Status and the brain.

I want to pass on this summary by Utevsky and Platt of the article by Noonan et al. (both are PLOS open source) on brain neural circuits that covary with an individual's place in the social hierarchy:

Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one's own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan and colleagues explore the neural correlates of social rank in macaques. Using both structural and functional brain imaging, they found neural changes associated with individual monkeys' social status, including alterations in the amygdala, hypothalamus, and brainstem—areas previously implicated in dominance-related behavior in other vertebrates. A separate but related network in the temporal and prefrontal cortex appears to mediate more cognitive aspects of strategic social behavior. These findings begin to delineate the neural circuits that enable us to navigate our own social worlds. A major remaining challenge is identifying how these networks contribute functionally to our social lives, which may open new avenues for developing innovative treatments for social disorders.

The good order - creativity needs routine

I really liked David Brooks' recent OpEd piece in the NYTimes. It is one of many published comments praising Obama's recent speech at the United Nations on the world order, putting it in the context of the general conditions required for building and maintaining the kind of order required for creativity at individual, political, and global levels. The piece starts by noting the disciplined routines of creative writers (which makes me feel much better about my fuddy-duddy rigid morning schedule of thinking and writing from exactly 8:30 till 11:30 a.m. every weekday.) Some clips:

..Maya Angelou..would go off to a hotel room she kept — a small modest room...She would arrive at the room at 7 a.m. and write until 12:30 p.m. or 2 o’clock....John Cheever would get up...ride the elevator in his apartment building down to a storage room in the basement.. and write until noon...Anthony Trollope would arrive at his writing table at 5:30 each morning... He would write 250 words every 15 minutes for two and a half hours every day... “I cannot imagine life without work as really comfortable,” Sigmund Freud wrote... W.H. Auden...checked his watch constantly, making sure each task filled no more than its allotted moment. “A modern stoic,” he argued, “knows that the surest way to discipline passion is to discipline time..”

..Children need emotional and physical order so they can go off and explore.

..Communities need order to thrive and cooperate since where there is chaos and disorder there is distrust and withdrawal.

..The world needs order, too, a set of assumed norms and routines that all nations adhere to. You can’t have freedom, trust, democracy and self-determination when thugs like Vladimir Putin of Russia are rampaging across borders and monsters like the Islamic State are killing innocents.

..Building and maintaining order — whether artistic, political or global — seems elementary, but it’s surprisingly hard...Preserving world order is even harder. President Obama showed that kind of toughness in his United Nations address this week (you knew I was going to make this leap). It was one of the finest speeches of his presidency.

...the order of global civilization, like the order in a poet’s mind, is something that has to be fought and imposed every day. The best life is a series of daring excursions from a secure and orderly base.

Hearing and imagination shape what we see.

Vetter et al. have done the interesting experiment of blindfolding people and then scanning their brains while they listened to birds singing, traffic noise, or people talking. They were able to identify the category of sounds just by examining the pattern of activity in the primary visual cortex, thus making a nice demonstration of the interconnectedness of the brain's sensory systems.

Highlights

•Early visual cortex receives nonretinal input carrying abstract information 

•Both auditory perception and imagery generate consistent top-down input 

•Information feedback may be mediated by multisensory areas 

•Feedback is robust to attentional, but not visuospatial, manipulation

Summary

Human early visual cortex was traditionally thought to process simple visual features such as orientation, contrast, and spatial frequency via feedforward input from the lateral geniculate nucleus. However, the role of nonretinal influence on early visual cortex is so far insufficiently investigated despite much evidence that feedback connections greatly outnumber feedforward connections. Here, we explored in five fMRI experiments how information originating from audition and imagery affects the brain activity patterns in early visual cortex in the absence of any feedforward visual stimulation. We show that category-specific information from both complex natural sounds and imagery can be read out from early visual cortex activity in blindfolded participants. The coding of nonretinal information in the activity patterns of early visual cortex is common across actual auditory perception and imagery and may be mediated by higher-level multisensory areas. Furthermore, this coding is robust to mild manipulations of attention and working memory but affected by orthogonal, cognitively demanding visuospatial processing. Crucially, the information fed down to early visual cortex is category specific and generalizes to sound exemplars of the same category, providing evidence for abstract information feedback rather than precise pictorial feedback. Our results suggest that early visual cortex receives nonretinal input from other brain areas when it is generated by auditory perception and/or imagery, and this input carries common abstract information. Our findings are compatible with feedback of predictive information to the earliest visual input level, in line with predictive coding models.

