Blinking and the Brain: Pathways and Pathology

A blink is a rapid bilateral eyelid closure and co-occurring eye movement. The eyes rotate down towards the tip of the nose and back up again. Seemingly, this generally unnoticed often repeated action is not very spectacular. However, if not for the occasional blink we would all be blind. A blink is an interesting phenomenon worth investigating. Through its role as a protective barrier for the eye and as a distributor of the eye’s tearfi lm, blinking is a necessity for our well-being but is also an important tool for neuroscience research and physicians. It is an extremely useful model to study motor performance, motor control, synaptic plasticity and is an excellent physiological instrument for the assessment of internal networks and nuclei [Nishimura, T. and Mori, K, 1996]. The blink rate, refl ex blink characteristics and learned blinks are the three main parameters that can be studied to this end. The blink rate is the frequency with which spontaneous blinks occur and can give information about the dopaminergic system [Karson 1988] and might even be usable as a measure of fatigue [Stern et al. 1994]. The refl ex blink is a rapid involuntary response evoked by external stimulation of the eye or eyelid. It has a protective function and is for instance used in research and physiological tests that use the blink to provide important information on the integrity of afferent and efferent pathways. However, important gaps remain in the knowledge of pathways underlying blinking, and aberrations in pathways or compensatory mechanisms are not fully understood. The learned blink is acquired during eyeblink or eyelid conditioning in which an involuntary blink-evoking stimulus is repeatedly combined with a neutral stimulus. After training the neutral stimulus can evoke the learned blink

Critical slowing down in momentary affect as early warning signal of impending transitions in depression

Based on dynamical systems theory, the current study aimed to investigate if recurrence of depression is systematically preceded by within-person early warning signals (EWS) in positive and negative affect. Ecological momentary assessments were collected 5 times a day for a period of 4 months (averaging 524 assessments per individual) in 37 formerly depressed individuals discontinuing antidepressant medication. EWS (increases in window autocorrelation and variance) preceded recurrence of depression in 32.9% of the participants across robustness checks. Compared to participants that remained in remission, participants with a recurrence showed (1) significantly more positive trends in the variance, but not in autocorrelation, and (2) the average number of significant EWS was over three times larger across tested affect variables. Although the results provide the first systematic evidence that EWS occur more often before the recurrence of depression, the low sensitivity of EWS poses a substantial challenge for clinical applications

Detecting impending symptom transitions using early warning signals in individuals receiving treatment for depression

Background: The path to depressive symptom improvement during therapy is often complex, as many individuals experience periods of instability and discontinuous symptom change. If the process of remission follows complex dynamic systems principles, early warning signals (EWS) may precede such depressive symptom transitions. Aims: We aimed to test whether EWS, in the form of rises in lag-1 autocorrelation and variance, occur in momentary affect time series preceding transitions towards lower levels of depressive symptoms during therapy. We also investigated the presence of EWS in patients without symptom transitions. Methods: In a sample of 41 depressed individuals who were starting psychological treatment, positive affect and negative affect (high and low arousal) were measured five times a day using ecological momentary assessments (EMA) for four months (521 observations per individual on average; yielding 25,197 observations in total), and depressive symptoms were assessed weekly over six months. We used a moving window method and time-varying autoregressive generalized additive modeling (TV-AR GAM) to determine whether EWS occurred in these momentary affect measures, within-persons. Results: For the moving-window autocorrelation, 89% of individuals with transitions showed at least one EWS in one of the variables (versus 62.5% in the no-transition group), and the proportion of EWS in the separate variables was consistently higher (~44% across affect measures) than for individuals without transitions (~27%). Rising variance was found for few individuals, both preceding transitions (~11%) and for individuals without a transition (~12%). Conclusions: The process of symptom remission showed critical slowing down in at least part of our sample. Our findings indicate that EWS are not generic across all affect measures and may have limited value as a personalized prediction method

Pain Experience is Somatotopically Organized and Overlaps with Pain Anticipation in the Human Cerebellum

Many fMRI studies have shown activity in the cerebellum after peripheral nociceptive stimulation. We investigated whether the areas in the cerebellum that were activated after nociceptive thumb stimulation were separate from those after nociceptive toe stimulation. In an additional experiment, we investigated the same for the anticipation of a nociceptive stimulation on the thumb or toe. For his purpose, we used fMRI after an electrical stimulation of the thumb and toe in 19 adult healthy volunteers. Following nociceptive stimulation, different areas were activated by stimulation on the thumb (lobule VI ipsilaterally and Crus II mainly contralaterally) and toe (lobules VIII-IX and IV-V bilaterally and lobule VI contralaterally), i.e., were somatotopically organized. Cerebellar areas innervated non-somatotopically by both toe and thumb stimulation were the posterior vermis and Crus I, bilaterally. In the anticipation experiment, similar results were found. However, here, the somatotopically activated areas were relatively small for thumb and negligible for toe stimulation, while the largest area was innervated non-somatotopically and consisted mainly of Crus I and lobule VI bilaterally. These findings indicate that nociceptive stimulation and anticipation of nociceptive stimulation are at least partly processed by the same areas in the cerebellum. This was confirmed by an additional conjunction analysis. Based on our findings, we hypothesize that input that is organized in a somatotopical manner reflects direct input from the spinal cord, while non-somatotopically activated parts of the cerebellum receive their information indirectly through cortical and subcortical connections, possibly involved in processing contextual emotional states, like the expectation of pain

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations

ein Rückblick auf meine Mitarbeit im Gebiete der Sprach- und Religionswissenschaft

Digitalisat der Ausgabe von 1927, erschienen 201

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms