De-identification procedures for magnetic resonance images and the impact on structural brain measures at different ages.

Surface rendering of MRI brain scans may lead to identification of the participant through facial characteristics. In this study, we evaluate three methods that overwrite voxels containing privacy-sensitive information: Face Masking, FreeSurfer defacing, and FSL defacing. We included structural T1-weighted MRI scans of children, young adults and older adults. For the young adults, test-retest data were included with a 1-week interval. The effects of the de-identification methods were quantified using different statistics to capture random variation and systematic noise in measures obtained through the FreeSurfer processing pipeline. Face Masking and FSL defacing impacted brain voxels in some scans especially in younger participants. FreeSurfer defacing left brain tissue intact in all cases. FSL defacing and FreeSurfer defacing preserved identifiable characteristics around the eyes or mouth in some scans. For all de-identification methods regional brain measures of subcortical volume, cortical volume, cortical surface area, and cortical thickness were on average highly replicable when derived from original versus de-identified scans with average regional correlations >.90 for children, young adults, and older adults. Small systematic biases were found that incidentally resulted in significantly different brain measures after de-identification, depending on the studied subsample, de-identification method, and brain metric. In young adults, test-retest intraclass correlation coefficients (ICCs) were comparable for original scans and de-identified scans with average regional ICCs >.90 for (sub)cortical volume and cortical surface area and ICCs >.80 for cortical thickness. We conclude that apparent visual differences between de-identification methods minimally impact reliability of brain measures, although small systematic biases can occur.

Using subjective expectations to model the neural underpinnings of proactive inhibition.

Proactive inhibition - the anticipation of having to stop a response - relies on objective information contained in cue-related contingencies in the environment, as well as on the subjective interpretation derived from these cues. To date, most studies of brain areas underlying proactive inhibition have exclusively considered the objective predictive value of environmental cues, by varying the probability of stop-signals. However, by only taking into account the effect of different cues on brain activation, the subjective component of how cues affect behavior is ignored. We used a modified stop-signal response task that includes a measurement for subjective expectation, to investigate the effect of this subjective interpretation. After presenting a cue indicating the probability that a stop-signal will occur, subjects were asked whether they expected a stop-signal to occur. Furthermore, response time was used to retrospectively model brain activation related to stop-expectation. We found more activation during the cue period for 50% stop-signal probability, when contrasting with 0%, in the mid and inferior frontal gyrus, inferior parietal lobe and putamen. When contrasting expected vs. unexpected trials, we found modest effects in the mid frontal gyrus, parietal, and occipital areas. With our third contrast, we modeled brain activation during the cue with trial-by-trial variances in response times. This yielded activation in the putamen, inferior parietal lobe, and mid frontal gyrus. Our study is the first to use the behavioral effects of proactive inhibition to identify the underlying brain regions, by employing an unbiased task-design that temporally separates cue and response.

The role of stop-signal probability and expectation in proactive inhibition.

The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop-signal probability and the subjective expectation that a stop-signal will or will not occur. Here we investigated the effects of stop-signal probability and the expectation of a stop-signal on proactive inhibition. Twenty participants performed a modified stop-signal anticipation task while being scanned with functional magnetic resonance imaging. At the beginning of each trial, the stop-signal probability was indicated by a cue (0% or > 0%), and participants had to indicate whether they expected a stop-signal to occur (yes/no/don't know). Participants slowed down responding on trials with a > 0% stop-signal probability, but this proactive response slowing was even greater when they expected a stop-signal to occur. Analyses were performed in brain regions previously associated with proactive inhibition. Activation in the striatum, supplementary motor area and left dorsal premotor cortex during the cue period was increased when participants expected a stop-signal to occur. In contrast, activation in the right inferior frontal gyrus and right inferior parietal cortex activity during the stimulus-response period was related to the processing of contextual cues signalling objective stop-signal probability, regardless of expectation. These data show that proactive inhibition depends on both the processing of objective contextual task information and the subjective expectation of stop-signals.

Distinct neural responses to conscious versus unconscious monetary reward cues.

Human reward pursuit is often assumed to involve conscious processing of reward information. However, recent research revealed that reward cues enhance cognitive performance even when perceived without awareness. Building on this discovery, the present functional MRI study tested two hypotheses using a rewarded mental-rotation task. First, we examined whether subliminal rewards engage the ventral striatum (VS), an area implicated in reward anticipation. Second, we examined differences in neural responses to supraliminal versus subliminal rewards. Results indicated that supraliminal, but not subliminal, high-value reward cues engaged brain areas involved in reward processing (VS) and task performance (supplementary motor area, motor cortex, and superior temporal gyrus). This pattern of findings is striking given that subliminal rewards improved performance to the same extent as supraliminal rewards. So, the neural substrates of conscious versus unconscious reward pursuit are vastly different-but despite their differences, conscious and unconscious reward pursuit may still produce the same behavioral outcomes.