The Human Dynamic Clamp

In my distant past when I was doing cellular neurophysiology we used a technique called the "voltage clamp", in which the electrophysiology equipment measuring a nerve signal was linked to a computer that could inject current to alter the signal's behavior in a bi-directional interaction, and thus test models for the ion fluxes underlying the signals. Dumas et al. ask if a similar approach could be applied to study human interactions:

For example, were a human to interact with a model constructed to behave like him- or herself, might this tell us something about human beings and how they work together?....scaling the dynamic clamp paradigm from neurons and neural ensembles to human beings and human brains in a principled fashion is nontrivial. A potential starting point is to ground the design of an HDC (Human Dynamic Clamp) in the empirically based theoretical models of coordination dynamics

From their introduction:

...We will describe the HDC for four classes of behavior. Basically, the HDC models the interactions between a human and a virtual partner (VP) in the language of informationally coupled, nonlinear dynamical systems. The movements of the human enter the equations of motion associated with a specific model. This produces the dynamics of the VP that are displayed on a video screen. To complete the reciprocal coupling between the human and VP, the subject sees the motion of the VP. In a first version, the rhythmic movements of the subject enter the equations of motion of the Haken–Kelso–Bunz (HKB) model, considered one of the most extensively tested quantitative models of human motor behavior. Then, we expand the behavioral repertoire of the VP through the excitator model, which describes both rhythmic and discrete movement generation. In a further elaboration, adaptive behavior is introduced through changing parameter dynamics, illustrated here by modifying the intrinsic frequency of the VP. Finally, to study how a VP may adopt a directed behavior and hence play the role of a “teacher,” we use an adaptation of the empirically verified Schöner–Kelso model of behavioral pattern change.

Here is a section of the article abstract (the article appears to be open source, more detailed procedures and equations can be found there):

...the HDC allows a person to interact in real time with a virtual partner itself driven by well-established models of coordination dynamics. People coordinate hand movements with the visually observed movements of a virtual hand, the parameters of which depend on input from the subject’s own movements. We demonstrate that HDC can be extended to cover a broad repertoire of human behavior, including rhythmic and discrete movements, adaptation to changes of pacing, and behavioral skill learning as specified by a virtual “teacher.” We propose HDC as a general paradigm, best implemented when empirically verified theoretical or mathematical models have been developed in a particular scientific field. The HDC paradigm is powerful because it provides an opportunity to explore parameter ranges and perturbations that are not easily accessible in ordinary human interactions. The HDC not only enables to test the veracity of theoretical models, it also illuminates features that are not always apparent in real-time human social interactions and the brain correlates thereof.

Finally, the conclusion sounds very cosmic!

The HDC offers a way to bring mind, brain, and machine together through behavior. Under such a framework, we have shown that it is possible to unify and generalize diverse functions and tasks. The approach is principled: Each new version of the HDC carries the mathematics of all previous versions (Table 1). As long as there is a medium for two-way interaction, a deeper understanding of both the model and what the model is purported to be of become possible. Once coupled bidirectionally to an unconstrained, open dynamical system like a human being, HDC’s behavioral repertoire becomes much richer—in a manner akin, perhaps, to the way human behavior develops and gains depth through social interactions. In experiments, the richness of HDC behavior already led to unsolicited verbal reactions by human subjects, e.g., attribution of agency to the VP. Such spontaneous expressions suggest that the HDC may qualify as a Turing test of humanness, even surpassing its original scope. The Turing test implies only that judges are unable to tell if an agent is a human or a machine, and as such says nothing about the genuineness of the path toward that decision. Here, the HDC is a tool to test hypotheses and gain understanding about how humans interact with each other as well as with machines. In the HDC paradigm, exploration of the machine’s behavior may be viewed as an exploration of us as well.

