It's well-known that exposure to psychological trauma (childhood/early life adversity, exposure to violence or assault, combat exposure, accidents, or natural disasters) can increase the risk of developing certain chronic physiological medical conditions (IBS, fibromyalgia, vascular disease, chronic pain, and cancer, among others).

Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis looks at the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology.

This article comes from Nature's Translational Psychiatry. It was published as open access,

Full Citation: 
Tursich M, Neufeld RWJ, Frewen PA, Harricharan S, Kibler JL, Rhind SG, and Lanius RA. (2014, Jul 22). Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Translational Psychiatry; 4, e413; doi:10.1038/tp.2014.56

Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis

M Tursich [1], R W J Neufeld [1,2,3], P A Frewen [1,2,3], S Harricharan [4], J L Kibler [5], S G Rhind [6] and R A Lanius [1,3]

1. Department of Psychiatry, University of Western Ontario, London, ON, Canada
2. Department of Psychology, University of Western Ontario, London, ON, Canada
3. Department of Neuroscience, University of Western Ontario, London, ON, Canada
4. Department of Biology, University of Western Ontario, London, ON, Canada
5. Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, FL, USA
6. Defence Research and Development Canada, Toronto Research Centre, Toronto, ON, Canada

Abstract

Exposure to psychological trauma (for example, childhood/early life adversity, exposure to violence or assault, combat exposure, accidents or natural disasters) is known to increase one’s risk of developing certain chronic medical conditions. Clinical and population studies provide evidence of systemic inflammatory activity in trauma survivors with various psychiatric and nonpsychiatric conditions. This transdiagnostic meta-analysis quantitatively integrates the literature on the relationship of inflammatory biomarkers to trauma exposure and related symptomatology. We conducted random effects meta-analyses relating trauma exposure to log-transformed inflammatory biomarker concentrations, using meta-regression models to test the effects of study quality and psychiatric symptomatology on the inflammatory outcomes. Across k=36 independent samples and n=14 991 participants, trauma exposure was positively associated with C-reactive protein (CRP), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (mean rs =0.2455, 0.3067, 0.2890, and 0.2998, respectively). No significant relationships were noted with fibrinogen, IL-2, IL-4, IL-8, or IL-10. In meta-regression models, the presence of psychiatric symptoms was a significant predictor of increased effect sizes for IL-1β and IL-6 (β=1.0175 and 0.3568, respectively), whereas study quality assessment scores were associated with increased effect sizes for IL-6 (β=0.3812). Positive correlations between inflammation and trauma exposure across a range of sample types and diagnoses were found. Although reviewed studies spanned an array of populations, research on any one specific psychiatric diagnosis was generally limited to one or two studies. The results suggest that chronic inflammation likely represents one potential mechanism underlying risk of health problems in trauma survivors.

Introduction

Chronic inflammation may be a hallmark of many chronic diseases, including cardiovascular disease (CVD), diabetes, and chronic pain disorders, among others. A history of exposure to traumatic events (for example, early life adversity, exposure to violence or assault, combat exposure, accidents, or natural disasters) is known to increase one’s risk of developing chronic medical problems,1,2 and research on inflammatory biomarkers has begun to elucidate some of the potential mechanisms underlying this increased risk.

Physiological mechanisms linking the experience of psychological stressors to immune functioning are complex, with influences exerted through various pathways. Briefly, in response to a traumatic stressor, the biological stress systems (including sympathetic/parasympathetic, catecholamine, hypothalamic-pituitary-adrenal axis, and immune system components) assist in promoting adaptive behavioral and physiological responses to the stressor.3, 4, 5 Severe, repeated and prolonged exposure to traumatic stressors, however, can lead to chronic dysregulation of these basic biological systems. Chronic, systemic inflammation has been posited as one mechanism underlying psychiatric symptomatology, across a range of disorders,6, 7, 8 as well as with increased risk of many physical health problems.2,9,10

Historically, research into the physiological mechanisms occurring within the context of psychopathology has been segregated according to diagnostic classification. However, despite differing symptom presentations, mounting evidence of neurobiological, genetic, and physiological mechanisms underlying a range of physical and psychological disorders has led to increasing recognition that current diagnostic classifications may no longer provide an adequate framework for psychobiological research or for translating this research into clinical practice.11,12 This awareness has led to transdiagnostic initiatives such as the US National Institutes of Mental Health (NIMH) Research Domain Criteria project.13 Indeed, studies of immune activity across multiple psychiatric disorders, including posttraumatic stress disorder (PTSD),5 major depression,14 and bipolar disorder15,16 have all identified disruptions in proinflammatory cytokines (such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β), among symptomatic individuals, as compared with healthy control participants. In addition, a convergence of evidence has identified lifetime trauma exposure, particularly early life adversity, as a major risk factor for a range of chronic physical and psychiatric conditions,1,2 and systemic inflammation has been suggested as one potential mechanism mediating this association.2,4,5,17

Despite a rapidly growing body of literature on the relationships between trauma exposure and inflammatory biomarkers (including cytokines and acute-phase proteins, such as C-reactive protein (CRP) and fibrinogen) in both clinical and nonclinical samples, few attempts have been made to quantitatively integrate this research. To our knowledge, all existing meta-analyses have been limited to disorder-specific comparisons of symptomatic vs asymptomatic individuals, such as in depressive disorders14,18, 19, 20, 21 or bipolar disorder.15,16 In addition to the narrow focus on specific psychiatric diagnoses, prior meta-analyses have faced methodological challenges, including skewed biomarker concentrations in primary studies, disparate statistical techniques used to evaluate data, and systematic exclusion of large, population-based regression studies, which are often better equipped to statistically control for covariates, such as body mass index (BMI), age, sex, and the use of medications or other substances, all of which have previously been identified as important in biobehavioral research.22 Using meta-analysis and meta-regression models, the present study therefore describes the relationships between trauma history and in vivo inflammatory biomarkers (that is, cytokines and acute-phase proteins) from a transdiagnostic perspective.

Materials and Methods

Protocol

This study adhered to PRISMA guidelines for meta-analysis.23 Search strategy and data extraction were informed by a preliminary review of the literature and further specified on the basis of data availability and methodological variation, including limiting the present analysis to unstimulated in vivo cytokines and acute-phase proteins.

Inclusion/exclusion criteria

To address the relevant transdiagnostic theoretical questions, we included all studies of adult participants that analyzed unstimulated, in vivo (circulating) inflammatory biomarkers in blood samples (that is, cytokines, CRP, or fibrinogen) in relation to measures of trauma exposure. We excluded child and adolescent samples due to evidence that cytokine production in children differs substantially from that of adults, even among healthy populations.24,25 Trauma exposure was defined either through self-report measures of trauma or abuse (for example, Adverse Childhood Experiences questionnaire26) or by exposure to events meeting criterion A for PTSD.27 Studies that only included pre-trauma cytokine measurements were excluded. The statistical analyses assessed the impact of trauma exposure, and meta-regression models assessed the impact of relevant covariates, including study quality and the presence or absence of psychiatric symptomatology within the samples. As trauma exposure can be assessed either as a continuous or dichotomous variable, our inclusion criteria were intentionally inclusive of either design. Because only a small number of studies had adequate data to test the relative contribution of posttraumatic symptomatology within trauma-exposed populations (that is, comparing trauma-exposed symptomatic individuals to trauma-exposed controls), such analyses were underpowered and are therefore reported solely as supplemental analyses (see Supplementary Material). Thus, we chose to exclude studies that did not include either a continuous measure of trauma exposure or a non-trauma-exposed comparison group.

