than sexual dimorphism. Instead of looking at just the phenotypic differences between males and females as the result of variations in function, Rhodes and Rubin coined the term ‘sexual diergism’ to describe differences in terms of physiology, biochemistry, and underlying behaviors.1 In particular, Rhodes and Rubin were interested in sex differences of the mammalian CNS and its relationship to the hypothalamic–pituitary–adrenal (HPA) axis. What they discovered was counter-intuitive: sex differences within the brain may allow male and female mammals to display remarkably similar behaviors, despite major differences in their physiological and hormonal conditions. In other words, sexual dimorphism may counteract sexual diergism. Additional studies conducted over the years have further clarified the roles of neurotransmitters and the environment in defining sex differences in the nervous system, as well as the effects of dimorphism and diergism on disease prevalence. The effect of the environment on the nervous system Research conducted by Janice Juraska at the University of Illinois concluded that the environment plays a critical role on dimorphism and differentiation of the CNS.3 More specifically, Juraska found that sexual dimorphism of the hippocampus accounts for differences in the performance of rats in maze learning, where male rats outperform females. Rat forebrain areas like the cerebral cortex and hippocampus exhibited sexual dimorphism in response to the environment: male rats had thicker dendritic branching in cortex pyramidal neurons and dentate gyral cells of the hippocampus.3 The branching in both brain areas was increased further in male rats by producing a stimulating environment, whereas this increased branching was not seen in females. These results suggest that sex differences in the size of an organism’s dendritic tree may lead to differences in how the organism interacts with its environment. Meanwhile, the environment itself also influences how each sex interacts with its surroundings. Dimorphism, diergism, and neurological disease Past studies on female rats have found that there is a higher vulnerability of the septo-hippocampal pathway to neurotoxins, which may imply a higher risk for neurological diseases.1 This finding may extend to humans. As recorded by a 2010 study done at the University of Valencia, women are more susceptible to Alzheimer’s disease, even after adjusting for the fact that females, on average, have longer life spans than males.7 According to Dr. Victor Henderson at the Stanford School of Medicine, this phenomenon could be the result of an accelerated degeneration of the CNS in women.8 In terms of other diseases, overproduction of dopamine receptors in the striatum and nucleus accumbens have been known to result in hyperactivity.1 A study conducted in the late 1990s by Dr. Susan Anderson at McClean Hospital in Massachusetts showed that overproduction of dopamine receptors in males compared to females during prepubertal development can possibly explain why more males than females are afflicted with attention-deficit/hyperactivity disorder (ADHD) and Tourette’s syndrome.9 Furthermore, differences in rates of psychiatric illness between the sexes are most pronounced before and after puberty. For females, illnesses increase dramatically after puberty while the reverse is true for males.[1] This further suggests hormones play a large role in influencing normal and pathological CNS function. Neurotransmitters and sexual diergism University of California Berkeley scientist Lynwood Clemens suggested that many behaviors which are expressed differently in male and female mammals could be the result of sexual diergism of neurotransmitter systems, or a combination of dimorphism and diergism.4 Behaviors Clemens looked at included sexual and social behavior, learning, vocalization, and regulation of food and water intake. Pharmacological studies suggest that both estrogen and testosterone (by conversion to estrogen), in addition to other neurotransmitters such as norepinephrine, can promote lordosis behavior (presenting an arched back and other postures to indicate receptivity to copulation) in rats. 4 In the late 1980s, psychologist James Pfaus also discovered beta-endorphin also might inhibit female sexual behavior.5 Currently it is well documented that the effects of castration on male sexual behavior can be reversed with both estrogen and testosterone treatments.6 Additionally, studies done throughout the 1990s suggest that serotonin and dopamine have regulatory roles: serotonin inhibits male sexual behavior while dopamine both inhibits and promotes it.1 When Rhodes and Rubin examined sexual dimorphism in the CNS in the late 1990s, they had to create a whole new term. They defined diergism as functional or physiological differences, which is oftentimes a byproduct of sexual dimorphism. Rhodes and Rubin realized that the genetics underlying sexual differences in the CNS is more complex than just steroid-dependent mechanisms and the environment plays a role in sexual differentiation as well. Current studies of dimorphism and diergism focus on furthering our understanding of the neurochemical basis of sexually dimorphic behavior and the mechanisms of disease. References • 1. Rhodes M, Rubin R. Functional sex differences (‘sexual diergism’) of central nervous system cholinergic systems, vasopressin, and hypothalamic–pituitary–adrenal axis activity in mammals: a selective review. Brain Research Reviews (1999) 30:135–152. doi: 10.1016/S0165-0173(99)00011-9 • 2. Breedlove M. Sexual Dimorphism in the Vertebrate Nervous System. The Journal of Neuroscience (1992) 12(11):4133-4142. • 3. Juraska J. Sex differences in ‘cognitive’ regions of the rat brain. Psychoneuroendocrinology (1991) 16: 109–155. • 4. Clemens L, Barr P, Dohanich G. Cholinergic regulation of female sexual behavior in rats demonstrated by manipulation of endogenous acetylcholine. Physiology & Behavior (1989) 45:437–442. • 5. Pfaus J, Gorzalka B. Opioids and sexual behavior. Neuroscience & Behavioral Reviews (1987) 11:1–34. • 6. Chen T, Wen T. Sex differences in estrogen and androgen receptors in hamster brain. Life Sciences (1992) 50:1639–1647. • 7. Vina J, Lloret A, Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. Journal of Alzheimer’s Disease (2010) 20:527-533. • 8. Henderson V, Buckwalter J. Cognitive déficits of men and women with Alzheimer’s disease. Neurology (1994) 44:90–96. • 9. Anderson S, Rutstein M, Benzo J, Hostetter J, Teicher M. Sex differences in dopamine receptor overproduction and elimination. NeuroReport (1997) 8:1495–1498.  