DEcreased Cognitive functiON, NEurovascular CorrelaTes and myocardial changes in women with a history of pre-eclampsia (DECONNECT): research protocol for a cross-sectional pilot study.

INTRODUCTION: Pre-eclampsia is a hypertensive disorder affecting up to 8% of pregnancies. After pre-eclampsia, women are at increased risk of cognitive problems, and cerebrovascular and cardiovascular disorders. These sequelae could result from microvascular dysfunction persisting after pre-eclampsia. This study will explore differences in cerebral and myocardial microvascular function between women after pre-eclampsia and women after normotensive gestation. We hypothesise that pre-eclampsia alters cerebral and myocardial microvascular functions, which in turn are related to diminished cognitive and cardiac performance. METHODS AND ANALYSIS: The cross-sectional 'DEcreased Cognitive functiON, NEurovascular CorrelaTes and myocardial changes in women with a history of pre-eclampsia' (DECONNECT) pilot study includes women after pre-eclampsia and controls after normotensive pregnancy between 6 months and 20 years after gestation. We recruit women from the Queen of Hearts study, a study investigating subclinical heart failure after pre-eclampsia. Neuropsychological tests are employed to assess different cognitive domains, including attention, processing speed, and cognitive control. Cerebral images are recorded using a 7 Tesla MRI to assess blood-brain barrier integrity, perfusion, blood flow, functional and structural networks, and anatomical dimensions. Cardiac images are recorded using a 3 Tesla MRI to assess cardiac perfusion, strain, dimensions, mass, and degree of fibrosis. We assess the effect of a history of pre-eclampsia using multivariable regression analyses. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of Maastricht University Medical Centre (METC azM/UM, NL47252.068.14). Knowledge dissemination will include scientific publications, presentations at conferences and public forums, and social media. TRIAL REGISTRATION NUMBER: NCT02347540.

Neural Correlates of Tooth Clenching in Patients with Bruxism and Temporomandibular Disorder-Related Pain.

AIMS: To measure brain activity in patients with bruxism and temporomandibular disorder (TMD)-related pain in comparison to controls using functional magnetic resonance imaging (fMRI) and to investigate whether modulations in jaw clenching led to different pain reports and/or changes in neural activity in motor and pain processing areas within and between both groups. METHODS: A total of 40 participants (21 patients with bruxism and TMD-related pain and 19 healthy controls) performed a tooth-clenching task while lying inside a 3T MRI scanner. Participants were instructed to mildly or strongly clench their teeth for brief periods of 12 seconds and to subsequently rate their clenching intensity and pain experience after each clenching period. RESULTS: Patients reported significantly more pain during strong clenching compared to mild clenching. Further results showed significant differences between patients and controls in activity in areas of brain networks commonly associated with pain processing, which were also correlated with reported pain intensity. There was no evidence for differences in activity in motor-related areas between groups, which contrasts with findings of previous research. CONCLUSIONS: Brain activity in patients with bruxism and TMD-related pain is correlated more with pain processing than with motoric differences.

Attenuated cognitive functioning decades after preeclampsia.

BACKGROUND: Preeclampsia, a hypertensive pregnancy disorder, is a leading cause of maternal and fetal morbidity and mortality, with remote cardio- and cerebrovascular implications. After preeclampsia, women may report serious disabling cognitive complaints, especially involving executive function, but the extent and time course of these complaints are unknown. OBJECTIVE: This study aimed to determine the impact of preeclampsia on perceived maternal cognitive functioning decades after pregnancy. STUDY DESIGN: This study is part of a cross-sectional case-control study named Queen of Hearts (ClinicalTrials.gov Identifier: NCT02347540), a collaboration study of 5 tertiary referral centers within the Netherlands investigating long-term effects of preeclampsia. Eligible participants were female patients aged ≥18 years after preeclampsia and after normotensive pregnancy between 6 months and 30 years after their first (complicated) pregnancy. Preeclampsia was defined as new-onset hypertension after 20 weeks of gestation along with proteinuria, fetal growth restriction, or other maternal organ dysfunction. Women with a history of hypertension, autoimmune disease, or kidney disease before their first pregnancy were excluded. Attenuation of higher-order cognitive functions, that is, executive function, was measured with the Behavior Rating Inventory of Executive Function for Adults. Crude and covariate-adjusted absolute and relative risks of clinical attenuation over time after (complicated) pregnancy were determined with moderated logistic and log-binomial regression. RESULTS: This study included 1036 women with a history of preeclampsia and 527 women with normotensive pregnancies. Regarding overall executive function, 23.2% (95% confidence interval, 19.0-28.1) of women experienced clinically relevant attenuation after preeclampsia, as opposed to 2.2% (95% confidence interval, 0.8-6.0) of controls immediately after childbirth (adjusted relative risk, 9.20 [95% confidence interval, 3.33-25.38]). Group differences diminished yet remained statistically significant (P < .05) at least 19 years postpartum. Regardless of history of preeclampsia, women with lower educational attainment, mood or anxiety disorders, or obesity were especially at risk. Neither severity of preeclampsia, multiple gestation, method of delivery, preterm birth, nor perinatal death was related to overall executive function. CONCLUSION: After preeclampsia, women were 9 times more likely to experience clinical attenuation of higher-order cognitive functions as opposed to after normotensive pregnancy. Despite overall steady improvement, elevated risks persisted over decades after childbirth.