Study selection

Studies were identified through systematic searches of PubMed, PsycInfo, PILOTS (Published International Literature on Traumatic Stress), and Ovid MEDLINE databases. Search criteria included peer-reviewed articles published in English, using terms related to inflammation (for example, interleukin, cytokine) and either traumatic event exposure (for example, trauma* stress, child* maltreatment) or psychiatric conditions commonly linked to trauma exposure (for example, PTSD, depression), limiting the results to human samples. Additional selected references were identified through limited update searches, citations in other papers, and personal communications with authors (see Supplementary Material for full search strategy).

Study characteristics and data extraction

Data extraction

A single effect size estimate was calculated from each fully independent sample of participants for each biomarker. Potential duplicate publications were identified (within each biomarker outcome) through cross-checking authors’ names and sample locations. Evaluation of inclusion/exclusion criteria and extraction of relevant data were conducted systematically by one of two coders, with a selection evaluated by both coders. Any disagreements (less than 5%) regarding eligibility or extracted data were settled by consensus.

Effect size and other study data were extracted from each of the published reports. Forms were piloted and revised as needed for extraction of relevant information. All assessments were made at the outcome level, with separate biomarkers analyzed independently. In the cases for which published data were insufficient, at least three attempts were made to contact authors. In total, the authors of 38 studies were contacted requesting information about sample independence, study eligibility or effect size calculation. Response rate was 76%, although some of these studies were not included in the present analyses (due to inclusion/exclusion criteria).

Data preparation and statistical analysis

Effect size preparation

A single effect size was calculated for each biomarker measured in an independent sample. Seven articles were confirmed by study authors to be duplicate samples, and one published report28 contained two independent subsamples (that is, African American and Caucasian participants), which were treated individually. Due to inclusion of both continuous and dichotomous predictors, we used correlation coefficients to synthesize the literature.29

As inflammatory biomarker distributions tend to be skewed, authors generally take one of three approaches to statistical testing and reporting of data: Use of nonparametric statistical methods, dichotomization according to clinically-relevant cut points (most frequently CRP>3 mg /L30), and logarithmic transformations to normalize the distributions before using parametric statistics.

Because data are log-transformed before statistical aggregation (individual data are converted into an exponent-scale before taking an arithmetic mean), effects based on log-transformed data cannot be mixed in the same analyses as raw (non-transformed) data. Log-transformed biomarker data are more likely to meet assumptions of normality than raw data; therefore, we chose to convert all raw effect sizes to estimated loge-transformed effect sizes,31 which were then converted to a log10 scale. When log-transformations were applied, any zero values were set to the smaller of the assay detection limit or a raw value of 1.0 (corresponding to a log-transformed value of 0), to allow for transformation and avoid artificially inflating the effect size estimate. Effect sizes for one study,32 for which we were unable to obtain effect size estimates by usual means, were extrapolated from a published scatterplot of individual participant data using WebPlotDigitizer, version 2.6 (http://arohatgi.info/WebPlotDigitizer/). Other effect size conversions were performed according to standard methods.29,33,34

Synthesis of results

We produced meta-analytic models for all analyses including at least three independent effect size estimates. Correlation coefficients were converted to Fisher’s Z-values for analyses and back-converted to correlations for interpretation. All meta-analysis and meta-regression models were fitted using Wilson’s meta-analysis macros for SPSS.35,36 Because we expected at least a moderate level of heterogeneity across studies, we used non-iterative method of moments random-effects models to integrate study findings. This approach produces wider confidence intervals and, thus, a more conservative estimate than either fixed- or other random-effects models.29 Forest plots were created,37 and heterogeneity analyses were conducted using the Q-test and I2 statistic.38

Publication bias and sensitivity analyses
Publication bias was assessed using funnel plots relating effect size to precision (inverse of standard error), two-tailed rank correlation tests,39 and trim and fill techniques,40 using the Comprehensive Meta-Analysis software, version 2.0. To provide protection against Type I error, publication bias was assessed only in those analyses which consisted of at least five studies. To evaluate the stability of results, we conducted sensitivity analyses by excluding samples consisting primarily of patients with known nonpsychiatric medical conditions (for example, CVD, migraine, pregnant samples), as the inflammatory processes could differ from those in the general population, despite study-level control. These post hoc models were fitted if there remained at least two studies for the analysis.

Study-level risk of bias

Risk of study-level bias was assessed with a checklist modeled after the Quality Assessment Tool for Quantitative Studies (QAT),41 modified slightly to fit our observational research question (see Supplementary Materials for details). We calculated both a categorical global rating (that is, high, moderate or low risk of bias), by using the QAT global rating instructions for relevant domains (selection bias, study design, control of relevant covariates, assessment validity, and use of appropriate data analysis techniques), and an average QAT score (average of the ordinal domain ratings). For each study, the percentage of recommended covariates (for example, age, sex, BMI, and the use of medications or other substances, among others)22 controlled either methodologically (that is, through exclusion or matching of subjects) or statistically was documented and entered as part of the QAT score (see Supplementary Material). Each domain was scored on a three-point likert scale (strong/moderate/weak); thus, both categorical and average QAT scores ranged between 1.0 and 3.0, with higher scores indicating greater potential for bias.

Meta-regression models

For each analysis, we tested the effect of average QAT scores using univariate models. We then conducted multivariate meta-regression models assessing the impact of a study’s inclusion of symptomatic individuals, while statistically controlling for study-level bias. Finally, we ran a series of dummy-coded meta-regression models to assess the effect of psychiatric diagnosis or symptom type. Due to the small number of studies of non-PTSD psychiatric populations, we used models comparing samples of non-comorbid PTSD participants to all other samples (including those using other psychiatric diagnoses and nonpsychiatric samples). Any models that displayed significant differences between the two groups (PTSD vs other samples) were then subjected to post hoc analyses to determine which symptom subgroups differed significantly from the PTSD samples. To increase power and interpretability, all meta-regression models were fitted only if at least four samples were included in the analysis.

Results

Study selection

A total of 3647 unique articles were identified through our searches, the majority of which were excluded through title or abstract screening (n=2919). Reasons for exclusion of full-text articles are shown in Figure 1. We identified 40 independent samples measuring 29 different cytokines, receptors or acute-phase proteins that met initial inclusion criteria. Of these, only biomarkers measured by at least three samples were included in our analyses. Three studies that failed to provide sufficient information to calculate log-transformed effect size estimates were not included. Thus, nine biomarkers from 36 independent samples were included in the meta-analysis (see Table 1).

Figure 1. Study screening and eligibility

 

Full figure and legend (142K)


Table 1 - Studies included in the meta-analysis.


Full table

None of the meta-analysis models for the anti-inflammatory cytokines (IL-4 and IL-10) was statistically significant (see Supplementary Figure 1), so we focus on presenting analyses of the acute-phase proteins (CRP and fibrinogen) and the proinflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, and TNF-α).

The results of the baseline models, based on 36 independent samples, are presented in Figure 2. As expected, there was evidence of significant heterogeneity across studies for all biomarkers. Although rank correlation tests revealed a significant correlation between the standardized effect size and the standard error for IL-6 (τ=0.2963, z=2.1889, P=0.0302), no imputed ‘missing studies’ were identified using the trim and fill method.40

Figure 2. Meta-analysis summary statistics.

 
Full figure and legend (95K)

Acute phase proteins

CRP

Analyses for CRP included 16 studies and a total of 13 374 participants. As shown in Figure 2, a significant association between CRP concentration and trauma exposure was detected (mean r=0.2507, P=0.0030).

Fibrinogen
Analysis of four studies involving 1890 participants showed no significant correlation between trauma exposure and fibrinogen (mean r=0.0675, P=0.1860; see Figure 2).