Palabra(s) clave: gender-differencesneuroanatomyneurobiologycentral nervous system (CNS)brain developmenthormonesneurotransmitters #### Neural Stem Cells Sprout Long Axons [719] #### Neural Stem Cells Sprout Long Axons Early neurons reprogrammed from human skin cells show unprecedented axonal growth in a rat model of spinal cord injury. By Jyoti Madhusoodanan Human embryonic stem cells | PLOS BIOLOGY, EUGENE RUSSO Stem cells derived from the skin of an 86-year-old man show a surprising capacity to survive and form long axons at the site of a spinal cord injury in rats. The results, published today (August 7) inNeuron, suggest that even induced pluripotent stem cells (iPSCs) reprogrammed from aging human cells have an intrinsic ability to overcome inhibitory factors to form neurons and extend axons. A rat neuronal stem cell (NSC) line had previously shown similar potential for regrowth: a 2012 study from the same research group demonstrated that rat NSCs could form axons that travelled great distances within rodent brains and spines, and restore movement to limbs after a spinal cord injury. “Both studies are very provocative in terms of the amount of axon growth observed,” said neuroscientist Philip Horner of the University of Washington, who studies axonal regeneration but was not involved with the study. “The questions that the paper raises, however, are whether this is good and controllable [growth].” Stem cell-based therapies hold tantalizing promise for treating spinal cord injuries. Previous studies have shown neural stem cells can extend axons far across lesions, remyelinate axons surrounding sites of partial injuries, and protect and restore conductivity across an injury. These properties raise intriguing prospects for experimental treatments. But suppressing a host’s immune system is crucial to the success of NSC grafts, and immunosuppression can pose high risks to patients already suffering spinal cord damage. Mark Tuszynski and Paul Lu of the University of California, San Diego, sought to circumvent this need for immunosuppression by using iPSCs, which can be derived from a patient’s own skin and, eventually, autotransplanted. The researchers began by transducing dermal fibroblasts from a healthy subject with retroviral vectors to induce stem cell formation. NSCs derived from this process were implanted in a fibrin matrix infused with a cocktail of growth factors. These human iPSC-turned-NSCs were then grafted into rats two weeks after a spinal cord injury. Three months after the stem cell transplant, axons derived from these early neurons were seen extending out of the lesion over long distances, reaching the brain and olfactory bulb, and the distal lumbar spine. The axons “essentially extended the entire length of the adult rat neuraxis,” the authors wrote in their paper. The NSC axons seen in this study were twice as long and approximately 41 percent more abundant than the axons derived from rat neural progenitor cells in the researchers’ previous work. “It’s a remarkable phenomenon that raises many basic neurobiological questions, [such as] whether we can try and modify adult injured neurons to behave similarly,” said Tuszynski. The results hint at a cellular phenotype that can overcome factors that inhibit cellular regrowth in spinal cord injury. “The question, to me, is to dial in and begin to understand what that neuronal phenotype is, and what those cells express,” said Horner. “Then we might be able to take components of that and engineer [better] transplants.” Unlike rat-derived axons, the human axons the researchers observed in the present study were not myelinated. Despite their proliferation in rats, these neurons did not improve limb movements impaired by the spinal cord injury. Tuszynski suggested several possible explanations for the lack of functional recovery beyond the lack of myelination, including cellular immaturity and the complexity of the movement that was tested. The experiments “show very robust engraftment and excellent axonal growth,” said neurobiologistBrian Cummings of the University of California, Irvine, who was not involved in the work. However, he added, “some of those pathways may be abnormal, so these cells may be surviving too well.” The researchers also observed the human iPSC-turned-NSCs spreading near the site of the graft, a sign of overgrowth. Although the spread did not cause abnormal symptoms, the researchers’ previous work demonstrated that rat NSCs formed ectopic masses of cells—or teratomas—in vivo, which had the potential to damage brain structures. “Before we can think about translation, there are several things we need to consider,” said Tuszynski. “For example, how stable these connections are, whether we can guide these axons, and that no teratomas are formed.” “It’s a very interesting and exciting first step,” said Cummings. “But they still need to figure out how to get iPS cells to cause functional recovery, and also how to control [cell] growth.” P. Lu et al., “Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury,” Neuron, doi:10.1016/j.neuron.2014.07.014, 2014.  Palabra(s) clave: Neural Stem CellsLong Axons #### Neurobiología: Entre la Juventud y la Senectud [686] #### Video: "Entre la Juventud y la Senectud" #### Neurobiological basis for tradeoff between honesty, self-interest [826] Digitally colored, superior view of the human brain. Credit: Heidi Cartwright / Wellcome Images ### Scientists find possible neurobiological basis for tradeoff between honesty, self-interest #### Average person usually averse to lying, researchers say What's the price of your integrity? Tell the truth; everyone has a tipping point. We all want to be honest, but at some point, we'll lie if the benefit is great enough. Now, scientists have confirmed the area of the brain in which we make that decision. The result was published online August 31 in Nature Neuroscience. "We prefer to be honest, even if lying is beneficial," said Lusha Zhu, the study's lead author and a postdoctoral associate at the Virginia Tech Carilion Research Institute, where she works with Brooks King-Casas and Pearl Chiu, who are