Underlying Neural Mechanisms of Cognitive Improvement in Fronto-striatal Response Inhibition in People Living with HIV Switching Off Efavirenz: A Randomized Controlled BOLD fMRI Trial.

INTRODUCTION: It is unclear whether neurotoxicity due to the antiretroviral drug efavirenz (EFV) results in neurocognitive impairment in people living with HIV (PLWH). Previously, we found that discontinuing EFV was associated with improved processing speed and attention on neuropsychological assessment. In this imaging study, we investigate potential neural mechanisms underlying this cognitive improvement using a BOLD fMRI task assessing cortical and subcortical functioning. METHODS: Asymptomatic adult PLWH stable on emtricitabine/tenofovirdisoproxil/efavirenz were randomly (1:2) assigned to continue their regimen (n = 12) or to switch to emtricitabine/tenofovirdisoproxil/rilpivirine (n = 28). At baseline and after 12 weeks, both groups performed the Stop-Signal Anticipation Task, which tests reactive and proactive inhibition (indicative of subcortical and cortical functioning, respectively), involving executive functioning, working memory, and attention. Behavior and BOLD fMRI activation levels related to processing speed and attention Z-scores were assessed in 17 pre-defined brain regions. RESULTS: Both groups had comparable patient and clinical characteristics. Reactive inhibition behavioral responses improved for both groups on week 12, with other responses unchanged. Between-group activation did not differ significantly. For reactive inhibition, positive Pearson coefficients were observed for the change in BOLD fMRI activation levels and change in processing speed and attention Z-scores in all 17 regions in participants switched to emtricitabine/tenofovir disoproxil/rilpivirine, whereas in the control group, negative correlation coefficients were observed in 10/17 and 13/17 regions, respectively. No differential pattern was observed for proactive inhibition. CONCLUSION: Potential neural mechanisms underlying cognitive improvement after discontinuing EFV in PLWH were found in subcortical functioning, with our findings suggesting that EFV's effect on attention and processing speed is, at least partially, mediated by reactive inhibition. TRIAL REGISTRATION: Clinicaltrials.gov identifier [NCT02308332].

The Effect of Efavirenz on Reward Processing in Asymptomatic People Living with HIV: A Randomized Controlled Trial.

Functional magnetic resonance imaging (fMRI) studies have demonstrated that HIV-infection affects the fronto-striatal network. It has not been examined what impact efavirenz (EFV), an antiretroviral drug notorious for its neurocognitive effects, has on the reward system: a key subcomponent involved in depressive and apathy symptoms. Therefore, this study aims to investigate the effect of EFV on reward processing using a monetary incentive delay (MID) task. In this multicenter randomized controlled trial, asymptomatic adult participants stable on emtricitabine/tenofovirdisoproxil fumarate (FTC/TDF)/EFV were randomly assigned in a 2:1 ratio to switch to FTC/TDF/rilpivirine (RPV) (n = 30) or continue taking FTC/TDF/EFV (n = 13). At baseline and 12 weeks after therapy switch, both groups performed an MID task. Behavior and functional brain activity related to reward anticipation and reward outcome were assessed with blood-oxygen-level-dependent fMRI. Both groups were matched for age, education level, and time since HIV diagnosis and on EFV. At the behavioral level, both groups had faster response times and better response accuracy during rewarding versus nonrewarding trials, with no improvement resulting from switching FTC/TDF/EFV to FTC/TDF/RPV. No significant change in activation related to reward anticipation in the ventral striatum was found after switching therapy. Both groups had significantly higher activation levels over time, consistent with a potential learning effect. Similar activity related to reward outcome in the orbitofrontal cortex was found. Discontinuing FTC/TDF/EFV was not found to improve activity related to reward anticipation in asymptomatic people living with HIV, with similar cortical functioning during reward outcome processing. It is therefore likely that EFV does not affect motivational control. Further research is needed to determine whether EFV affects motivational control in HIV populations with different characteristics.

Adverse childhood experiences and fronto-subcortical structures in the developing brain.