Rules of implicit evaluation by race, religion, and age.

Axt and collaborators look at a very large sample (N > 200,000) of people of varying race, religion, and age and find, that after ranking their own race, religion, or age most favorably, people rank remaining categories in the same hierarchy, suggesting that rules of social evaluation are pervasively embedded in culture and mind. The subjects in the study were American citizens who submitted data to Harvard's Project Implicit. Their abstract:

The social world is stratified. Social hierarchies are known but often disavowed as anachronisms or unjust. Nonetheless, hierarchies may persist in social memory. In three studies (total N > 200,000), we found evidence of social hierarchies in implicit evaluation by race, religion, and age. Participants implicitly evaluated their own racial group most positively and the remaining racial groups in accordance with the following hierarchy: Whites > Asians > Blacks > Hispanics. Similarly, participants implicitly evaluated their own religion most positively and the remaining religions in accordance with the following hierarchy: Christianity > Judaism > Hinduism or Buddhism > Islam. In a final study, participants of all ages implicitly evaluated age groups following this rule: children > young adults > middle-age adults > older adults. These results suggest that the rules of social evaluation are pervasively embedded in culture and mind.

The authors comment on the noteworthy finding that Black people generally received more positive implicit evaluations than Hispanic people.

Past research has indicated that Blacks occupy the lowest rung of the racial status hierarchy. Recent work suggests that Hispanics may in fact occupy a position of lower status in the United States. For example, Hispanic men and women have lower weekly earnings than their White, Asian, and Black counterparts (U.S. Department of Labor, 2013). Our Study now reveals that Hispanics are evaluated less positively on average than Blacks, at least implicitly.

Morality in real life versus the lab.

The majority of studies on morality have used artificial controlled laboratory settings where study participants respond to presented moral issues (such as the famous speeding trolley dilemma: Should you sacrifice one person to save five?). Hoffman et al. have now gone into the real world homeostasis of morality, by calling volunteer study participants on their cell phones at random times to note moral acts that they committed or were the target of, that they witnessed directly, or that they heard about. This allowed them to analyze daily dynamics in a way not possible in the laboratory studies. Their findings confirmed several laboratory studies on moral contagion (receiving a good deed makes it more likely for us to give one), moral licensing (doing good entitles a bit of doing bad), political differences in moral values and concerns, and overoptimistically predicting one's own future moral behavior but accurately predicting the not-so-moral future behavior of others. They found little difference in daily moral behavior between religious and nonreligious people.

The science of morality has drawn heavily on well-controlled but artificial laboratory settings. To study everyday morality, we repeatedly assessed moral or immoral acts and experiences in a large (N = 1252) sample using ecological momentary assessment. Moral experiences were surprisingly frequent and manifold. Liberals and conservatives emphasized somewhat different moral dimensions. Religious and nonreligious participants did not differ in the likelihood or quality of committed moral and immoral acts. Being the target of moral or immoral deeds had the strongest impact on happiness, whereas committing moral or immoral deeds had the strongest impact on sense of purpose. Analyses of daily dynamics revealed evidence for both moral contagion and moral licensing. In sum, morality science may benefit from a closer look at the antecedents, dynamics, and consequences of everyday moral experience.

Neuroanatomy predicts individual risk attitudes.

Gilaie-Dotan et al. show that the volume of a region in the right posterior parietal cortex is relatively larger in individuals with higher risk tolerance (i.e. those more likely to choose a risky option). This region had previously been linked to uncertainty of reward, decision making, and the subjective value of uncertain rewards in both monkey and human brains.

