Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Multimodal hypersensitivity derived from quantitative sensory testing predicts pelvic pain outcome: an observational cohort study.

ABSTRACT: Multimodal hypersensitivity (MMH)-greater sensitivity across multiple sensory modalities (eg, light, sound, temperature, pressure)-is associated with the development of chronic pain. However, previous MMH studies are restricted given their reliance on self-reported questionnaires, narrow use of multimodal sensory testing, or limited follow-up. We conducted multimodal sensory testing on an observational cohort of 200 reproductive-aged women, including those at elevated risk for chronic pelvic pain conditions and pain-free controls. Multimodal sensory testing included visual, auditory, and bodily pressure, pelvic pressure, thermal, and bladder pain testing. Self-reported pelvic pain was examined over 4 years. A principal component analysis of sensory testing measures resulted in 3 orthogonal factors that explained 43% of the variance: MMH, pressure pain stimulus response, and bladder hypersensitivity. The MMH and bladder hypersensitivity factors correlated with baseline self-reported menstrual pain, genitourinary symptoms, depression, anxiety, and health. Over time, MMH increasingly predicted pelvic pain and was the only component to predict outcome 4 years later, even when adjusted for baseline pelvic pain. Multimodal hypersensitivity was a better predictor of pelvic pain outcome than a questionnaire-based assessment of generalized sensory sensitivity. These results suggest that MMHs overarching neural mechanisms convey more substantial long-term risk for pelvic pain than variation in individual sensory modalities. Further research on the modifiability of MMH could inform future treatment developments in chronic pain.

Bladder Pain Sensitivity Is a Potential Risk Factor for Irritable Bowel Syndrome.

BACKGROUND: Although dysmenorrhea is a highly prevalent risk factor for irritable bowel syndrome (IBS), the factors underlying this risk are not fully understood. Prior studies support a hypothesis that repeated distressing menstrual pain promotes cross-organ pelvic sensitization with heightened visceral sensitivity. AIMS: To further explore cross-organ pelvic sensitization we examined the association of dysmenorrhea, provoked bladder pain, and other putative factors with self-reported IBS-domain pain frequency and new onset after 1-year follow up. METHODS: We measured visceral pain sensitivity with a noninvasive provoked bladder pain test in a cohort of reproductive-aged women, enriched for those reporting moderate-to-severe menstrual pain intensity but without any prior IBS diagnosis (n = 190). We analyzed the relationship between menstrual pain, provoked bladder pain, pain catastrophizing, anxiety, and depression with primary outcomes: (1) frequency of self-reported IBS-domain pain and (2) new onset of IBS-domain pain after 1-year follow up. RESULTS: All hypothesized factors correlated with the frequency of IBS-domain pain (p's ≤ 0.038). In a cross-sectional model, only menstrual pain (standardized adjusted odds ratio 2.07), provoked bladder pain (1.49), and anxiety (1.90) were independently associated with IBS-domain pain ≥ 2 days/month (C statistic = 0.79). One year later, provoked bladder pain (3.12) was the only significant predictor of new onset IBS-domain pain (C statistic = 0.87). CONCLUSION: Increased visceral sensitivity among women with dysmenorrhea could lead to IBS. Because provoked bladder pain predicted subsequent IBS, prospective studies should be performed to see if the early treatment of visceral hypersensitivity mitigates IBS.

Differential effects of semantic distance, distractor salience, and relations in verbal analogy.

Prior studies of A:B::C:D verbal analogies have identified several factors that affect performance, including the semantic similarity between source and target domains (semantic distance), the semantic association between the C-term and incorrect answers (distracter salience), and the type of relations between word pairs. However, it is unclear how these stimulus properties affect performance when utilized together. To test their interactive effects, we created a verbal analogy stimulus set that factorially crossed these factors and presented participants with an analogical stem (A:B::C:?) with two response choices: an analogically correct (D) and incorrect distracter (D') term. The semantic distance between source and target word pairs was manipulated creating near (BOWL:DISH::SPOON:SILVERWARE) and far (WRENCH:TOOL::SAD:MOOD) analogies. The salience of an incorrect distracter (D') was manipulated using the sematic distance with the C-term creating low (DRAWER) and high (FORK) salience distracters. Causal, compositional, and categorical relations were presented across these conditions. Accuracies were higher for semantically near than far analogies and when distracter salience was low than high. Categorical relations yielded better performance than the causal and compositional relations. Moreover, a three-way interaction demonstrated that the effects of semantic distance and distracter salience had a greater impact on performance for compositional and causal relations than for the categorical ones. We theorize that causal and compositional analogies, given their less semantically constrained responses, require more inhibitory control than more constraining relations (e.g., categorical).