Multisensory synchrony of contextual boundaries affects temporal order memory, but not encoding or recognition.

We memorize our daily life experiences, which are often multisensory in nature, by segmenting them into distinct event models, in accordance with perceived contextual or situational changes. However, very little is known about how multisensory boundaries affect segmentation, as most studies have focused on unisensory (visual or audio) segmentation. In three experiments, we investigated the effect of multisensory boundaries on segmentation in memory and perception. In Experiment 1, participants encoded lists of pictures while audio and visual contexts changed synchronously or asynchronously. After each list, we tested recognition and temporal associative memory for pictures that were encoded in the same audio-visual context or that crossed a synchronous or an asynchronous multisensory change. We found no effect of multisensory synchrony for recognition memory: synchronous and asynchronous changes similarly impaired recognition for pictures encoded at those changes, compared to pictures encoded further away from those changes. Multisensory synchrony did affect temporal associative memory, which was worse for pictures encoded at synchronous than at asynchronous changes. Follow up experiments showed that this effect was not due to the higher dimensionality of multisensory over unisensory contexts (Experiment 2), nor that it was due to the temporal unpredictability of contextual changes inherent to Experiment 1 (Experiment 3). We argue that participants formed situational expectations through multisensory synchronicity, such that synchronous multisensory changes deviated more strongly from those expectations than asynchronous changes. We discuss our findings in light of supportive and conflicting findings of uni- and multi-sensory segmentation.

Time changes: Timing contexts support event segmentation in associative memory.

We tend to mentally segment a series of events according to perceptual contextual changes, such that items from a shared context are more strongly associated in memory than items from different contexts. It is also known that timing context provides a scaffold to structure experiences in memory, but its role in event segmentation has not been investigated. We adapted a previous paradigm, which was used to investigate event segmentation using visual contexts, to study the effects of changes in timing contexts on event segmentation in associative memory. In two experiments, we presented lists of 36 items in which the interstimulus intervals (ISIs) changed after a series of six items ranging between 0.5 and 4 s in 0.5 s steps. After each list, participants judged which one of two test items were shown first (temporal order judgment) for items that were either drawn from the same context (within an ISI) or from consecutive contexts (across ISIs). Further, participants judged from memory whether the ISI associated to an item lasted longer than a standard interval (2.25 s) that was not previously shown (temporal source memory). Experiment 2 further included a time-item encoding task. Results revealed an effect of timing context changes in temporal order judgments, with faster responses (Experiment 1) or higher accuracy (Experiment 2) when items were drawn from the same context, as opposed to items drawn from across contexts. Further, in both experiments, we found that participants were well able to provide temporal source memory judgments based on recalled durations. Finally, replicated across experiments, we found subjective duration bias, as estimated by psychometric curve fitting parameters of the recalled durations, correlated negatively with within-context temporal order judgments. These findings show that changes in timing context support event segmentation in associative memory.

7T dynamic contrast-enhanced MRI for the detection of subtle blood-brain barrier leakage.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) can be employed to assess the blood-brain barrier (BBB) integrity. Detection of BBB leakage at lower field strengths (≤3T) is cumbersome as the signal is noisy, while leakage can be subtle. Utilizing the increased signal-to-noise ratio at higher field strengths, we explored the application of 7T DCE-MRI for assessing BBB leakage. METHODS: A dual-time resolution DCE-MRI method was implemented at 7T and a slow injection rate (0.3 ml/s) and low dose (3 mmol) served to obtain signal changes linearly related to the gadolinium concentration, that is, minimized for T2* degradation effects. With the Patlak graphical approach, the leakage rate (Ki ) and blood plasma volume fraction (vp ) were calculated. The method was evaluated in 10 controls, an ischemic stroke patient, and a patient with a transient ischemic attack. RESULTS: Ki and vp were significantly higher in gray matter compared to white matter of all participants. These Ki values were higher in both patients compared to the control subjects. Finally, for the lesion identified in the ischemic stroke patient, higher leakage values were observed compared to normal-appearing tissue. CONCLUSION: We demonstrate how a dual-time resolution DCE-MRI protocol at 7T, with administration of half the clinically used contrast agent dose, can be used for assessing subtle BBB leakage. Although the feasibility of DCE-MRI for assessing the BBB integrity at 3T is well known, we showed that a continuous sampling DCE-MRI method tailored for 7T is also capable of assessing leakage with a high sensitivity over a range of Ki values.

Transcranial alternating current stimulation at theta frequency to left parietal cortex impairs associative, but not perceptual, memory encoding.