Over the course of the last decade a multitude of studies have investigated the relationship between neural activations and individual human decision-making. Here we asked whether the anatomical features of individual human brains could be used to predict the fundamental preferences of human choosers. To that end, we quantified the risk attitudes of human decision-makers using standard economic tools and quantified the gray matter cortical volume in all brain areas using standard neurobiological tools. Our whole-brain analysis revealed that the gray matter volume of a region in the right posterior parietal cortex was significantly predictive of individual risk attitudes. Participants with higher gray matter volume in this region exhibited less risk aversion. To test the robustness of this finding we examined a second group of participants and used econometric tools to test the ex ante hypothesis that gray matter volume in this area predicts individual risk attitudes. Our finding was confirmed in this second group. Our results, while being silent about causal relationships, identify what might be considered the first stable biomarker for financial risk-attitude. If these results, gathered in a population of midlife northeast American adults, hold in the general population, they will provide constraints on the possible neural mechanisms underlying risk attitudes. The results will also provide a simple measurement of risk attitudes that could be easily extracted from abundance of existing medical brain scans, and could potentially provide a characteristic distribution of these attitudes for policy makers.

Synchrony between observers' brains during action observation.

Nummenmaa et al. (free access article, check out the nice graphics) have examined how we can understand what another person might be thinking or feeling just by observing their actions:

A frontoparietal action–observation network (AON) has been proposed to support understanding others' actions and goals. We show that the AON “ticks together” in human subjects who are sharing a third person's feelings. During functional magnetic resonance imaging, 20 volunteers watched movies depicting boxing matches passively or while simulating a prespecified boxer's feelings. Instantaneous intersubject phase synchronization (ISPS) was computed to derive multisubject voxelwise similarity of hemodynamic activity and inter-area functional connectivity. During passive viewing, subjects' brain activity was synchronized in sensory projection and posterior temporal cortices. Simulation induced widespread increase of ISPS in the AON (premotor, posterior parietal, and superior temporal cortices), primary and secondary somatosensory cortices, and the dorsal attention circuits (frontal eye fields, intraparietal sulcus). Moreover, interconnectivity of these regions strengthened during simulation. We propose that sharing a third person's feelings synchronizes the observer's own brain mechanisms supporting sensations and motor planning, thereby likely promoting mutual understanding.

Female hurricanes are deadlier than male hurricanes

The fact that I am driving away from Madison Wisconsin tomorrow, to my cold weather nest in Fort Lauderdale Florida, made me recall this interesting bit on hurricanes, which are still a possibility for a month or two after my arrival in Florida.

Meteorologists and geoscientists have called for greater consideration of social science factors that predict responses to natural hazards. We answer this call by highlighting the influence of an unexplored social factor, gender-based expectations, on the human toll of hurricanes that are assigned gendered names. Feminine-named hurricanes (vs. masculine-named hurricanes) cause significantly more deaths, apparently because they lead to lower perceived risk and consequently less preparedness. Using names such as Eloise or Charlie for referencing hurricanes has been thought by meteorologists to enhance the clarity and recall of storm information. We show that this practice also taps into well-developed and widely held gender stereotypes, with potentially deadly consequences. Implications are discussed for understanding and shaping human responses to natural hazard warnings.

Music shapes how we think - whether we see the forrest or the trees.

Hansen and Melzner do a fascinating piece on how musical cues that vary in distance and abstractness versus proximity and concreteness influence us. Think of the difference between the first two notes of “Maria” in West Side Story - a dissonant interval, the tritone - versus the first two notes of Twinkle, Twinkle, Little Star” - a consonant interval, the perfect fifth. They find the former makes us more likely to perceive the global aspects of a visual pattern, the latter enhances perception of its discrete elements (i.e. the forrest versus the trees).