assistant professors at the institute and with Virginia Tech's Department of Psychology. "How does the brain make the choice to be honest, even when there is a significant cost to being honest?" Previous studies have shown that brain areas behind the forehead, called the dorsolateral prefrontal cortex and orbitofrontal cortex, become more active during functional brain scanning when a participant is told to lie or to be honest. But there's no way to know if those parts of the brain are engaged because an individual is lying or because he or she prefers to be honest, King-Casas said. This time, researchers asked a different question. "We asked whether there's a switch in the brain that controls the cost and benefit tradeoff between honesty and self-interest," Chiu said. "The answer to this question will help shed light on the nature of honesty and human preferences." Researchers compared the decisions of healthy participants with decisions made by participants with damaged dorsolateral prefrontal cortices or orbitofrontal cortices. The team, including scientists from the Virginia Tech Carilion Research Institute and the University of California at Berkeley, had volunteers decide between honesty and self-interest in an economic "signaling game," which has been extensively studied in behavioral economics, game theory, and evolutionary biology. In one game, the researchers presented participants with an option that gave them more money at a cost to an anonymous opponent, and an option that gave the opponent more money at a cost to the participant. Unsurprisingly, participants chose the option that filled their own pockets. In a different game, the researchers presented participants with the same options and but asked the participants to send a message to their opponents, recommending one option over the other. The participants either lie and reap the reward, or tell the truth and suffer a loss. "The average person usually shows lie aversion," Zhu said. "If they don't need to send a message, they prefer the option that gives them more money. If they do need to send a message, they're more likely to send a message that will benefit the other person even at a loss to themselves. They want to be honest, at the cost of their own wallet." Participants with damage in the dorsolateral prefrontal cortex were not as averse to lying as the two comparison groups. They were more likely to pick the practical option and were less concerned about the potential cost to self-image. In the game where no message was required, however, participants with dorsolateral prefrontal cortex damage showed the same pattern of decision-making as the comparison groups, suggesting that for each group, the baseline tendency to give to others is the same. "These results suggest that the dorsolateral prefrontal cortex, a brain region known to be critically involved in cognitive control, may play a causal role in enabling honest behavior," Chiu said. "People feel good when they're honest and they feel bad when they lie," King-Casas said. "Self-interest and self-image are both powerful factors influencing a person's decision to be honest." Previous studies, according to King-Casas, were unable to control for an important distinction. "In past studies, participants are typically instructed by the experimenter to lie or be honest. There's no consequence for lying; the subject is just complying," said King-Casas. "One of the real strengths of our study is that we're able to see how a person's tradeoffs change when we add in responsibility." Another strength is the measurable tradeoff – when will an honest person decide the benefit is worth the lie? "We manipulated the costs and benefits of honesty to quantify the tipping point for each person," said Chiu. "We picked tough dilemmas where, for example, telling a lie might harm the other player one cent, whereas being honest will cost you20. And you might decide that being seen as an honest person is worth more than $20, so you won't lie even though it costs you, or you might decide that one cent of harm isn't so bad." The study sheds light on the neuroscientific basis and broader nature of honesty. Moral philosophers and cognitive psychologists have had longstanding, contrasting hypotheses about the mechanisms governing the tradeoff between honesty and self-interest. The "Grace" hypothesis, suggests that people are innately honest and have to control honest impulses if they want to profit. The "Will" hypothesis holds that self-interest is our automatic response. "The prefrontal cortex is key to controlling our behavior and helps to override our natural impulses to be either honest or self-interested," King-Casas said. "Knowing this, we can test whether 'Grace' or 'Will' is dominant. By including participants with lesions in the prefrontal cortex, we were able to test whether honesty requires us to actively resist self-interest – in which case disrupting the prefrontal cortex would reduce the influence of honesty preferences – or whether we are automatically predisposed toward honesty, in which case disrupting the prefrontal cortex would instead enhance honest behavior. And our results show a necessary role for prefrontal control in generating honest behavior by overriding our tendencies to be self-interested. "Our next step will be to combine functional brain imaging with economic modeling to understand how the brain computes the tradeoff between the costs and benefits of lying," King-Casas added. "Then we can begin to understand the nature of honesty." Note: Material may have been edited for length and content. For further information, please contact the cited source. Virginia Tech - Original reporting by: Ashley Wenners Herron Publication Lusha Zhu, Adrianna C Jenkins, Eric Set, Donatella Scabini, Robert T Knight, Pearl H Chiu, Brooks King-Casas, Ming Hsu. Damage to dorsolateral prefrontal cortex affects tradeoffs between honesty and self-interest. Nature Neuroscience, Published Online August 31 2014. doi: 10.1038/nn.3798 Tags  Palabra(s) clave: neurobiological basistradeoff between honesty, self-interest #### Neurociencia Cognitiva: ¿una ciencia base para la psicología? [617] #### La neurociencia cognitiva ¿una ciencia base para la psicología? por Fernando Maureira Para algunos autores la psicología se encuentra en un estado de pre-ciencia ya que carece del marco teórico necesario para sustentar su accionar. Por otra parte, hay quienes postulan que la neurociencia cognitiva, como la ciencia que trata de entender la relación entre la función cerebral y los estados mentales, debe constituirse como la base teórica y empírica de la psicología. De esta forma, se vuelve posible generar un vocabulario científico adecuado que permita explicar los procesos psicológicos, que se convierte en la necesidad más apremiante para elaborar un marco teórico en psicología. Resulta fundamental integrar las neurociencias cognitivas a la formación de los psicólogos como base para su futura práctica clínica. Sin duda que la neurociencia cognitiva debe convertirse en la base científica que justifique el quehacer de la psicología. Ver documento adjunto.  