Proinflammatory cytokines

IL-1β

Meta-analysis of four studies (304 participants) showed a significant relationship between IL-1β and trauma exposure (mean r=0.3169, P=0.0322), displayed in Figure 2.

IL-2

Overall analyses of four studies (362 participants) revealed no statistically significant association between IL-2 and trauma exposure (mean r=0.3627, P=0.1256; see Figure 2).

IL-6

As shown in Figure 2 analysis of 26 studies with 7295 participants showed a significant relationship between trauma exposure and IL-6 (mean r=0.3029, P<0.0001).

IL-8

No significant overall correlation relating trauma exposure to IL-8 was detected, based on five studies with 349 participants (mean r=0.4649, P=0.1609; see Figure 2).

TNF-α

As presented in Figure 2 TNF-α was significantly associated with trauma exposure in analysis of 11 studies with 1899 participants (mean r=0.2998, P=0.0288).

Meta-regression models and sensitivity analyses

As shown in Table 2, risk of study-level bias (defined as the average of the applicable QAT domains: selection bias, study design, covariate control, assessment reliability/validity, and statistical analysis) was a significant predictor of heterogeneity in meta-regression models for the proinflammatory cytokines IL-6 and IL-8, such that higher risk of bias was associated with larger effect size estimates. In models controlling for risk of bias, studies that included participants with psychiatric disorders yielded larger effects for IL-1β and IL-6.

Table 2 - Meta-regression models.


Full table

None of the meta-regression models comparing PTSD samples with all other samples was statistically significant, with the exception of fibrinogen (which did not include any psychiatric samples) and IL-6 (see Supplementary Table 2). Post hoc comparisons coding non-PTSD psychiatric samples separate from asymptomatic samples revealed no differences in effect sizes for IL-6 between non-comorbid PTSD vs other types of psychiatric disturbance.

Sensitivity analyses showed that the findings were robust to exclusion of medical samples, which did not significantly change the pattern or significance of findings for any of the biomarkers except TNF-α (see Supplementary Figure 1). Although of increased magnitude, the TNF-α mean effect size was no longer statistically significant, once medical samples were excluded (k=6, mean r=0.4579, P=0.0857).

Discussion

To our knowledge, this is the first meta-analysis of trauma exposure as a risk factor for inflammation to utilize a transdiagnostic perspective. We integrated all available studies measuring trauma exposure, rather than limiting the analysis to a single diagnostic category. Further, to reflect the true status of the current literature, we incorporated both continuous and categorical measures. Although this procedure is likely to increase the observed heterogeneity in effect sizes across studies, it is essential to represent the diversity of study designs to obtain an accurate and comprehensive review of inflammation in trauma survivors. A growing body of evidence suggests that there may be a dose-response relationship between physical health problems and increased levels of exposure to traumatic events.75,76 Within the field of trauma research, however, it has been difficult to arrive at a single adequate method of quantifying cumulative trauma exposure, taking into account differences in number, frequency and severity of potentially traumatic experiences. As a result, there was insufficient literature to assess the potential impact of continuous vs categorical measures or to assess variability across different continuous measures of trauma exposure.

As expected, increased inflammation in trauma-exposed samples was found across a range of biomarkers. In particular, we noted moderate-to-large correlations relating trauma exposure to circulating concentrations of the proinflammatory cytokines IL-1β, IL-6, and TNF-α and of the acute-phase protein CRP. On the basis of our meta-regression models, the relationship between trauma exposure and the proinflammatory cytokines IL-1β and IL-6 was especially pronounced in samples that included, at least in part, clinical populations, as compared with samples which did not specifically recruit symptomatic individuals. No significant differences were observed as a function of the specific psychiatric diagnosis, although the statistical power was likely insufficient, at least in most analyses, to detect such relationships if they exist.

Because it was not possible to obtain log-transformed effect sizes for all studies, we produced log-transformed effect size estimates following accepted techniques.31 When we were unable to confirm with authors the base of the logarithm applied, we assumed the use of log-10 transformations, in accordance with similar studies. In keeping with prior recommendations for biomarker research,77 we advocate for greater consistency in reporting of methods, including transformations applied, sample demographics and characteristics, and covariates controlled in statistical analyses. Although it is beyond the scope of this study to recommend specific statistical techniques, other authors have endorsed the use of log-transformation when data are log-normally distributed, due to its flexibility in allowing for the use of traditional (parametric) statistical techniques and due to the ability to back-transform (exponentiate) geometric means to facilitate interpretation and comparison.77

Despite recent interest in these questions, research on the relationships among trauma exposure, psychiatric symptomatology, and inflammatory biomarkers has historically been limited to the PTSD literature. Thus, our power to detect differences between diagnostic groups was somewhat limited by a relative scarcity of reporting or measurement of trauma histories in non-PTSD psychiatric samples. Given the evidence that trauma exposure, particularly when prolonged and/or occurring early in life, is associated with a wide range of chronic medical and psychological health problems2,26 even after accounting for the effects of psychiatric disorders,75,76 it would be useful for future research to routinely include measures of trauma exposure in both medical and psychiatric populations.

Our analyses were also limited by the number of published biomarker studies providing information on participants’ trauma history. Although the numbers of studies included in our meta-analyses are comparable with other early meta-analyses on inflammation and psychiatric disorders,14, 15, 16, 18, 19,20, 21 further research is necessary to determine whether replicable relationships exist between trauma exposure and those biomarkers with relatively few published studies (for example, fibrinogen, IL-1β, IL-2, and IL-8).

Our findings suggest that the risk of study-level bias, especially related to the control of relevant covariates,22 such as medication use, BMI, and comorbid medical conditions, was significantly related to heterogeneity of effect sizes observed across studies. That is, higher QAT scores (indicating greater risk of bias) were associated with larger correlations between trauma exposure and IL-4, IL-6, IL-8 and IL-10. We therefore advocate for wider adoption of accepted standards for control of these potentially relevant covariates in future studies.

Another important question concerns the longitudinal course of inflammation in trauma-exposed individuals. We were unable to evaluate the effects of treatment or to examine the longitudinal course of inflammation following traumatic events in our analyses. However, there is preliminary evidence56,72,78,79 to suggest that successful treatment of trauma-related psychopathology may lead to improvements in the chronic immune dysregulation observed in our analyses, although results to date have been somewhat contradictory and unclear. This lack of consistency may be due, at least in part, to methodological differences among studies. Further research is needed to better understand the time course of inflammatory biomarkers following successful psychological or pharmacological treatment.

Conclusions

The relevance of inflammation in the pathophysiology and consequences of psychiatric disorders and general medical conditions has been increasingly recognized within research, clinical and public health arenas.9,10,80,81 The results of this meta-analysis are in keeping with a growing body of cross-disciplinary evidence11,12,82 which provides a framework for examination of transdiagnostic relationships among psychiatric risk factors (such as trauma exposure) and both psychological and physiological dysfunction. In our review of 36 samples with 14 991 participants, we found moderate correlations between inflammatory biomarker concentrations (IL-1β, IL-6, TNF-α, and CRP) and trauma exposure (mean rs=0.2455, 0.3067, 0.2890, and 0.2998, respectively) across 36 independent samples with a total of 14 991 participants. Further research is needed to confirm this association in a broader range of psychiatric and general medical populations, and to determine whether these findings extend to other inflammation-related biomarkers.