Highlights

• Auditory cues related to distance and abstractness trigger abstract construal.
• Auditory cues related to proximity and concreteness trigger concrete construal.
• Distance/abstractness cues in sounds instigate the formation of broader categories.
• Distance/abstractness cues increase preference for global visual patterns.
• Also, these cues increase the weight placed on aggregate vs. single information.

Abstract

Psychological distance and abstractness primes have been shown to increase one's level of construal. We tested the idea that auditory cues which are related to distance and abstractness (vs. proximity and concreteness) trigger abstract (vs. concrete) construal. Participants listened to musical sounds that varied in reverberation, novelty of harmonic modulation, and metrical segmentation. In line with the hypothesis, distance/abstractness cues in the sounds instigated the formation of broader categories, increased the preference for global as compared to local aspects of visual patterns, and caused participants to put more weight on aggregated than on individualized product evaluations. The relative influence of distance/abstractness cues in sounds, as well as broader implications of the findings for basic research and applied settings, is discussed.

And here is their exposition of construal level theory:

Construal level theory proposes that psychological distance from objects (i.e., temporal, spatial, social, or probabilistic) enhances the tendency to build more high-level construals, whereas proximity enhances the tendency to build more low-level construals of objects. High-level construals are less diverse and include fewer details and less contextual information than low-level construals. High-level construals are abstract mental representations that extract the essential, core aspects of objects. Moving from a concrete representation of an object to a more abstract representation involves retaining central features and omitting features that may vary without significantly changing the meaning of the represented information.

Low-level, concrete construals, in contrast, consist of rich and specific details. They emphasize subordinate (vs. superordinate) features of an object, focusing on local (vs. global) perceptual elements, and processing information in a detailed-oriented (vs. holistic) manner.

Parasites practicing mind control.

Zimmer points to a further installment in the fascinating story of Toxoplasma gondii parasites, who can infect any mammal or bird, but can reproduce only inside of a cat whose feces then contain cysts that infect new hosts. Infected rats and mice become unafraid of feline odor, and thus become easier prey. It turns out the parasites use a very elegant technique to alter their host's behavior: they use an enzyme to remove inhibiting methyl groups from the arginine vasopressin gene, and the resulting increase in arginine vasopressin makes rats become more fearless. The abstract:

Male rats (Rattus novergicus) infected with protozoan Toxoplasma gondii relinquish their innate aversion to the cat odors. This behavioral change is postulated to increase transmission of the parasite to its definitive felid hosts. Here, we show that the Toxoplasma gondii infection institutes an epigenetic change in the DNA methylation of the arginine vasopressin promoter in the medial amygdala of male rats. Infected animals exhibit hypomethylation of arginine vasopressin promoter, leading to greater expression of this nonapeptide. The infection also results in the greater activation of the vasopressinergic neurons after exposure to the cat odor. Furthermore, we show that loss of fear in the infected animals can be rescued by the systemic hypermethylation, and recapitulated by directed hypomethylation in the medial amygdala. These results demonstrate an epigenetic proximate mechanism underlying the extended phenotype in the Rattus novergicus – Toxoplasma gondii association.

Associative memory enhanced by brain stimulation.

Wang et al. do a proof that the hippocampus facilitates associative memory formation in humans by interacting with distributed brain regions. Here is a description of their approach (sufficiently sophisticated that one will probably not be seeing DIY self help kits on the internet anytime soon!):

We ...developed methods to modulate cortical-hippocampal brain networks in healthy adults (n = 16 subjects) in order to test their role in associative memory. We focused modulatory stimulation on the lateral parietal cortex component of a well-characterized cortical-hippocampal network on the basis of hypothesized interactions between hippocampus and lateral parietal cortex in memory as well as robust functional connectivity between these regions, which is likely mediated by lateral parietal projections to retrosplenial and parahippocampal cortex. We defined a target within the left hippocampus for each subject and used resting-state fMRI to identify a subject-specific left lateral parietal location that demonstrated high functional connectivity with the hippocampal target. Noninvasive high-frequency repetitive transcranial magnetic stimulation (rTMS) was delivered to the parietal location for 5 consecutive days on the basis of evidence that rTMS can induce changes in connectivity within stimulated networks and that such effects can increase over multiple-day stimulation sessions.