The impact of adverse childhood experiences (ACEs) differs between individuals and depends on the type and timing of the ACE. The aim of this study was to assess the relation between various recently occurred ACEs and morphology in the developing brain of children between 8 and 11 years of age. We measured subcortical volumes, cortical thickness, cortical surface area and fractional anisotropy in regions of interest in brain scans acquired in 1,184 children from the YOUth cohort. ACEs were based on parent-reports of recent experiences and included: financial problems; parental mental health problems; physical health problems in the family; substance abuse in the family; trouble with police, justice or child protective services; change in household composition; change in housing; bereavement; divorce or conflict in the family; exposure to violence in the family and bullying victimization. We ran separate linear models for each ACE and each brain measure. Results were adjusted for the false discovery rate across regions of interest. ACEs were reported for 83% of children in the past year. Children were on average exposed to two ACEs. Substance abuse in the household was associated with larger cortical surface area in the left superior frontal gyrus, t(781) = 3.724, p FDR = 0.0077, right superior frontal gyrus, t(781) = 3.409, p FDR = 0.0110, left pars triangularis, t(781) = 3.614, p FDR = 0.0077, left rostral middle frontal gyrus, t(781) = 3.163, p FDR = 0.0195 and right caudal anterior cingulate gyrus, t(781) = 2.918, p FDR = 0.0348. Household exposure to violence (was associated with lower fractional anisotropy in the left and right cingulum bundle hippocampus region t(697) = -3.154, p FDR = 0.0101 and t(697) = -3.401, p FDR = 0.0085, respectively. Lower household incomes were more prevalent when parents reported exposure to violence and the mean parental education in years was lower when parents reported substance abuse in the family. No other significant associations with brain structures were found. Longer intervals between adversity and brain measurements and longitudinal measurements may reveal whether more evidence for the impact of ACEs on brain development will emerge later in life.

Right inferior frontal gyrus and ventromedial prefrontal activation during response inhibition is implicated in the development of PTSD symptoms.

Background: Inhibition is a critical executive control process and an established neurobiological phenotype of PTSD, yet to our knowledge, no prospective studies have examined this using a contextual cue task that enables measurement of behavioural response and neural activation patterns across proactive and reactive inhibition. Objective: The current longitudinal study utilised functional magnetic resonance imaging (fMRI) to examine whether deficits in proactive and reactive inhibition predicted PTSD symptoms six months after trauma. Method: Twenty-three (65% males) medical patients receiving emergency medical care from a level 1 trauma centre were enrolled in the study and invited for an MRI scan 1-2-months post-trauma. PTSD symptoms were measured using self-report at scan and 6-months post-trauma. A stop-signal anticipation task (SSAT) during an fMRI scan was used to test whether impaired behavioural proactive and reactive inhibition, and reduced activation in right inferior frontal gyrus (rIFG), ventromedial prefrontal cortex (vmPFC), and bilateral hippocampus, were related to PTSD symptoms. We predicted that lower activation levels of vmPFC and rIFG during reactive inhibition and lower activation of hippocampus and rIFG during proactive inhibition would relate to higher 6-month PTSD symptoms. Results: No significant associations were found between behavioural measures and 6-month PTSD. Separate linear regression analyses showed that reduced rIFG activation (F1,21 = 9.97, R2 = .32, p = .005) and reduced vmPFC activation (F1,21 = 5.19, R2 = .20, p = .03) significantly predicted greater 6-month PTSD symptoms; this result held for rIFG activation controlling for demographic variables and baseline PTSD symptoms (ß = -.45, p = .04) and Bonferroni correction. Conclusion: Our findings suggest that impaired rIFG and, to a lesser extent, vmPFC activation during response inhibition may predict the development of PTSD symptoms following acute trauma exposure. Given the small sample size, future replication studies are needed. HIGHLIGHTS: Impaired inhibition may be an important risk factor for the development of PTSD following trauma, with less right inferior frontal gyrus and ventromedial prefrontal cortex activation during response inhibition predicting PTSD development.