Although prior systematic reviews on inflammatory biomarkers in PTSD have provided a qualitative synthesis of the literature,4,5,81,83, 84, 85 to our knowledge, this is the first meta-analysis to examine the relationship of trauma to proinflammatory cytokines and acute-phase proteins. Meta-analyses of inflammatory activity observed within other psychiatric disorders (for example, depression14,18, 19, 20, 21 and bipolar disorder15,16) have found evidence of systemic inflammation, but none have yet examined the impact of trauma on these relationships. Our findings are also consistent with the results of two recent studies59,61 (included within our analysis), which found significantly higher inflammatory biomarkers only in those psychotic patients with a trauma history, as compared with healthy control participants. In both studies, patients without a trauma history did not significantly differ from controls. However, the majority of studies in psychiatric populations that we screened did not assess participants’ histories of trauma exposure, so further research is needed to confirm and clarify these findings. We therefore endorse routine assessment and reporting of trauma exposure within immunological research studies.

Conflict of interest

The authors declare no conflict of interest.

References at the Nature Translational Psychiatry page.

Discoverers of Brain’s Navigation System Awarded Nobel Prize in Physiology or Medicine

Yesterday the Nobel Prize for physiology or medicine went to three researchers -- Edvard Moser, May-Britt Moser and John O’Keefe -- for their discovery of the brain's navigation system. Here are two reports on their work, first from Nature and then from WIRED.

Nobel prize for decoding brain’s sense of place

Discoverers of brain’s navigation system get physiology Nobel

Alison Abbott & Ewen Callaway
06 October 2014


From left: Edvard Moser, May-Britt Moser and John O’Keefe.
Christian Charisius/dpa/Corbis; David Bishop/UCL
Brain cells that make up the biological equivalent of a satellite-navigation system have garnered three scientists the 2014 Nobel Prize in Physiology or Medicine. The discovery of the cells sheds light on one of neuroscience’s great mysteries — how we know where we are in space.

John O’Keefe of University College London won half of the prize for his discovery in 1971 of ‘place’ cells in the hippocampus, a part of the brain associated with memory. Edvard and May-Britt Moser, who are married and jointly run a lab at the Kavli Institute for Systems Neuroscience in Trondheim, Norway, share the other half for their 2005 discovery of ‘grid’ cells in an adjacent brain structure, the entorhinal cortex. Along with other navigation cells, grid and place cells allow animals to keep track of their position. Both cell types were discovered in rats, but have since been found in humans.

“Understanding where we are in space is one of the most fundamental issues for survival,” says Tobias Bonhoeffer, director of the Max Planck Institute of Neurobiology in Martinsried, Germany.

The discoveries will also be key to answering the broader question of how the brain makes sense of the world, says neuro­scientist Botond Roska of the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. “These are three deep-thinking people who have changed the way we think about the brain,” he says.

Most neuroscientists once doubted that brain activity could be linked with behaviour, but in the late 1960s, O’Keefe began to record signals from individual neurons in the brains of rats moving freely in a box. He put electrodes in the hippocampus and was surprised to find that individual cells fired when the rats moved to particular spots. He concluded that the memory of an environment may be stored as a specific combination of place-cell activities in the hippo­campus (J. O’Keefe and J. Dostrovsky Brain Res. 34, 171–175; 1971). “I realized that if you put them all together, you could have something like a map,” says O’Keefe.

Fast-forward to the 1990s, and his work attracted the attention of the Mosers, then PhD students at the University of Oslo. They joined him in London as postdocs, but within months they had moved to the Norwegian University of Science and Technology in Trondheim to set up their own lab. There they discovered that some cells in the entorhinal cortex fire when rats pass the points of a hexagonal grid. They found out that the brain uses this pattern as a coordinate system for spatial navigation (T. Hafting et al. Nature 436, 801–806; 2005).

The pattern constitutes what is known as a neural code. It is the only one known to be generated entirely in the brain, marking a milestone for computational neuroscience (see page 154).

Both place and grid cells have practical relevance. The early stages of Alzheimer’s disease affect the entorhinal cortex, and one of the first symptoms is losing one’s way. The disease goes on to devastate the hippocampus, stripping sufferers of their memories. “It is a good example of how very basic research can help us gain the deeper understanding we need in such devastating diseases to move towards therapies,” says Richard Morris, a memory researcher at the University of Edinburgh, UK.

May-Britt was presiding over a lab meeting when the call came from the Nobel committee in Stockholm. “I hesitated to answer it,” she told Nature, laughing. “But I did — and I couldn’t believe it; I even cried.” Edvard’s excitement was delayed: he was on a aeroplane to Munich, Germany, when his wife got the call. O’Keefe heard the news while working on a grant revision at home. “I’m totally delighted and thrilled,” he said in front of a phalanx of television cameras at a London press conference.

The Mosers once described their time in O’Keefe’s lab as “probably the most intense learning experience in our lives”. O’Keefe has similar memories. “It was intense — because they’re intense. They’re absolutely superb scientists.”

09 October 2014
Nature; 514(53). doi:10.1038/514153a

From elsewhere

• Moser lab
• John O’Keefe
• Nobel prize announcement 2014
• Kavli Foundation

* * * * *

Beyond the Nobel: What Scientists Are Learning About How Your Brain Navigates

By Greg Miller | 10.06.14 


Kevin Dooley/Flickr
“Can you point to Center City?” neuroscientist Russell Epstein likes to ask visitors to his office at the University of Pennsylvania in Philadelphia. Sometimes they can do it. Sometimes they have a little trouble. And sometimes, Epstein says, “they have no idea how they’d even begin to solve that problem.”

Epstein studies the way people navigate through space and orient to their surroundings–which turns out to be a very challenging problem for some people. His work builds on the research in rats that earned three scientists the Nobel Prize in Physiology or Medicine this morning. The prize-winning work identified certain types of neurons in the brain that are integral to the brain’s internal navigation system.

Epstein is one of several researchers trying to connect the dots between that rodent research and individual differences in people’s ability to orient to their surroundings and find their way from one place to another. As you may have noticed, all people are not equally good at this.

In a study published last year, his lab teamed up with psychologists from nearby Temple University to investigate what happens as people get to know a new place over the course of a few weeks. They took Temple students to a suburban campus they’d never seen before and showed them two short walking routes that passed by four buildings that served as landmarks. To keep the students from making a connection between the two routes, they blindfolded them and pushed them in wheelchairs from one to the other.

In subsequent visits, the researchers showed the students two different paths that connected the two routes they’d learned. Then they did some tests to try to see which students had put all the pieces together into a mental map of the new campus. For example, they’d ask a student to imagine standing in front of one of the eight buildings and point to the other seven. “Some people could do it well, and other people couldn’t do it all that well,” Epstein said. “That’s not terribly surprising.” What he and his colleagues really want to know is what’s going on in the students’ brains that might account for that difference.

When they did MRI scans of the brains of 13 of the students, they found a correlation between the size of the right hippocampus—a region with important roles in memory and navigation, and the focus of the Nobel-winning research—and how well a person had done on the imaginary pointing task. That suggests to Epstein that people with a bigger right hippocampus, and even more specifically, the posterior or back end of the right hippocampus, may be better able to get oriented to new places.

It’s just one study, and a fairly small one at that, but the findings fit with other research. The most famous of these are the cab driver studies by Eleanor Maguire and her colleagues at University College London. Since the early 2000s, Maguire and her team have studied London cabbies as they learn The Knowledge, the navigational wherewithal to get a passenger from point A to B through the city’s medieval maze of streets without looking at a map or using GPS as a crutch.

London streets. Map: OpenStreetMap contributors

A few years ago, Maguire’s team scanned the brains of 79 cabbie wannabes just about to embark on the three to four year training program, and they scanned most of them again afterwards (only 39 had managed to pass the qualifying exam—London is confusing!). MRI scans showed that the posterior hippocampus had gotten slightly larger in those who’d successfully crammed The Knowledge into their heads. Those who flunked out showed no change, the researchers reported in Current Biology.