Here is their abstract:

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.

Norm enforcement is biased from its emergence.

Interesting work from Jordan et al. on the appearance of in-group bias in punishing selfish behaviors in insiders versus outsiders:

When enforcing norms for cooperative behavior, human adults sometimes exhibit in-group bias. For example, third-party observers punish selfish behaviors committed by out-group members more harshly than similar behaviors committed by in-group members. Although evidence suggests that children begin to systematically punish selfish behavior around the age of 6 y, the development of in-group bias in their punishment remains unknown. Do children start off enforcing fairness norms impartially, or is norm enforcement biased from its emergence? How does bias change over development? Here, we created novel social groups in the laboratory and gave 6- and 8-year-olds the opportunity to engage in costly third-party punishment of selfish sharing behavior. We found that by age 6, punishment was already biased: Selfish resource allocations received more punishment when they were proposed by out-group members and when they disadvantaged in-group members. We also found that although costly punishment increased between ages 6 and 8, bias in punishment partially decreased. Although 8-y-olds also punished selfish out-group members more harshly, they were equally likely to punish on behalf of disadvantaged in-group and out-group members, perhaps reflecting efforts to enforce norms impartially. Taken together, our results suggest that norm enforcement is biased from its emergence, but that this bias can be partially overcome through developmental change.

Early music training improves neural encoding of speech in children and arrests auditory decline in older adults.

Fascinating work from Kraus et al.:

Musicians are often reported to have enhanced neurophysiological functions, especially in the auditory system. Musical training is thought to improve nervous system function by focusing attention on meaningful acoustic cues, and these improvements in auditory processing cascade to language and cognitive skills. Correlational studies have reported musician enhancements in a variety of populations across the life span. In light of these reports, educators are considering the potential for co-curricular music programs to provide auditory-cognitive enrichment to children during critical developmental years. To date, however, no studies have evaluated biological changes following participation in existing, successful music education programs. We used a randomized control design to investigate whether community music participation induces a tangible change in auditory processing. The community music training was a longstanding and successful program that provides free music instruction to children from underserved backgrounds who stand at high risk for learning and social problems. Children who completed 2 years of music training had a stronger neurophysiological distinction of stop consonants, a neural mechanism linked to reading and language skills. One year of training was insufficient to elicit changes in nervous system function; beyond 1 year, however, greater amounts of instrumental music training were associated with larger gains in neural processing. We therefore provide the first direct evidence that community music programs enhance the neural processing of speech in at-risk children, suggesting that active and repeated engagement with sound changes neural function.

This same group has also documented how older adults benefit from early music training:

Aging results in pervasive declines in nervous system function. In the auditory system, these declines include neural timing delays in response to fast-changing speech elements; this causes older adults to experience difficulty understanding speech, especially in challenging listening environments. These age-related declines are not inevitable, however: older adults with a lifetime of music training do not exhibit neural timing delays. Yet many people play an instrument for a few years without making a lifelong commitment. Here, we examined neural timing in a group of human older adults who had nominal amounts of music training early in life, but who had not played an instrument for decades. We found that a moderate amount (4–14 years) of music training early in life is associated with faster neural timing in response to speech later in life, long after training stopped (>40 years). We suggest that early music training sets the stage for subsequent interactions with sound. These experiences may interact over time to sustain sharpened neural processing in central auditory nuclei well into older age.

Study on relationship between genomics and well being receives a critical trashing.