Palabra(s) clave: NEUROCIENCIAPSICOLOGÍA #### Neurociencia y los Textos Sagrados [908] #### Los textos sagrados y las neurociencias ### Isaías y la Neurociencia Social “Compartir tu pan con el hambriento y albergar a los pobres sin techo, cubrir al que veas desnudo y no despreocuparte de tu propia carne. / Entonces despuntará tu luz como la aurora, y tu llaga no tardará en cicatrizar, delante de ti avanzará la justicia y detrás de ti irá la gloria del Señor. / Entonces llamarás, y el Señor responderá; pedirás auxilio, y el dirá: ¡Aquí estoy! Si ofreces tu pan al hambriento, y sacias al que vive en la penuria, la luz se alzará en las tinieblas y tu oscuridad será como el mediodía” Is. 58, 7 – 10 Resulta llamativo recurrir a un texto sagrado para vincular con los nuevos hallazgos en el campo de la Neurociencia Social, es cierto. Sin embargo, traer desde la memoria remota contenidos de la sabiduría humana de la antigüedad resulta un modo muy poderoso de constatar que los mecanismos que hoy se descubren y aparecen a la luz de la ciencia y la divulgación científica, fueron y son de práctica habitual entre los seres humanos de todas las épocas. De hecho recientemente leí un atinado artículo en el que se recurre a textos talmúdicos y a experiencias de rabís con el fin de instruir a estudiantes de medicina en la práctica de las entrevistas médicas, con el fin de desarrollar un mayor nivel de empatía y de pensamiento integrador. Vale decir entonces que, recurrir a estos textos, tiene ventajas nada despreciables: despiertan nuestra atención, condensan sabiduría de siglos, y permiten que al vincularlos con conocimientos actuales desarrollemos nuestro propio pensamiento integrador. Debo destacar una ventaja adicional: nos advierte que la historia humana no comenzó con nosotros, que el homo sapiens ha desarrollado una sabiduría eficaz y eficiente aún antes de que naciera lo que hoy conocemos como ciencia, y que la sabiduría de los siglos bien puede ser integrada lo que redunda necesariamente en una potenciación de los saberes y vuelve más poderosos nuestros propios fundamentos. Niveles de análisis: El sustancioso texto de Isaías acepta por lo menos tres niveles de análisis. El primero de ellos es el del contenido teológico al que incluso podríamos llamar religioso sin caer en una confusión de ambos términos. En este nivel, se pondera la interacción humana a la luz de la mirada de lo sagrado que valora en grado sumo el servicio que los hombres se prestan entre sí. Esa actitud servicial posee su mérito y promueve una respuesta amorosa de Dios que se congracia con los hombres manifestándoles su complacencia. Estas actitudes serán aún más fomentadas en el Evangelio, dándoles valor de obras de misericordia, siendo especialmente destacadas en la parábola del Buen Samaritano en donde se identifica al otro necesitado como al genuino prójimo / próximo. Un segundo nivel de análisis es el sociológico. El cuidado, la atención por aquel que pertenece a la misma comunidad o grupo, contribuye a la consolidación del tejido social. Quien auxilie a un prójimo acuciado por algún tipo de necesidad, colabora con el restablecimiento de un miembro de la comunidad, fortaleciendo de ese modo a la totalidad del grupo. Esa actitud merece el agradecimiento y el reconocimiento del resto de la sociedad que ambos contribuyen a constituir. Finalmente podemos considerar el nivel de existencia. El hombre es quien es, sólo en el seno de un grupo en el que es reconocido, nombrado y distinguido. El hombre no existe en soledad, depende de una comunidad en cuyo seno nace, se desarrolla y muere, no sólo como una entidad biológica que cumple su ciclo vital, sino como integrante de un mundo social en el que ocupa un lugar único al que accede rodeado del cuidado de una madre, la contención de una familia, protegido y circunstanciado en el seno de un grupo social en el que es reconocido por su nombre. Nos concedemos la licencia de denominarlo nivel de existencia, pues en el cuidado del otro que implica su reconocimiento como un genuino otro, el yo se edifica y fortalece al punto de poseer una auto y hétero confirmación de su propia existencia. El ser humano ‘es’ en el ‘mundo’ en la medida en que su singularidad ha sido iniciada, sostenida y fomentada por una serie más o menos extensa de otros. Podríamos decir que el ser humano, es el resultado de las interacciones humanas de las que participó a lo largo de su existencia. Su dotación genética originalmente única, redobla la apuesta de singularidad al estar expuesta a los cambios epigenéticos provocados por el ambiente físico / geográfico, por las circunstancias históricas / biográficas, y por el contacto ininterrumpido con los otros hombres constituidos en grupo, por lo tanto, rodeado de un ‘mundo’ social cultural y normativamente diferenciado y diferenciante. Ese es el ser humano que, al decir de Isaías mediante una sencilla inferencia del tipo p entonces q, se siente confirmado en su existencia gracias a sus acciones generosas: “Si ofreces tu pan al hambriento, y sacias al que vive en penuria, (entonces) tu luz se alzará en las tinieblas y tu oscuridad será como el mediodía”. Si cuidas de tu prójimo, entonces serás reconocido como el que eres. Siempre es conveniente recordar que las cosas pueden ser de otro modo. El carácter de recomendación enfática, casi de mandato, que el texto de Isaías posee, está determinado justamente por la posibilidad humana de hacer todo lo contrario a lo indicado. Es preciso tener acceso a lo íntimamente humano como para humillar, torturar, envilecer y aniquilar a otro ser humano. Los mismos mecanismos que nos acercan a los hombres, nos