Epstein says those findings show pretty convincingly that intensive geographical training can increase the volume of the posterior hippocampus. It’s the same area Epstein’s campus navigation study implicated, but in that case he suspects the students’ performance was impacted by pre-existing differences in their brains. “People came in with these differences [in the size of their posterior hippocampus] and that affected how well they learned the campus,” he said.

But what does this little chunk of the brain actually do?

Important clues have come from work honored by today’s Nobel. Half of the prize went to John O’Keefe, a neuroscientist at University College London, for the discovery of “place cells.” In the early 1970s, O’Keefe used hair-thin electrodes to record the electrical activity of neurons in the hippocampus of rats as they ran around an enclosure. Place cells, as their name suggests, fire only when the rat passes through a particular place. The other half of the Nobel went to May-Britt and Edvard Moser, neuroscientists at the Norwiegian University of Science and Technology in Trondheim for the more recent discovery of “grid cells” in 2005. These cells fire at regular intervals as a rat moves through space, marking out an imaginary grid.

The mouse hippocampus. Image: ZEISS Microscopy/Flickr

Put those cell types together and you’ve got something a rat could actually use to get around. The grid and place cells form a kind of map: The grid cells mark out a reference grid, roughly analogous to latitude and longitude lines (the graticule, if you want to get technical about it), and the place cells are like pins indicating specific places. A third type of hippocampal neuron, the so-called “head direction cells,” act like an internal compass, with certain ones firing depending on which way the rat is pointing its nose.”

In the rat equivalent of the posterior hippocampus, the place cells are finely tuned—they only fire when the rat passes through a specific spot. Perhaps people who remember locations better and don’t get lost as much have more of those finely tuned cells packed into a larger than average posterior hippocampus, Epstein says. He admits that’s speculative, however.

Grid cells tend to fire at fixed points on a triangular grid. Image: Torkel Hafting/WikiCommons

Scientists don’t really know if all of the rat findings apply to humans as well, but recent studies suggest that humans do at least have place and grid cells, and probably head direction cells too. A few clever experiments have turned up evidence of these cells by having people explore virtual reality environments inside an fMRI scanner. Even more direct and compelling evidence comes from monitoring electrodes inserted into the hippocampi of human epilepsy patients prior to surgery.

The hippocampus isn’t the only part of the brain important for navigation though. Several studies suggest which other brain regions may contribute: Taking note of landmarks seems to be the job of the parahippocampal place area; triangulating the position of different landmarks in relation to each other may be the responsibility of the retrosplenial cortex; and storing cognitive maps of the places we’ve been is probably the job of the medial temporal lobe, which includes the hippocampus and its neighbors.

Epstein suspects we have different types of mental maps filed away in our brains. We might have highly detailed maps of important places like our homes and offices, he hypothesizes, but only looser representations of the spaces in between. Or, zooming out a bit: “I might have good map of Philly and a good map of New York City, but it’s not like I have a complete map of New Jersey,” he said.

How the brain stores those different maps and calls them up when we need them is the sort of thing Epstein wants to understand. He and his colleagues are still a long way from a complete account of how the human brain navigates and what makes some people’s brains better at it than others. But they’re beginning to put a few points on the map.

From Neuroscientifically Challenged, this is an excellent explainer on the state of research into depression, including the rise and fall of the serotonin theory and the rise and struggle of the neurogenesis model. Fortunately, there is science, and the scientific method.

Serotonin, depression, neurogenesis, and the beauty of science

October 05, 2014
 

If you asked any self-respecting neuroscientist 25 years ago what causes depression, she would likely have only briefly considered the question before responding that depression is caused by a monoamine deficiency. Specifically, she might have added, in many cases it seems to be caused by low levels of serotonin in the brain. The monoamine hypothesis that she would have been referring to was first formulated in the late 1960s, and at that time was centered primarily around norepinephrine. But in the decades following the birth of the monoamine hypothesis, its focus shifted to serotonin, in part due to the putative success of antidepressant drugs that targeted the serotonin transporter (e.g. selective serotonin reuptake inhibitors, or SSRIs). The monoamine/serotonin hypothesis eventually became generally recognized as viable by the scientific community. Interestingly, it also became widely accepted by the public, who were regularly exposed to television commercials for antidepressant drugs like Prozac, Lexapro, and Celexa--drugs whose commercials specifically mentioned a serotonin imbalance as playing a role in depression.

Over the years, however, the scientific method quietly and efficiently went to work. Evidence gradually accumulated that indicated that the serotonin hypothesis does a very inadequate job of explaining depression. For example, although SSRIs increase serotonin levels within hours after drug administration, if their administration leads to beneficial effects--a big if--it usually takes 2-4 weeks of daily administration for those effects to appear. One would assume that if serotonin levels were causally linked to depression, then soon after serotonin levels increased, mood would begin to improve. Also, reducing levels of serotonin in the brain does not cause depression. The list of studies that don't fully support the serotonin hypothesis of depression is actually quite lengthy, and most of the scientific community now agrees that the hypothesis is insufficient as a standalone explanation of depression.

In the 1990s another hypothesis, known as the neurogenic hypothesis, was proposed with the hopes of filling in some of the holes in the etiology of depression that the monoamine hypothesis seemed to be unable to fill. The neurogenic hypothesis suggests that depression is at least partially caused by an impairment of the brain's ability to produce new neurons, a process known as neurogenesis. Specifically, researchers have focused on neurogenesis in the hippocampus, one of the only areas in the brain where neurogenesis has been observed in adulthood (the other being the subventricular zone).

The neurogenic hypothesis was formulated based on several observations. First, depressed patients seem to have smaller hippocampi than the general population, and their hippocampi also appear to be smaller during periods of depression than during periods of remission. Second, glucocorticoids like cortisol are elevated in depression, and glucocorticoids appear to inhibit neurogenesis in the hippocampus in rodents and non-human primates. Finally, there is evidence that the chronic administration of antidepressants increases neurogenesis in the hippocampus in rodents.

The neurogenic hypothesis thus suggests that depression is associated with a reduction in the birth of new neurons in the hippocampus, an area of the brain important to stress regulation, cognition, and mood. According to this hypothesis, when someone takes antidepressants, the drugs do raise levels of monoamines like serotonin, but they also enact long-term processes that increase neurogenesis in the hippocampus. This neurogenesis is hypothesized to be a crucial part of the reason antidepressants work, and the fact that it takes some time for hippocampal neurogenesis to return to normal may help to explain why antidepressants take several weeks to have an effect.

This may all sound logical, but the neurogenic hypothesis has its own share of problems. For example, while stress-related impairment of neurogenesis has been observed in rodents, we don't have definitive evidence it occurs in humans. Human studies thus far have relied on comparing the size of the hippocampi in depressed and non-depressed patients. While smaller hippocampi have been observed in depressed individuals, it is not clear that this is due to reduced neurogenesis rather than some other type of structural changes that might have occurred during depression.

Similarly, while the administration of antidepressants has been associated with increased neurogenesis in rodent models of stress, we don't have clear evidence of this in humans. In humans we again have to rely on looking at things like hippocampal size. Because there could be a number of explanations for changes in the size of the hippocampi, we can't assume neurogenesis is the sole factor involved--or that it is involved at all. Additionally, some studies in rodents have found that antidepressants lead to a reduction in anxiety or depressive symptoms in the absence of increased hippocampal neurogenesis.