Cortical mechanisms of visual hypersensitivity in women at risk for chronic pelvic pain.

ABSTRACT: Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n = 147) who had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. We administered 2 experimental tasks to evaluate the cross-modal relationship between visual and visceral sensitivity. Visual sensitivity was probed by presenting participants with a periodic pattern-reversal checkerboard stimulus presented across 5 brightness intensities during electroencephalography recording. Self-reported visual unpleasantness ratings for each brightness intensity were simultaneously assessed. Visceral sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visually evoked cortical activity increased with brightness intensity across the entire scalp, especially at occipital electrode sites. Visual stimulation-induced unpleasantness was associated with provoked bladder pain and evoked primary visual cortex activity. However, the relationship between unpleasantness and cortical activity was moderated by provoked bladder pain. These results demonstrate that activity in the primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.

Cortical Mechanisms of Visual Hypersensitivity in Women at Risk for Chronic Pelvic Pain.

Multisensory hypersensitivity (MSH), which refers to persistent discomfort across sensory modalities, is a risk factor for chronic pain. Developing a better understanding of the neural contributions of disparate sensory systems to MSH may clarify its role in the development of chronic pain. We recruited a cohort of women ( n =147) enriched with participants with menstrual pain at risk for developing chronic pain. Visual sensitivity was measured using a periodic pattern-reversal stimulus during EEG. Self-reported visual unpleasantness ratings were also recorded. Bladder pain sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visual stimulation induced unpleasantness was associated with bladder pain and evoked primary visual cortex excitation; however, the relationship between unpleasantness and cortical excitation was moderated by bladder pain. Thus, future studies aimed at reversing the progression of MSH into chronic pain should prioritize targeting of cortical mechanisms responsible for maladaptive sensory input integration.

Navigating Increasing Levels of Relational Complexity: Perceptual, Analogical, and System Mappings.

Relational thinking involves comparing abstract relationships between mental representations that vary in complexity; however, this complexity is rarely made explicit during everyday comparisons. This study explored how people naturally navigate relational complexity and interference using a novel relational match-to-sample (RMTS) task with both minimal and relationally directed instruction to observe changes in performance across three levels of relational complexity: perceptual, analogy, and system mappings. Individual working memory and relational abilities were examined to understand RMTS performance and susceptibility to interfering relational structures. Trials were presented without practice across four blocks, and participants received feedback after each attempt to guide learning. Experiment 1 instructed participants to select the target that best matched the sample, whereas Experiment 2 additionally directed participants' attention to same and different relations. Participants in Experiment 2 demonstrated improved performance when solving analogical mappings, suggesting that directing attention to relational characteristics affected behavior. Higher performing participants-those with above-chance performance on the final block of system mappings-solved more analogical RMTS problems and had greater visuospatial working memory, abstraction, verbal analogy, and scene analogy scores compared to lower performers. Lower performers were less dynamic in their performance across blocks and demonstrated negative relationships between analogy and system mapping accuracy, suggesting increased interference between these relational structures. Participant performance on RMTS problems did not change monotonically with relational complexity, suggesting that increases in relational complexity places nonlinear demands on working memory. We argue that competing relational information causes additional interference, especially in individuals with lower executive function abilities.

Executive function training in chronic traumatic brain injury patients: study protocol.