separan de ellos. El odio racial, la exclusión definitiva del otro, presupone el reconocimiento de la diferencia y la confirmación de su existencia. El ser humano es capaz de aniquilar a ese único otro que, entre las nebulosas de la miseria y la negrura del odio, reconoce y afirma su existencia. Es decir cometer el crimen más absurdo, hacer desaparecer a aquel gracias al cual mi identidad original estaba asegurada. La introducción de este párrafo se funda en que es conveniente anunciar la propia pérdida de la inocencia. Habiendo sido ciudadanos del siglo XX, debemos reconocer en el hombre toda su abnegación y a la vez toda su abyección, además es preciso, a los fines del presente escrito, destacar que ambas se fundan en los mismos mecanismos subyacentes. Hecha esta salvedad, continuemos con nuestro recorrido. Hacia la Neurociencia Social: Matt Lieberman, acaso el neurocientífico social de mayor vigencia en la actualidad, en la introducción de su libro “Social” de reciente aparición detalla algunos aspectos que podemos, a nuestros fines considerar básicos. Hace un pormenorizado recorrido sosteniendo la afirmación básica de la obra: “Somos criaturas sociales, aún más de lo que nos atrevemos a reconocer” Es una elaborada y concienzuda publicación de la cual sólo destacaremos algunos aspectos rudimentarios. "El éxito evolutivo del Homo Sapiens se funda en esta habilidad de pensar socialmente" El autor refiere que son tres los procesos adaptativos ocurridos en nuestros cerebros que nos capacitan para conectar con el mundo social, y en él obtener un lugar desde el cual disfrutar de las ventajas de la inserción en grupos y organizaciones, a las cuales además contribuimos a edificar más sólidamente: La superposición neural de los sistemas del dolor físico con los del malestar social. Esa realidad facilita los procesos empáticos ya que las experiencias que a otros les ocurren pueden ser traducidas en nuestro propio sistema neural de acuerdo a nuestras experiencias previas y las sensaciones de dolor físico o social que pueden producirnos. Ello significa que podemos entender en nuestro propio sistema los sufrimientos ajenos, y además que las experiencias de dolor social, como la exclusión, el castigo o la vergüenza son registradas por regiones cerebrales comunes con las que registran el dolor físico. Podemos entender empáticamente el dolor físico del otro cuando se golpea el dedo con un martillo o se cae de una bicicleta, es como si nos doliera a nosotros. Asimismo nos resulta posible entender el dolor social del otro cuando resulta ser un marginado social, un habitante de la calle, o ha sufrido la pérdida de un ser querido. En nuestro cerebro se activan los centros del dolor cuando vemos que alguien es menospreciado o sometido a una situación vergonzante. Lo que afirma Lieberman es que ese proceso empático, localizado en centros comunes al dolor físico y dolor social es que efectivamente podemos ponderar, en grados de dolor personal, las experiencias negativas de los demás. Sea por manifestaciones de displacer o por explosiones de alegría de personas o grupo de personas, somos influidos en nuestro propio estado anímico y también en los comportamientos que puedan surgir a partir de ellos. Lo más probable es que reaccionemos con pánico ante una situación que produce pánico generalizado, es altamente posible que acompañemos con una sonrisa la explosión de alegría de un grupo de personas que asiste a una situación placentera. Es decir, somos muy propensos al contagio social, y ese contagio no sólo se produce por solidaridad cognitiva o adhesión simpática, sino porque áreas vinculadas con el placer y el displacer físico y social se hallan en una vinculación muy estrecha, es más, de acuerdo a lo afirmado por Lieberman, son las mismas. Los pensamientos, los sentimientos y las personalidades son entidades invisibles que sólo pueden ser inferidas por nosotros. Lo interesante es que nuestra capacidad de inferencia de esos estados, al contar con un aparato cerebral de alta sensibilidad, tiene muchas posibilidades de resultar acertada. Afirma Lieberman que el éxito evolutivo del Homo Sapiens se funda en esta habilidad de pensar socialmente. Para ampliar y aclarar podemos ir adelantando conceptos que contextúan lo dicho y a la vez anticipan lo por venir. “Los procesos psicosociales (también llamados en conjunto Cognición Social) Tienen que ver básicamente con el entendimiento de lo que hacen los demás y de sus estados mentales. Este proceso comienza con la percepción de los rostros, cuerpos y acciones de los otros. Con base en la percepción de estos estímulos visuales inferimos además que sus acciones poseen intencionalidad, y que tienen, como nosotros, estados mentales privados.” Esto puede ser denominado estado de conexión entre los integrantes de la especie, situación que puede ser extendida a la mayoría de los mamíferos, sobre todo aquellos que tienen hábitos gregarios o emprenden con frecuencia acciones colectivas. Es propio también del estado del niño humano a poco de nacer y hasta más o menos el año de vida. Se trata de un estado fundamentalmente egocéntrico basado en el reconocimiento del otro y en la necesidad que se tiene de él a la hora de acometer acciones conjuntas o de recibir cuidado cuando es necesario que así acontezca. Nuestra capacidad de leer la mente de los otros "Nuestros cerebros están equipados para detectar signos y efectuar inferencias que nos permitan ‘leer’ la mente de nuestros congéneres" Saber lo que el otro piensa y poder anticiparnos en su toma de decisiones es el sueño de todo ser humano en medio del mundo. Para quien efectúa una negociación, define una táctica militar, programa una acción de juego en cualquier deporte, conocer lo que el contrincante hará representa una ventaja no sólo considerable sino definitiva. Nuestros cerebros están equipados para detectar signos y efectuar inferencias que nos permitan ‘leer’ la mente de nuestros congéneres. Poder efectuar dicha lectura, sin lugar a dudas representa una ventaja evolutiva que parece haberse inaugurado en nuestro planeta con la aparición de los primates. Sin embargo, en el ser humano ha alcanzado sus mayores niveles de sensibilidad y definición. Nuestros cerebros no sólo están capacitados para entender conductas de los otros, predecir acciones, compartir acciones coordinadas, sino que va más allá. Nuestro cerebro nos capacita