Another problem is that when neurogenesis is experimentally decreased in rodents, the animals don't usually display depressive symptoms. Experiments of this type haven't been performed with humans or non-human primates, so we don't know if a reduction in neurogenesis in any species is actually sufficient to cause depression. And no studies have found that increasing neurogenesis alone is enough to alleviate depressive-like symptoms.

Of course none of this means the neurogenic hypothesis is incorrect, but it does suggest there is a long way to go before we can feel confident about incorporating it fully into our understanding of depression. In the reluctance of the scientific community to embrace this hypothesis is where I see the beauty of science. Although it took decades of testing and revising before the monoamine hypothesis became a widely accepted explanation for depression, one could argue (based on its now recognized shortcomings) that we accepted it too readily.

However, it seems that many in the scientific community have learned from that mistake. Although there is no shortage of publications whose authors may be too willing to anoint the neurogenic hypothesis as a new unifying theory of depression, overall the tone when speaking of the neurogenic hypothesis seems to be cautious and/or critical. There is also a great deal of discussion now in the literature about the complexity of mood disorders like depression, and how it is unlikely to be able to explain their manifestation in a diverse population of individuals with just one mechanism, whether it be impaired neurogenesis or a serotonin deficiency.

Thus, the neurogenic hypothesis will require much more testing before we can consider it an important piece in the puzzle of depression. Even if further testing supports it, however, it will likely be considered just that--a piece in the puzzle, instead of an overarching explanation of the disorder. And that circumspect approach to explaining depression represents an important advancement in the way we look at psychiatric disorders.

See also: http://www.neuroscientificallychallenged.com/blog/2008/04/serotonin-hypothesis-and-neurogenesis

Miller, B., & Hen, R. (2015). The current state of the neurogenic theory of depression and anxiety Current Opinion in Neurobiology, 30, 51-58 DOI: 10.1016/j.conb.2014.08.012

Danny Dorling - Inequality and the 1% (The RSA)

Danny Dorling is the author of Inequality and the 1% (2014, Oct 7), and he recently spoke the The Royal Society for the encouragement of Arts, Manufactures and Commerce (The RSA) about his new book.

Even before birth, being born outside the 1% will have dramatic effect on the rest of your life: reducing life expectancy, educational and work prospects, as well as mental health.

For reals.

Inequality and the 1%

25th Sept 2014 | The RSA

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(full recording including audience Q&A)

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Inequality in the UK is increasing. More and more people are being driven towards the poverty line, and this has deep cultural and social impacts.

Even before birth, being born outside the 1% will have dramatic effect on the rest of your life: reducing life expectancy, educational and work prospects, as well as mental health.

Leading social geographer Danny Dorling visits the RSA to unpack the latest research into how the lives and ideas of the 1 percent impact the remaining 99%, revealing that inequality is about much more than just economics.

Speaker: Danny Dorling, professor of geography, University of Oxford.

Chair: Zoe Williams, columnist, The Guardian

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Speakers

• Zoe Williams
• Danny Dorling

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• Inequality and the 1% - Danny Dorling (Verso Books, Oct. 7, 2014)

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Buddhist Geeks 335: Practicing with the Brain in Mind (by Rick Hanson)

Here is part one of the Buddhist Geeks interview with Buddhist neuropsychologist Dr. Rick Hanson. Ever since the publication of Buddha's Brain: The Practical Neuroscience of Happiness, Love, and Wisdom (2009), Hanson has been one of the prolific and popular authors and teachers in the Buddhist world.

BG 335: Practicing with the Brain in Mind

by Rick Hanson

Podcast: Download

Episode Description:

Rick Hanson, Ph.D., is a neuropsychologist, Senior Fellow of the Greater Good Science Center at UC Berkeley, and New York Times best-selling author. He’s been an invited speaker at Oxford, Stanford, and Harvard, and taught in meditation centers worldwide.

In this first part of the keynote address Rick presented at the 2013 Buddhist Geeks Conference, he explores the intersection between dharma practice and neuroscience. Rick explains the basic mechanisms of brain change, the power of mindfulness, how to activate the neural networks of self-compassion, how to tap the hidden power of everyday experiences to grow happiness and other inner strengths in your brain, and why our planet needs us to take charge of our Stone Age brains in the 21st century.

This is part one of a two part series.

Episode Links:

• RickHanson.net
• Buddhist Geeks Conference

Transcript coming soon…

Rick Hanson

Rick Hanson, Ph.D., is a neuropsychologist and New York Times best-selling author. His books include Hardwiring Happiness, Buddha's Brain, Just One Thing, and Mother Nurture. Founder of the Wellspring Institute for Neuroscience and Contemplative Wisdom, and on the Advisory Board of the Greater Good Science Center at UC Berkeley, he's been an invited speaker at Oxford, Stanford, and Harvard, and taught in meditation centers worldwide. He has several audio programs and his free Just One Thing newsletter has over 100,000 subscribers.

Website: RickHanson.net

Why Stanislaw Lem’s Futurism Deserves Attention

In this article, Lee Billings riffs on Stanislaw Lem's relatively unknown book of philosophical essays, Summa Technologiae (Electronic Mediations), written in 1964 but not fully translated into English until 2013. Lem is known primarily for his science fiction writing, especially the 1961 novel Solaris, adapted into a meditative film by Andrei Tarkovsky in 1972.

In the Summa, however, Lem meditates on topics that were still fully "fantastic" in 1964, but now are topics of conversation within the realm of the possible, such as virtual reality, nanotechnology, artificial intelligence and the technological singularity.

The Book No One Read

Why Stanislaw Lem’s futurism deserves attention

By Lee Billings | October 2, 2014

I remember well the first time my certainty of a bright future evaporated, when my confidence in the panacea of technological progress was shaken. It was in 2007, on a warm September evening in San Francisco, where I was relaxing in a cheap motel room after two days covering The Singularity Summit, an annual gathering of scientists, technologists, and entrepreneurs discussing the future obsolescence of human beings.
In math, a “singularity” is a function that takes on an infinite value, usually to the detriment of an equation’s sense and sensibility. In physics, the term usually refers to a region of infinite density and infinitely curved space, something thought to exist inside black holes and at the very beginning of the Big Bang. In the rather different parlance of Silicon Valley, “The Singularity” is an inexorably-approaching event in which humans ride an accelerating wave of technological progress to somehow create superior artificial intellects—intellects which with predictable unpredictability then explosively make further disruptive innovations so powerful and profound that our civilization, our species, and perhaps even our entire planet are rapidly transformed into some scarcely imaginable state. Not long after The Singularity’s arrival, argue its proponents, humanity’s dominion over the Earth will come to an end.

I had encountered a wide spectrum of thought in and around the conference. Some attendees overflowed with exuberance, awaiting the arrival of machines of loving grace to watch over them in a paradisiacal post-scarcity utopia, while others, more mindful of history, dreaded the possible demons new technologies could unleash. Even the self-professed skeptics in attendance sensed the world was poised on the cusp of some massive technology-driven transition. A typical conversation at the conference would refer at least once to some exotic concept like whole-brain emulation, cognitive enhancement, artificial life, virtual reality, or molecular nanotechnology, and many carried a cynical sheen of eschatological hucksterism: Climb aboard, don’t delay, invest right now, and you, too, may be among the chosen who rise to power from the ashes of the former world!