BACKGROUND: Some individuals who sustain traumatic brain injuries (TBIs) continue to experience significant cognitive impairments chronically (months to years post injury). Many tests of executive function are insensitive to these executive function impairments, as such impairments may only appear during complex daily life conditions. Daily life often requires us to divide our attention and focus on abstract goals. In the current study, we compare the effects of two 1-month electronic cognitive rehabilitation programs for individuals with chronic TBI. The active program (Expedition: Strategic Advantage) focuses on improving goal-directed executive functions including working memory, planning, long-term memory, and inhibitory control by challenging participants to accomplish life-like cognitive simulations. The challenge level of the simulations increases in accordance with participant achievement. The control intervention (Expedition: Informational Advantage) is identical to the active program; however, the cognitive demand level is capped, preventing participants from advancing beyond a set level. We will evaluate these interventions with a military veteran TBI population. METHODS/DESIGN: One hundred individuals will be enrolled in this double-blinded clinical trial (all participants and testers are blinded to condition). Each individual will be randomly assigned to one of two interventions. The primary anticipated outcomes are improvement of daily life cognitive function skills and daily life functions. These are measured by a daily life performance task, which tests cognitive skills, and a survey that evaluates daily life functions. Secondary outcomes are also predicted to include improvements in working memory, attention, planning, and inhibitory control as measured by a neuropsychological test battery. Lastly, neuroimaging measures will be used to evaluate changes in brain networks supporting cognition pre and post intervention. DISCUSSION: We will test whether electronically delivered cognitive rehabilitation aimed at improving daily life functional skills will provide cognitive and daily life functional improvements for individuals in the chronic phase of TBI recovery (greater than 3 months post injury). We aim to better understand the cognitive processes involved in recovery and the characteristics of individuals most likely to benefit. This study will also address the potential to observe generalizability or to transfer from a software-based cognitive training tool toward daily life improvement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03704116 . Retrospectively registered on 12 Oct 2018.

The time course of semantic and relational processing during verbal analogical reasoning.

Analogy is an important ability that allows humans to discover relationships between information domains that often vary in surface and relational characteristics. Cognitive neuroscience studies of analogy have demonstrated the importance of the prefrontal cortex during relational comparisons, but little is known about how semantic and relational similarity interact throughout its time course. We used scalp electroencephalography (EEG) analyzed with event-related potentials (ERPs) to examine the neural time course of analogical reasoning while 16 participants solved four-term verbal analogies. Semantic similarity was manipulated by increasing the semantic distance between source and target analogs creating semantically near and far analogies. Relational similarity was manipulated by creating relationally valid and invalid analogies. Only valid analogies were impacted by semantic distance such that far analogies were solved slower and less accurately than near analogies. Correctly solving near analogies elicited more positive waveforms at the N400 and during later relational processing. However, valid analogies elicited more positive signals during only later relational processing and not during the N400. These results suggest that semantic information impacts both early semantic and late relational comparison stages, while relational properties exert more influence in later stages of analogical reasoning. The degree of semantic similarity shared between knowledge domains demonstrated a potent effect throughout the time course of analogy that affected not only semantic access, but also the mapping of relational structures.

A method for characterizing semantic and lexical properties of sentence completions in traumatic brain injury.

Clinical investigations of individuals with chronic stage traumatic brain injury (TBI) showing mild-to-moderate levels of residual impairment largely use standardized neuropsychological assessments to measure executive functioning. The Hayling Sentence Completion Test (HSCT) relies upon several executive functions but detects cognitive impairments across studies inconsistently. We sought to (a) further characterize sentence completions on the HSCT by quantifying their semantic and lexical properties and (b) investigate cognitive components important for HSCT performance. A sample of 108 mild-to-moderate participants with TBI underwent a comprehensive neuropsychological assessment that evaluated verbal ability, working memory, processing speed, task switching, and inhibitory control. Multiple regression analyses suggest that these 5 cognitive components differentially contribute to describing HSCT performance and measures of semantic and lexical properties of unconnected sentence completions. Across all 3 measures, verbal ability was most predictive of performance, while inhibitory control was the least predictive. Working memory capacity also predicted HSCT performance, while processing speed and task switching ability predicted lexical measures. We present a method for quantitatively measuring the semantic and lexical properties of generated words on the HSCT and how these additional measures relate to executive functions. (PsycINFO Database Record

Emotionally anesthetized: media violence induces neural changes during emotional face processing.

Media violence exposure causes increased aggression and decreased prosocial behavior, suggesting that media violence desensitizes people to the emotional experience of others. Alterations in emotional face processing following exposure to media violence may result in desensitization to others' emotional states. This study used scalp electroencephalography methods to examine the link between exposure to violence and neural changes associated with emotional face processing. Twenty-five participants were shown a violent or nonviolent film clip and then completed a gender discrimination stop-signal task using emotional faces. Media violence did not affect the early visual P100 component; however, decreased amplitude was observed in the N170 and P200 event-related potentials following the violent film, indicating that exposure to film violence leads to suppression of holistic face processing and implicit emotional processing. Participants who had just seen a violent film showed increased frontal N200/P300 amplitude. These results suggest that media violence exposure may desensitize people to emotional stimuli and thereby require fewer cognitive resources to inhibit behavior.