para acceder de manera conjetural al sistema de valores de nuestros congéneres, incluso a su universo de creencias. “Según algunas investigaciones recientes en neurociencia cognitiva, entendemos las acciones de los demás porque la observación de éstas provoca que en nuestros cerebros se activen representaciones motoras de las mismas acciones.” Ya han pasado más de dos décadas desde que científicos italianos descubrieran, en el cerebro de monos, las tan célebres neuronas en espejo. Ese sistema de imitación especular de características motoras fue luego asimilado al cerebro humano en una región de la corteza premotora denominada F5. Las expectativas que rodearon al descubrimiento de las neuronas espejo como modo explicativo sólido y completo acerca del proceso empático, parece no haber satisfecho tanto entusiasmo. Hoy se entiende que hay mecanismos espontáneos tanto de tipo motor como sensitivos que se activan despertando similitud empática inmediata, sin embargo se entiende que el conjunto de los procesos de relacionados con la empatía y la imitación social, se basan en complejos mecanismos en los cuales están incluidos la proximidad afectiva de las personas, sus interacciones previas y, fundamentalmente el contexto general y particular en el que se realiza la interacción. Es decir, el proceso de ‘lectura’ mental implica todo un intrincado sistema que compromete a diversas áreas cerebrales y es capaz de proveernos de una información valiosa y detallada acerca de los estados mentales de otros individuos, así como de su complejo entramado cultural, contexto normativo, gustos personales, escala axiológica y creencias. Esa realidad nos otorga una idea concreta acerca de quién tenemos en frente y cuál puede ser nuestro modo de acción más eficaz para el éxito del valor social. "Somos lo que son los otros" Somos nuestros valores y creencias sin embargo podemos hablar de una ‘inoculación’ durante toda nuestra vida con los valores y creencias de las otras personas. Por lo tanto de algún modo y en una nueva y original síntesis, somos lo que son los otros. “Las investigaciones han dejado en claro que la autoconciencia no puede explorarse sin atender a la conciencia que tenemos de los demás. De hecho la investigación en neurociencias cognitivas ha mostrado que las representaciones a nivel neuronal que tenemos de nosotros mismos y de los demás se superponen, lo que ha conducido a la sugerencia de que a nivel neuronal existen representaciones compartidas yo – otro. Nuestras decisiones y acciones están condicionadas y coordinadas con las acciones de los otros, nos retroalimentamos de los otros para conseguir un aceptable entendimiento de nosotros mismos. Sobre la base de ello, y confiados en nuestra Teoría de la Mente (ToM) damos sentido a las acciones de las otras personas y regulamos las nuestras atentos a una armonización de los grupos sociales que integramos. El Dr. Mattheuw D. Lieberman en su citado libro “Social” se atreve a efectuar una afirmación plena de sentido y de alto valor descriptivo: “Mi yo se parece más a una superautopista para la influencia social, que a esa impenetrable fortaleza que pensamos ser”. Conviene aclarar que la Neurociencia Social tiene una pretendida capacidad explicativa que es menester considerar que se realiza en un multinivel que puede llegar a confundir y a sacar conclusiones apresuradas. Nos estamos refiriendo a que estamos valorando simultáneamente el nivel molecular, el celular, el tisular, el orgánico, el personal y en sistema social. En ese contexto es muy importante no caer en reduccionismos ni en determinismos eliminativistas apresurados. Es menester ser conscientes del nivel en el que se halla nuestra fuente de información, y a partir de ello realizar inferencias a otros niveles con un cuidado extremo. Desde el punto de vista epistemológico es una advertencia que es necesario efectuar con el fin de evitar afirmaciones aventuradas e irresponsables. El universo de las Neurociencias Sociales es inmenso y variadamente multidisciplinario, por lo tanto riquísimo para el intercambio de saberes, para efectuar síntesis creativas, pero peligroso para realizar aseveraciones conclusivas con pretensiones de afirmaciones definitivas. Armonización Social Finalmente, en su tercer estadio Lieberman propone una adaptación cerebral que se hace presente en los seres humanos después de los 11 años de edad y se desarrolla durante la adolescencia y la adultez. Esta adaptación es, además, propia de los seres humanos y consiste en lo que él denomina "armonización". Se trata de un estado en el cual nuestro self que como hemos destacado, es socialmente muy maleable, puede llevarnos a asistir y cooperar con los otros incluso contra nuestros propios intereses y prioridades. “La sensación de self (ser uno mismo) es el más reciente regalo que de la evolución, los humanos hemos recibido. Si bien el self puede ser distinguido como un mecanismo para distinguirnos de los otros y de ese modo acentuar nuestra particular originalidad, en realidad realmente opera como una poderosísima fuerza de cohesión social. Mientras la conexión se refiere a nuestro deseo de ser social, la armonización se refiere a las adaptaciones neurales que permiten que los valores y creencias del grupo influyan en nosotros mismos.” Se trata de un paso inmenso en pos de la cohesión social, ya que permite un posicionamiento que permite el desplazamiento del Yo al Nosotros en el contexto social. Permite la creación consensuada de normas y códigos de convivencia y a la vez nos capacita para saltar por sobre lo que se halla consensuado para ir en beneficio del otro sin priorizar el interés propio, es más priorizando el interés del otro. Nos permite saltar de una justicia basada en la equidad distributiva a una justicia basada en el amor. Nos habilita a superar las premisas clásicas y las éticas normativa y utilitarista a una ética de la virtud. “Incluyen no sólo la red de la cognición social, sino una red de ‘mentalización’ (intuir lo que los otros piensan) y una de ‘armonización’ (usar el autocontrol para no alienar a los demás).” Llegados a este punto del presente texto, podemos considerar pertinente incursionar en toda la bibliografía generada por la Filosofía del Diálogo (G. Marcel, M. Buber, Rosensweig, y tantos otros). Soportados en estas consideraciones procedentes desde las Neurociencias Sociales, nos podemos atrever a enunciar