Over vegetarian hors d’oeuvres and red wine at a Bay Area villa, I had chatted with the billionaire venture capitalist Peter Thiel, who planned to adopt an “aggressive” strategy for investing in a “positive” Singularity, which would be “the biggest boom ever,” if it doesn’t first “blow up the whole world.” I had talked with the autodidactic artificial-intelligence researcher Eliezer Yudkowsky about his fears that artificial minds might, once created, rapidly destroy the planet. At one point, the inventor-turned-proselytizer
 Ray Kurzweil teleconferenced in to discuss,
among other things, his plans for becoming transhuman, transcending his own biology to 
achieve some sort of
 eternal life. Kurzweil
 believes this is possible, 
even probable, provided he can just live to see
 The Singularity’s dawn, 
which he has pegged at 
sometime in the middle of the 21st century. To this end, he reportedly consumes some 150 vitamin supplements a day.

Returning to my motel room exhausted each night, I unwound by reading excerpts from an old book, Summa Technologiae. The late Polish author Stanislaw Lem had written it in the early 1960s, setting himself the lofty goal of forging a secular counterpart to the 13th-century Summa Theologica, Thomas Aquinas’s landmark compendium exploring the foundations and limits of Christian theology. Where Aquinas argued for the certainty of a Creator, an immortal soul, and eternal salvation as based on scripture, Lem concerned himself with the uncertain future of intelligence and technology throughout the universe, guided by the tenets of modern science.

To paraphrase Lem himself, the book was an investigation of the thorns of technological roses that had yet to bloom. And yet, despite Lem’s later observation that “nothing ages as fast as the future,” to my surprise most of the book’s nearly half-century-old prognostications concerned the very same topics I had encountered during my days at the conference, and felt just as fresh. Most surprising of all, in subsequent conversations I confirmed my suspicions that among the masters of our technological universe gathered there in San Francisco to forge a transhuman future, very few were familiar with the book or, for that matter, with Lem. I felt like a passenger in a car who discovers a blindspot in the central focus of the driver’s view.

Such blindness was, perhaps, understandable. In 2007, only fragments of Summa Technologiae had appeared in English, via partial translations undertaken independently by the literary scholar Peter Swirski and a German software developer named Frank Prengel. These fragments were what I read in the motel. The first complete English translation, by the media researcher Joanna Zylinska, only appeared in 2013. By Lem’s own admission, from the start the book was a commercial and a critical failure that “sank without a trace” upon its first appearance in print. Lem’s terminology and dense, baroque style is partially to blame—many of his finest points were made in digressive parables, allegories, and footnotes, and he coined his own neologisms for what were, at the time, distinctly over-the-horizon fields. In Lem’s lexicon, virtual reality was “phantomatics,” molecular nanotechnology was “molectronics,” cognitive enhancement was “cerebromatics,” and biomimicry and the creation of artificial life was “imitology.” He had even coined a term for search-engine optimization, a la Google: “ariadnology.” The path to advanced artificial intelligence he called the “technoevolution” of “intellectronics.”

Even now, if Lem is known at all to the vast majority of the English-speaking world, it is chiefly for his authorship of Solaris, a popular 1961 science-fiction novel that spawned two critically acclaimed film adaptations, one by Andrei Tarkovsky and another by Steven Soderbergh. Yet to say the prolific author only wrote science fiction would be foolishly dismissive. That so much of his output can be classified as such is because so many of his intellectual wanderings took him to the outer frontiers of knowledge.

Lem was a polymath, a voracious reader who devoured not only the classic literary canon, but also a plethora of research journals, scientific periodicals, and popular books by leading researchers. His genius was in standing on the shoulders of scientific giants to distill the essence of their work, flavored with bittersweet insights and thought experiments that linked their mathematical abstractions to deep existential mysteries and the nature of the human condition. For this reason alone, reading Lem is an education, wherein one may learn the deep ramifications of breakthroughs such as Claude Shannon’s development of information theory, Alan Turing’s work on computation, and John von Neumann’s exploration of game theory. Much of his best work entailed constructing analyses based on logic with which anyone would agree, then showing how these eminently reasonable premises lead to astonishing conclusions. And the fundamental urtext for all of it, the wellspring from which the remainder of his output flowed, is Summa Technologiae.

The core of the book is a heady mix of evolutionary biology, thermodynamics—the study of energy flowing through a system—and cybernetics, a diffuse field pioneered in the 1940s by Norbert Wiener studying how feedback loops can automatically regulate the behavior of machines and organisms. Considering a planetary civilization this way, Lem posits a set of feedbacks between the stability of a society and its degree of technological development. In its early stages, Lem writes, the development of technology is a self-reinforcing process that promotes homeostasis, the ability to maintain stability in the face of continual change and increasing disorder. That is, incremental advances in technology tend to progressively increase a society’s resilience against disruptive environmental forces such as pandemics, famines, earthquakes, and asteroid strikes. More advances lead to more protection, which promotes more advances still.

And yet, Lem argues, that same technology-driven positive feedback loop is also an Achilles heel for planetary civilizations, at least for ours here on Earth…

The full article appears in the Fall 2014 Nautilus Quarterly. Subscribe today!

Freelance writer Lee Billings is the author of Five Billion Years of Solitude: The Search for Life Among the Stars.

Photograph by Forum/UIG/Getty Images

This is a cool study, and it helps me understand why it's often very easy for me to learn new things. I am curious about so many things.

First up a summary of the research from Sci-News.com, then the abstract for the original article from Neuron (the full article is paywalled).

New Study Provides Insight into How Piquing Curiosity Changes Our Brains

Oct 3, 2014 by Sci-News.com

The more curious we are about a topic, the easier it is to learn information about that topic. A new study carried out by California University scientists provides insights into what happens in our brains when curiosity is piqued.

Curiosity helps learning and memory, scientists say. Anonymous painter, 15th century – Cahiers de Science et Vie no. 114.

Participants in the study first rated their curiosity about the answers to a series of trivia questions. Later, they had their brains scanned via functional magnetic resonance imaging while they learned the answers to these questions.

The participants were presented with a selected trivia question and while they waited for the answer to pop up on the screen, they were shown a picture of a neutral, unrelated face.

Afterwards, they performed a surprise recognition memory test for the presented faces, followed by a memory test for the answers to the trivia questions.

As expected, when people were highly curious to find out the answer to a question, they were better at learning that information.

More surprising, however, was that once their curiosity was aroused, they showed better learning of entirely unrelated information that they encountered but were not necessarily curious about.

The participants were also better able to retain the information learned during a curious state across a 24-hour delay.

“Our findings potentially have far-reaching implications for the public because they reveal insights into how a form of intrinsic motivation – curiosity – affects memory,” said Dr Matthias Gruber, who is the first author of the paper published in the journal Neuron.

“These findings suggest ways to enhance learning in the classroom and other settings.”

He added: “curiosity may put the brain in a state that allows it to learn and retain any kind of information, like a vortex that sucks in what you are motivated to learn, and also everything around it.”

The scientists also discovered that when curiosity is stimulated, there is increased activity in the brain circuit related to reward.

“We showed that intrinsic motivation actually recruits some of the same brain areas that are heavily involved in tangible, extrinsic motivation. This reward circuit relies on dopamine, a chemical that relays messages between neurons.”

In addition, they found that when learning was motivated by curiosity, there was increased activity in the hippocampus, a brain region that is important for forming new memories, as well as increased interactions between the hippocampus and the dopamine reward circuit.

Prof Charan Ranganath, who is the senior author on the study, explained: “so curiosity recruits the reward system, and interactions between the reward system and the hippocampus seem to put the brain in a state in which you are more likely to learn and retain information, even if that information is not of particular interest or importance.”