Neural oscillations in the theta range (4-8 Hz) are thought to underlie associative memory function in the hippocampal-cortical network. While there is ample evidence supporting a role of theta oscillations in animal and human memory, most evidence is correlational. Non-invasive brain stimulation (NIBS) can be employed to modulate cortical oscillatory activity to influence brain activity, and possibly modulate deeper brain regions, such as hippocampus, through strong and reliable cortico-hippocampal functional connections. We applied focal transcranial alternating current stimulation (tACS) at 6 Hz over left parietal cortex to modulate brain activity in the putative cortico-hippocampal network to influence associative memory encoding. After encoding and brain stimulation, participants completed an associative memory and a perceptual recognition task. Results showed that theta tACS significantly decreased associative memory performance but did not affect perceptual memory performance. These results show that parietal theta tACS modulates associative processing separately from perceptual processing, and further substantiate the hypothesis that theta oscillations are implicated in the cortico-hippocampal network and associative encoding.

Corticolimbic Circuitry in Chronic Pain Tracks Pain Intensity Relief Following Exposure In Vivo.

Background: A subset of patients with chronic pain who receive exposure in vivo (EXP) treatment experience clinically relevant relief of pain intensity. Although pain relief is not an explicit therapeutic target, it is important to understand how and why this concomitant effect occurs in some patients but not others. This longitudinal study therefore aimed to characterize brain plasticity as well as to explore pretreatment factors related to pain relief. Methods: Resting-state functional magnetic resonance imaging data were acquired in 30 patients with chronic pain. Twenty-three patients completed EXP, and 6-month follow-up data were available in 20 patients (magnetic resonance imaging data in 17 patients). Pain-free control data were acquired at two time points (n = 29, n = 21). Seed-based resting-state functional connectivity (rsFC) analyses were performed, with seeds in the amygdala, hippocampus, and nucleus accumbens. Results: Pain relief after EXP was highly variable, with 60% of patients reporting a clinically relevant improvement. Amygdala rsFC with the middle frontal gyrus decreased significantly over time in patients but was not associated with pain relief. In contrast, greater pain relief was associated with greater decreases over time in hippocampus rsFC with the precuneus, which was related to reductions in catastrophizing (EXP therapeutic target) as well. Greater pain relief was also associated with lower pretreatment rsFC between nucleus accumbens and postcentral gyrus. Conclusions: While changes in hippocampus rsFC were associated with pain relief after EXP, pretreatment nucleus accumbens rsFC showed potential prognostic value. Our findings further support the importance of corticolimbic circuitry in chronic pain, emphasizing its relation to pain relief and identifying potential underlying mechanisms and prognostic factors, warranting further testing in independent samples.

Hippocampus plays a role in speech feedback processing.

There is increasing evidence that the hippocampus is involved in language production and verbal communication, although little is known about its possible role. According to one view, hippocampus contributes semantic memory to spoken language. Alternatively, hippocampus is involved in the processing the (mis)match between expected sensory consequences of speaking and the perceived speech feedback. In the current study, we re-analysed functional magnetic resonance (fMRI) data of two overt picture-naming studies to test whether hippocampus is involved in speech production and, if so, whether the results can distinguish between a "pure memory" versus a "prediction" account of hippocampal involvement. In both studies, participants overtly named pictures during scanning while hearing their own speech feedback unimpededly or impaired by a superimposed noise mask. Results showed decreased hippocampal activity when speech feedback was impaired, compared to when feedback was unimpeded. Further, we found increased functional coupling between auditory cortex and hippocampus during unimpeded speech feedback, compared to impaired feedback. Finally, we found significant functional coupling between a hippocampal/supplementary motor area (SMA) interaction term and auditory cortex, anterior cingulate cortex and cerebellum during overt picture naming, but not during listening to one's own pre-recorded voice. These findings indicate that hippocampus plays a role in speech production that is in accordance with a "prediction" view of hippocampal functioning.

Hippocampal-striatal functional connectivity supports processing of temporal expectations from associative memory.

The hippocampus and dorsal striatum are both associated with temporal processing, but they are thought to play distinct roles. The hippocampus has been reported to contribute to storing temporal structure of events in memory, whereas the striatum contributes to temporal motor preparation and reward anticipation. Here, we asked whether the striatum cooperates with the hippocampus in processing the temporal context of memorized visual associations. In our task, participants were trained to implicitly form temporal expectations for one of two possible time intervals associated to specific cue-target associations, and subsequently were scanned using ultra-high-field 7T functional magnetic resonance imaging. During scanning, learned temporal expectations could be violated when the pairs were presented at either the associated or not-associated time intervals. When temporal expectations were met during testing trials, activity in left and right hippocampal subfields and right putamen decreased, compared to when temporal expectations were not met. Further, psycho-physiological interactions showed that functional connectivity between left hippocampal subfields and caudate decreased when temporal expectations were not met. Our results indicate that the hippocampus and striatum cooperate to process implicit temporal expectation from mnemonic associations. Our findings provide further support for a hippocampal-striatal network in temporal associative processing.