algunos rasgos de las más genuinas manifestaciones humanas. Martin Buber fué un pensador judío que nació en Austria y más tarde se fue a vivir a Israel, es famoso por su Filosofía de las Relaciones. Sus escritos tuvieron impacto en varios campos del saber, como la filosofía, la psicología, el asesoramiento filosófico y la religión. También ha tenido notable influencia en la Teoría de la Comunicación Humana, y resulta ser un referente en la construcción de una ética de la interacción entre los seres humanos. A diferencia de muchos otros pensadores, Buber prevé la transformación de sí que, no es una transformación interior. No es un cambio dentro de mí (self), sino entre yo y los demás. Esto es así porque, según él, las relaciones son un aspecto central de lo que somos. Una persona nunca es un átomo aislado, sino que siempre es una “persona-en-relación”. La identidad personal se basa en las relaciones con los amigos y miembros de la familia, con compañeros y vecinos, con árboles, animales, naturaleza, incluso con Dios. Estas relaciones son una parte esencial de lo que el ser humanos es, no puede estar separado de ellas. Puesto en palabras propias del presente escrito, el ser humano ‘es’ en relación con los otros, el ser humano ‘es’ un ser social. Gracias a nuestra dotación neural nuestro ‘si mismo’ se va edificando en la capacidad de conexión con el otro y en la capacidad de ‘leer’ la mente de los demás y se manifiesta de manera plena en la armonización que se produce en el contexto social humano. El ser humano en ese contexto social, se manifiesta como el ‘animal social’ al que Aristóteles hacía referencia, en el que sin dejar de lado la introspección como fundamentación del self, se solidifica y prioriza la interacción como fundante de ese mismo ‘Self’. Buber distingue entre dos tipos de relaciones: Yo-Ello y Yo-Tú. En las relaciones Yo-Ello, nos referimos a la otra persona como un "Ello", como una cosa. Es considerada como algo que está ahí delante, como algo sobre lo cual se puede pensar, algo que experimento o conozco, manipulo, deseo, o trato de ayudar o explotar. Si, por ejemplo, pensamos: "Me pregunto cómo se siente ahora", entonces estamos en una relación Yo-Ello. Por el contrario, Yo-Tú es una relación de cercanía, de estar juntos. En las relaciones Yo-Tú en las que yo estoy con la otra persona (o con un animal, un árbol, etc.) Yo no trato de entenderlo, Yo no lo uso, Yo no lo experimento, Yo no lo examino desde la distancia. No usamos instrumentos de medida ni lo sometemos a comparaciones, no usamos adjetivos de calidad ni de cantidad. Estoy totalmente junto con él, y no hay ninguna distancia que nos separe entre nosotros. Aunque continuamos siendo dos personas y no una (las relaciones sólo pueden existir entre dos individuos diferentes), estamos plenamente el uno con el otro. Esta cercanía implica todo mi ser, a diferencia de las relaciones “Yo-Ello” que involucran sólo a una parte limitada de mí: sólo mi pensamiento, por ejemplo, o sólo la curiosidad, la necesidad, la utilidad, la ventaja, etc. “Así como una melodía no está compuesta por tonos, ni un poema está compuesto por palabras, ni una escultura está compuesta por líneas… Así pasa con el ser humano a quien yo le digo: Tú. Puedo abstraer de Él el color de su pelo o el color de su habla o el color de su bondad… pero entonces Él inmediatamente dejaría de ser Tú.” Concluyendo: Hemos hecho un recorrido multidisciplinario. Hemos partido de un texto religioso, transcurrimos por afirmaciones y constataciones científicas de la Neurociencia Social, finalmente hemos recurrido a aportaciones filosóficas y éticas. ¿Es que es correcto hacer esta mixtura? Desde el punto de vista de un texto científico se trata de una desprolijidad y de una riesgosa mezcla de saberes que no necesariamente pueden se traducidos o vinculados sin correr graves peligros semánticos. Somos conscientes de eso, pero nos aferramos a las ventajas de un ensayo, es decir, crear un texto que ponga de manifiesto las reflexiones y sentimientos del autor con la mayor creatividad y libertad expresiva. Ahora volvamos a Isaías: Podemos ahora reencontrarnos y asignar una nueva significación al texto de Isaías. Nos resulta posible entrever los tres niveles asignados en el comienzo, y complementarlos con los contenidos provenientes de las neurociencias. De ese modo registramos el nivel del reconocimiento básico del otro en tanto posibilitador de mi propia identidad. Un nivel para el cual la neurociencia afirma que nacemos con la dotación suficiente y necesaria para comenzar, en la jerga neurocientífica decimos que ‘venimos cableados’ para lograr de manera eficaz y eficiente la conexión esencial. Reconocemos en segundo lugar el nivel de la conexión social, el que habíamos denominado sociológico. Aquel que permite la lectura de la mente de los otros, la detección de la intencionalidad y la previsibilidad de sus acciones. Podríamos además llamarlo el nivel del acuerdo y la convivencia. En él se edifican los códigos y las normas que permiten asegurar una convivencia relativamente pacífica que fomente la humanidad de los que concurren al acuerdo. Un nivel de riesgo, en el que pueden ocurrir profundas e insalvables diferencias que acaso deriven en explosivas pujas de poder, y en la mutua aniquilación. Por fin, advertimos el nivel que denominamos teológico, en el que impera el reconocimiento del otro más allá de lo pragmático y utilitario, y más allá de lo acordado y de las obligaciones contraídas. Es el nivel del amor, en donde palabras como culpa, justicia, castigo, equidad, propiedad, libertad, adquieren una nueva dimensión bajo el signo del amor y la responsabilidad. Es el momento en el que el Rostro del otro acontece y me lanza un imperativo – ¡no me mates! – y tal como lo afirmaba Emmanuel Levinas se inaugura el espacio – tiempo de la ética de la responsabilidad y el amor. Dr. Ricardo T. Ricci Médico Clínico Médico asistencial de ASPE (UNT) Profesor Adjunto de Epistemología Médica. Sec. De Posgrado de la Facultad de Medicina (UNT). A cargo del dictado de la materia en la Carrera de Especialización en Docencia Universitaria y en el Doctorado Estructurado en Medicina. Profesor Titular Interino de Antropología Médica. Fac. de Medicina de la UNT. Profesor de Bioética en la Licenciatura de Fonoaudiología (Convenio FM – UNT / Decroly) Director de la Unidad de Formación en Docencia