I recently did a post passing on (as usual, uncritically) what looked like a neat correlation between genomics and human well-being. Brown et al. now issue a foot stomping refutation of that work:

Fredrickson et al. [Fredrickson BL, et al. (2013) Proc Natl Acad Sci USA 110(33):13684–13689] claimed to have observed significant differences in gene expression related to hedonic and eudaimonic dimensions of well-being. Having closely examined both their claims and their data, we draw substantially different conclusions. After identifying some important conceptual and methodological flaws in their argument, we report the results of a series of reanalyses of their dataset. We first applied a variety of exploratory and confirmatory factor analysis techniques to their self-reported well-being data. A number of plausible factor solutions emerged, but none of these corresponded to Fredrickson et al.’s claimed hedonic and eudaimonic dimensions. We next examined the regression analyses that purportedly yielded distinct differential profiles of gene expression associated with the two well-being dimensions. Using the best-fitting two-factor solution that we identified, we obtained effects almost twice as large as those found by Fredrickson et al. using their questionable hedonic and eudaimonic factors. Next, we conducted regression analyses for all possible two-factor solutions of the psychometric data; we found that 69.2% of these gave statistically significant results for both factors, whereas only 0.25% would be expected to do so if the regression process was really able to identify independent differential gene expression effects. Finally, we replaced Fredrickson et al.’s psychometric data with random numbers and continued to find very large numbers of apparently statistically significant effects. We conclude that Fredrickson et al.’s widely publicized claims about the effects of different dimensions of well-being on health-related gene expression are merely artifacts of dubious analyses and erroneous methodology.

A new compound that ameliorates cognitive dysfunction.

Alzheimer's disease is thought ultimately to be caused by the accumulation of the excess proteins found in plaques and tangles in the brain, but the prior defect that leads to this accumulation is not known. Here is a story about how searching for a drug for that defect led to the serendipitous finding of an impurity that turned out to be very useful...From Robinson's review of Xu et al.:

One implicated pathway involves striatal-enriched protein tyrosine phosphatase, or STEP, a neuron-specific enzyme that, among other jobs, regulates the trafficking of synaptic glutamate receptors and the activity of a group of widely active kinases. STEP is overactive in AD, in part because it isn't degraded fast enough, and its overactivity disrupts the post-synaptic events that underlie learning and memory. In animal models of AD, knocking out STEP improves cognition. Thus, STEP inhibition is a potential target for treatment of AD. In this issue of PLOS Biology, Jian Xu, Paul Lombroso, and colleagues report their discovery of a new class of STEP inhibitor—a discovery that involved a small but significant bit of serendipity—and demonstrate its potential in an AD animal model.

The authors began by conducting a high-throughput screen of 150,000 compounds, testing the ability of each to inhibit STEP's phosphatase activity. As is usual in such screens, a number of good candidates emerged. These were winnowed down to eight, chosen for their high activity at low concentration and favorable properties, such as likely ability to cross the blood-brain barrier and absence of known toxic moieties, all important for developing a centrally active drug. Following standard practice, next, they synthesized the molecules from scratch, and here got a surprise—the compounds displayed little STEP inhibitory activity. Some chemical detective work revealed the true inhibitor was elemental sulfur, S8, present as an impurity in the commercially obtained samples used in the screening. This ring compound doesn't make a good drug, so the authors investigated a structurally related compound, benzopentathiepin, containing a ring of six carbons fused to a ring of five sulfurs. A derivative, TC-2153, was known to have low toxicity and was likely to cross the blood-brain barrier, and, they found, was a potent inhibitor of STEP.

To test whether TC-2153 could reverse some of the cognitive effects of STEP overactivity, the authors turned to the “triple transgenic” mouse model, with mutations in three genes known to cause AD: presenilin 1, amyloid precursor protein, and tau. Compared to vehicle, intraperitoneal injection of TC-2153 improved spatial working memory, novel object recognition, and reference memory, all standard tests of cognitive function in AD models. The treatment had no effect on either a-beta, found in amyloid plaques outside of cortical neurons, or phospho-tau, found in neurofibrillary tangles inside them, indicating that the beneficial effect of TC-2153 was not due to alteration of events upstream of STEP overactivity.