_____

Matthias J. Gruber et al. (2014, Oct 2). States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit. Neuron; doi: 10.1016/j.neuron.2014.08.060

* * * * *

States of Curiosity Modulate Hippocampus-Dependent Learning via the Dopaminergic Circuit

Matthias J. Gruber, Bernard D. Gelman, Charan Ranganath

Highlights

• People are better at learning information that they are curious about
• Memory for incidental material presented during curious states was also enhanced
• Curiosity associated with anticipatory activity in nucleus accumbens and midbrain
• Memory benefits for incidental material depend on midbrain-hippocampus involvement

Summary

People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences.

The Neuroscientific Legacy of the Vietnam War

From The Atlantic, Emily Anthes takes a look at how the Vietnam War (as a result of The Vietnam Head Injury Study) has helped us understand a great deal about the human brain.

Vietnam’s Neuroscientific Legacy

By Emily Anthes  | October 2, 2014

Credit Illustration by Nicole Rifkin

In 1967, William F. Caveness, a neurologist and veteran of the Korean War, began building a registry of living soldiers who had suffered head trauma in Vietnam. Studies of veterans of the Second World War had suggested that penetrating head injuries could cause seizures, and Caveness, who had documented post-traumatic epilepsy in soldiers injured during the Korean War, was eager to understand more about this connection. “He saw that the Vietnam War was heating up, and he wanted to study some American combat veterans who suffered penetrating brain injuries and survived,” said Jordan Grafman, the director of brain-injury research at the Rehabilitation Institute of Chicago.

Caveness, the chief of the Laboratory of Experimental Neurology at the National Institute of Neurological and Communicative Disorders and Stroke, asked military field surgeons to fill out a form whenever they treated an American soldier with a head injury. The doctors would note the date, time, and geographic location of each injury, and whether the soldier had been wearing a helmet when he was wounded. They would mark the position of the wound on a diagram of a human head, as well as record a heap of clinical information: What was the patient’s pulse, blood pressure, and temperature? Had he lost consciousness, sight, or speech? Could he respond to pain or commands? Were all his reflexes intact?

“I’m sure Bill Caveness thought, ‘We aren’t going to get much here because it’s the heat of combat,’ ” Grafman said. But forms came pouring in from the battlefields and military hospitals of Vietnam, describing young men who’d been hit with shells, missile fragments, and other shrapnel. Caveness ultimately received information about approximately two thousand servicemen who’d suffered traumatic brain injuries between 1967 and 1970.

Scientists have been learning from these men ever since. The Vietnam Head Injury Study, as it is now known, has allowed researchers to track the long-term consequences of head injuries, identify the factors that influence recovery, and even map the cognitive architecture of the brain. This year alone, Grafman has published papers on the neural basis of social problem-solving, pathological aggression after brain damage, and the relationship between caregiver style and cognitive decline—all based on Caveness’s research. The study has yielded more than one hundred scientific papers so far and is likely to yield many more. “It’s the gift that keeps on giving,” Grafman said.

The registry began paying dividends almost immediately. Even before it was complete, information about the most common locations of head wounds prompted the military to redesign its helmets. When the war ended, and Caveness and his colleagues began reviewing the veterans’ medical records, they made discoveries that taught doctors the best way to treat penetrating head injuries: nearly half of the men had had their skulls rebuilt in a procedure known as a cranioplasty. Analyzing these cases, the researchers found that cranioplasties were less likely to cause complications such as infection or a leakage of cerebrospinal fluid when they took place at least a year after the injuries. The team recommended that, in the future, neurosurgeons follow that timetable when reconstructing damaged skulls.

In the years that followed, Caveness secured a grant to continue studying the men and convinced the Air Force to fly the veterans to Washington, D.C. so that he could examine them in person. Caveness died before he could assemble his research subjects, but Grafman and other researchers took over. Between 1981 and 1984, the Air Force ferried five hundred and twenty Vietnam veterans to the Walter Reed National Army Medical Center, and the new scientific team performed a weeklong assessment of each of them. They collected more than twenty thousand pieces of data on each participant, including information about post-traumatic epilepsy, Caveness’s original area of interest. The researchers learned that fifty-three per cent of the servicemen had developed seizures in the years after the war and identified several factors—including bleeding in or around the brain and the presence of unrecovered metal fragments—that made epilepsy more likely.

As the scientists continued to track the veterans over the decades, they documented the long-term cognitive repercussions of brain trauma. Before joining the military, the men had all taken the Armed Forces Qualification Test (A.F.Q.T.), which measures several aspects of intelligence. These scores served as valuable benchmarks, giving researchers insight into each man’s cognitive aptitude before his injury. Scientists found that as the veterans aged, they lost cognitive skills more quickly than uninjured vets. But high levels of intelligence were protective; among the wounded vets, those who had scored the highest on the A.F.Q.T. deteriorated more slowly than those who had performed poorly. Researchers have now also used the tools of molecular genetics to peer inside the veterans’ cells, identifying several genes that seemed to influence how well they recovered from their head trauma. “Having a good or bad variant of a gene can predispose an individual to a better or worse outcome,” said Aron Barbey, who joined the project, in 2009, when he was a post-doctoral fellow at the National Institute of Neurological Disorders and Stroke, where Grafman was working. (Barbey now directs the Decision Neuroscience Laboratory at the University of Illinois at Urbana-Champaign.)

In addition to expanding our knowledge about devastating head injuries, the Vietnam Head Injury Study has also provided insight into how healthy brains function. Although shrapnel is a horror for soldiers, it can be useful for neuroscientists, as it tends to cause damage that is limited and localized, rather than distributed across the entire wrinkly organ. By studying the cognitive, behavioral, or emotional deficits that occur after an injury to a specific neural structure, scientists can deduce something about that structure’s typical role in the brain. One series of studies revealed that Vietnam veterans with damage to a particular area of the frontal lobe—a region known as the ventromedial prefrontal cortex (vmPFC)—were more aggressive, had reduced emotional intelligence, and demonstrated more stereotypical attitudes about gender than control subjects or veterans with lesions in other areas, providing evidence that the vmPFC is involved in social cognition and conduct.

By cataloguing the areas of brain damage in the veterans, and cross-referencing that information with data on their deficits and difficulties, Barbey, Grafman, and their colleagues have been able to map out the neural circuits involved in general intelligence, emotional intelligence, and social problem-solving. They recently discovered that many of the same brain areas—a network of structures in the frontal lobe and parietal cortex—underlie all three of these abilities. Historically, many psychologists have viewed general intelligence as separate from social and emotional intelligence, Barbey said. But these results fit with the more recent view that these skills are intertwined and interrelated. “The brain is not making a strong distinction between these forms of intelligence,” Barbey said.

And for all they have taught us about damage and destruction, these men are also a testament to the brain’s ability to recover from seemingly catastrophic injury. “If you just look at the CT scans and saw the amount of brain tissue missing, you’d say, ‘Oh my god, they’ll have to be in nursing homes,’ ” Grafman said. But many went on to have relatively normal lives. They got married and started families. Most went back to work. Some even stayed in the military. “They had their own impairments and deficits, but through a combination of motivation and will, and the care of their family and friends, the majority of them managed to reënter society,” Grafman said. One man, known as J. S., sustained a gunshot wound that obliterated most of his left hemisphere. He struggled with words after his injury but remained capable with numbers and spent many years living on his own, in a trailer by a lake.

There is still more to learn from these veterans, most of whom are now in their sixties and seventies; some of the men have even expressed interest in donating their brains after their deaths. The study participants have been “extremely devoted,” Grafman told me. “They felt they wanted to help veterans in the future.” And, over the decades, the researchers and their subjects have developed close bonds. “I’m just grateful to know these guys and to hear their stories,” Grafman said. “I hope we gave something back to them as well, because they gave a whole lot to us.”

To read more about the mind and the brain, visit our collection of archive selections and new stories on the subject.