Universitaria, área Antropología Médica. Director del Proyecto de Formación de Recursos Humanos en el tema: “Los Sistemas Complejos Adaptativos y su aplicación a la Relación Médico – Paciente” (2008) Director del Proyecto de Formación de Recursos Humanos en el tema: “Evaluación de la calidad educativa en la Facultad de Medicina – UNT” Director suplente del Departamento de Salud Mental, Ciencias Sociales y Humanidades Médicas de la Fac. de Medicina de la UNT Miembro del Instituto de Epistemología de la Fac. de Filosofía y Letras de la UNT. Docente autorizado de Epistemología Médica. Secretario de la Asociación Argentina de Ciencias del Comportamiento (AACC)  Palabra(s) clave: NeurocienciaTextos Sagrados #### Neurociencias [609] #### "En el siglo XXI, la biología de la mente será un fenómeno análogo al de la biología del gen en el siglo XX ..." In search of memory, the emergence of a new Sciencia of Mind / Erik R. Kandel (2006) Las neurociencias son un conjunto de disciplinas científicas que estudian la estructura y la función, el desarrollo de la bioquímica, la farmacología, y la patología del sistema nervioso y de cómo sus diferentes elementos interactúan, dando lugar a las bases biológicas de la conducta. El estudio biológico del cerebro es un área multidisciplinar que abarca muchos niveles de estudio, desde el puramente molecular hasta el específicamente conductual y cognitivo, pasando por el nivel celular (neuronas individuales), los ensambles y redes pequeñas de neuronas (como las columnas corticales) y los ensambles grandes (como los propios de la percepción visual) incluyendo sistemas como la corteza cerebral o el cerebelo, y, por supuesto, el nivel más alto del Sistema Nervioso. En el nivel más alto, las neurociencias se combinan con la psicología para crear la neurociencia cognitiva, una disciplina que al principio fue dominada totalmente por psicólogos cognitivos. Hoy en día, la neurociencia cognitiva proporciona una nueva manera de entender el cerebro y la conciencia, pues se basa en un estudio científico que une disciplinas tales como la neurobiología, la psicobiología o la propia psicología cognitiva, un hecho que con seguridad cambiará la concepción actual que existe acerca de los procesos mentales implicados en el comportamiento y sus bases biológicas. Las neurociencias ofrecen un apoyo a la psicología con la finalidad de entender mejor la complejidad del funcionamiento mental. La tarea central de las neurociencias es la de intentar explicar cómo funcionan millones de células nerviosas en el encéfalo para producir la conducta y cómo a su vez estas células están influidas por el medio ambiente. Tratando de desentrañar la manera de cómo la actividad del cerebro se relaciona con la psiquis y el comportamiento, revolucionando la manera de entender nuestras conductas y lo que es más importante aún: cómo aprende, cómo guarda información nuestro cerebro, y cuáles son los procesos biológicos que facilitan el aprendizaje. Las neurociencias exploran campos tan diversos como: Entre las áreas relacionadas con la neurociencia se encuentran:  Palabra(s) clave: NeurocienciaDefinición #### NEUROMODULATION 2.0 [820] ### NEUROMODULATION 2.0: NEW DEVELOPMENTS IN BRAIN IMPLANTS, SUPER SOLDIERS AND THE TREATMENT OF CHRONIC DISEASE Written By: Steven Kotler Brain implants here we come. DARPA just announced the ElectRX program, a$78.9 million attempt to develop miniscule electronic devices that interface directly with the nervous system in the hopes of curing a bunch of chronic conditions, ranging from the psychological (depression, PTSD) to the physical (Crohn’s, arthritis). Of course, the big goal here is to usher in a revolution in neuromodulation—that is, the science of modulating the nervous system to fix an underlying problem.

We have known for a while that neuromodulation is effective. Cochlear implants, for example, use electricity to modulate the auditory nerve (really the whole auditory system), while deep brain stimulation has proven itself effective at regulating erroneous neuralelectrical activity and mitigating everything from the tremors of Parkinson’s to the terrors of chronic pain.

The potential is there. But so are the issues.

As the folks at Extreme Tech recently pointed out:

So far, these implants have been fairly big things — about the size of a deck of cards — which makes their implantation fairly invasive (and thus quite risky). Most state-of-the-art implants also lack precision — the stimulating electrodes are usually placed in roughly the right area, but it’s currently very hard to target a specific nerve fiber (a bundle of nerves). With ElectRx, DARPA wants to miniaturize these neuromodulation implants so that they’re the same size as a nerve fiber. This way they can be implanted with a minimally invasive procedure (through a needle) and attached to specific nerve fibers, for very precise stimulation.

What makes all of this so much more interesting is the fact that, unlike all the other systems of the body, which tend to reject implants, the nervous system is incorporative—meaning it’s almost custom-designed to handle these technologies. In other words, the nervous system is like your desktop computer— as long as you have the right cables, you can hook up just about any peripheral device you want.

Complete neuron cell diagram: Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves.

And that’s exactly what DARPA is doing here: they’re giving us the right cables.

Of course, the gap between neuromodulation and neuroaugmentation is slender and the number of abilities—cognitive, emotional, physical—that will be improved is growing. To put this in different terms, earlier versions of this work—also done at DARPA—focused on sensor capability. The goal was to build technology that could monitor a soldier’s brain activity in real time, with the obvious aim of using this to develop better warriors. Those better soldiers have been sidelined for now, as DARPA is now pushing into the far less controversial healing space, but make no mistake this transition is temporary.

We’re still building super soldiers, even if we’re soft selling the idea right now.

[Image credits: Technological implant courtesy of Shutterstock, neuron cell diagram/Wikipedia]

This entry was posted in Cyborg and tagged brain implantscochlear implantsdarpaelectrx,neuroaugmentationneuromodulationPTSDsuper soldiers.