Upstairs/Downstairs in our Brain – What’s running our show?

Although I mentioned this in Tuesday's post, I wanted to more explicitly point MindBlog readers to this web version of a talk I gave at the Sept. 9, 2014, session of the University of Wisconsin-Madison Chaos and Complexity Seminar Series. The link is also now in the left column of this page under "MindBlog Web Lectures." Here is a description of the talk:

This talk starts with a brief brain 101 elementary anatomy review, and then offers a  cherry picking review of recent trends in brain systems research that correlate what is going on in our brains with our behaviors. We want to know what normally makes us tick, what distortions might underlie addictive, impulsive, aggressive, stressed, depressed, or anxious behaviors, and what therapies might counter these distortions.  I will focus on structure-activity-behavior correlations in three brain state distinctions that are currently being emphasized:  Upstairs/downstairs and attentional/default mode systems that are a spontaneous part of our normal behavioral repertoire, and the cognitive therapy or mediation systems whose training, development, and expression can alter them.

MindBlog's other half - a Sunday afternoon recital at Twin Valley

This past Sunday afternoon my partner Len and I hosted a musical/social event for 50 friends at our Twin Valley home in Middleton Wisconsin. Our good friend Roy Wesley used his iPhone to make a video of the music, and I pass on his clip of one of the pieces in the program I played, the Debussy Nocturne (1892).



The program also included three pieces from Grieg's Lyric Suites and, Poulenc Improvisations #7 and #13 and, Prokofiev Romeo and Juliette

Reboot, reset, your brain - take a break - a walk, or better, a vacation.

I've done a number of posts on the attentional and default modes of our brain (in fact, I'm doing on a talk on this topic today at the Physics Department's chaos and complexity seminar series at the Univ. of Wisconsin.) I wanted to point to a number of recent popular articles pointing out how important it is for us to be able to detach from our attentional mode constantly processing overwhelming input streams of email, media, work demands, etc. While this more focused attentional mode tends to get a better press than the mind-wandering default mode, it is the latter state in which novel, spontaneous, and creative connections are likely to be made. Levitin does a NYTimes essay that notes the real world relevance of his 2008 publication on switching between central executive and default-mode networks, and notes that we should beware of the 'false break' in which we in fact remain attentive to email and other customary inputs, thus blocking real disengagement and mind wandering. Anna North and Gretchen Reynolds each do articles reinforcing this idea and point to articles studying the boosts in creativity and productivity that can accompany just taking a long walk or break.

MDMA (Ecstasy) as an affiliative social drug

Wardle et al. probe an interesting bit of social neurochemistry:

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is used recreationally to improve mood and sociability, and has generated clinical interest as a possible adjunct to psychotherapy. One way that MDMA may produce positive ‘prosocial’ effects is by changing responses to emotional stimuli, especially stimuli with social content. Here, we examined for the first time how MDMA affects subjective responses to positive, negative and neutral emotional pictures with and without social content. We hypothesized that MDMA would dose-dependently increase reactivity to positive emotional stimuli and dampen reactivity to negative stimuli, and that these effects would be most pronounced for pictures with people in them. The data were obtained from two studies using similar designs with healthy occasional MDMA users (total N = 101). During each session, participants received MDMA (0, 0.75 and 1.5 mg/kg oral), and then rated their positive and negative responses to standardized positive, negative and neutral pictures with and without social content. MDMA increased positive ratings of positive social pictures, but reduced positive ratings of non-social positive pictures. We speculate this ‘socially selective’ effect contributes to the prosocial effects of MDMA by increasing the comparative value of social contact and closeness with others. This effect may also contribute to its attractiveness to recreational users.

MDMA primarily triggers transporter-mediated release of serotonin, suggesting that serotonin is a good candidate for being a key regulator of the desire to affiliate and bond with others. It also increases levels of oxytocin in the blood, but recent work indicates that there is no correlation between the changes in oxytocin in the plasma and changes in social behavior.