Antecedentes: La inhibición es un proceso de control ejecutivo crítico, y un fenotipo neurobiológico establecido del TEPT, sin embargo, en nuestro conocimiento no hay estudios prospectivos que hayan examinado esto usando una tarea con claves contextuales que permita medir la respuesta conductual y los patrones de activación neuronal en la inhibición proactiva y reactiva.Objetivo: El siguiente estudio es de diseño longitudinal y utilizó resonancia magnética funcional (fMRI por sus siglas en inglés) para examinar si los déficit en inhibición proactiva y reactiva predijeron los síntomas de TEPT 6 meses después del trauma.Método: 23 pacientes (65% hombres) que recibieron cuidado médico de emergencia en un centro de trauma nivel 1 se enrolaron en el estudio y se les invitó a una RNM (resonancia nuclear magnética) 1­2 meses después del trauma. Los síntomas de TEPT se midieron usando auto-reporte al momento de la exploración y 6 meses después del trauma. Se uso una tarea de anticipación de señal de parada (SSAT por sus siglas en inglés) durante la RNM funcional para evaluar si la alteración en la inhibición proactiva y reactiva, y la reducción de la activación en el giro frontal inferior derecho (rIFG por sus siglas en inglés), la corteza prefrontal ventromedial (vmPFC por sus siglas en inglés), y el hipocampo bilateral, estuvieron relacionadas a los síntomas de TEPT. Predijimos que niveles bajos de activación de vmPFC y rIFG durante la inhibición proactiva se relacionaría con mayores síntomas de TEPT a los 6 meses.Resultados: No se encontraron asociaciones significativas entre medidas conductuales y TEPT a los 6 meses. Los análisis de regresión lineal separados mostraron que una activación reducida de rIFG (F1,21 = 9.97, R2 = .32, p = .005) y una activación reducida de vmPFC (F1,21 = 5.19, R2 = .20, p = .03) predijeron significativamente mayores síntomas de TEPT a los 6 meses; este resultado fue corroborado para la activación de rIFG controlando para variables demográficas y síntomas basales de TEPT (ß = −.45, p = .04) y para la corrección de Bonferroni.Conclusión: Nuestros hallazgos sugieren que una rIFG deficiente y, en menor grado, la activación del vmPFC durante la inhibición de la respuesta pueden predecir el desarrollo de síntomas de TEPT tras la exposición a un trauma agudo. Dado lo pequeño de la muestra, se requieren futuros estudios de replicación.

Towards an integrated account of the development of self-regulation from a neurocognitive perspective: A framework for current and future longitudinal multi-modal investigations.

Self-regulation is the ability to monitor and modulate emotions, behaviour, and cognition in order to adapt to changing circumstances. Developing adequate self-regulation is associated with better social coping and higher educational achievement later in life; poor self-regulation has been linked to a variety of detrimental developmental outcomes. Here, we focus on the development of neurocognitive processes essential for self-regulation. We outline a conceptual framework emphasizing that this is inherently an integrated, dynamic process involving interactions between brain maturation, child characteristics (genetic makeup, temperament, and pre- and perinatal factors) and environmental factors (family characteristics, parents and siblings, peers, and broader societal influences including media development). We introduce the Consortium of Individual Development (CID), which combines a series of integrated large-scale, multi-modal, longitudinal studies to take essential steps towards the ultimate goal of understanding and supporting this process.

The YOUth cohort study: MRI protocol and test-retest reliability in adults.

The YOUth cohort study is a unique longitudinal study on brain development in the general population. As part of the YOUth study, 2000 children will be included at 8, 9 or 10 years of age and planned to return every three years during adolescence. Magnetic resonance imaging (MRI) brain scans are collected, including structural T1-weighted imaging, diffusion-weighted imaging (DWI), resting-state functional MRI and task-based functional MRI. Here, we provide a comprehensive report of the MR acquisition in YOUth Child & Adolescent including the test-retest reliability of brain measures derived from each type of scan. To measure test-retest reliability, 17 adults were scanned twice with a week between sessions using the full YOUth MRI protocol. Intraclass correlation coefficients were calculated to quantify reliability. Global brain measures derived from structural T1-weighted and DWI scans were reliable. Resting-state functional connectivity was moderately reliable, as well as functional brain measures for both the inhibition task (stop versus go) and the emotion task (face versus house). Our results complement previous studies by presenting reliability results of regional brain measures collected with different MRI modalities. YOUth facilitates data sharing and aims for reliable and high-quality data. Here we show that using the state-of-the art YOUth MRI protocol brain measures can be estimated reliably.

The YOUth study: Rationale, design, and study procedures.

Behavioral development in children shows large inter-individual variation, and is driven by the interplay between biological, psychological, and environmental processes. However, there is still little insight into how these processes interact. The YOUth cohort specifically focuses on two core characteristics of behavioral development: social competence and self-regulation. Social competence refers to the ability to engage in meaningful interactions with others, whereas self-regulation is the ability to control one's emotions, behavior, and impulses, to balance between reactivity and control of the reaction, and to adjust to the prevailing environment. YOUth is an accelerated population-based longitudinal cohort study with repeated measurements, centering on two groups: YOUth Baby & Child and YOUth Child & Adolescent. YOUth Baby & Child aims to include 3,000 pregnant women, their partners and children, wheras YOUth Child & Adolescent aims to include 2,000 children aged between 8 and 10 years old and their parents. All participants will be followed for at least 6 years, and potentially longer. In this paper we describe in detail the design of this study, the population included, the determinants, intermediate neurocognitive measures and outcomes included in the study. Furthermore, we describe in detail the procedures of inclusion, informed consent, and study participation.

Striatal activity during reactive inhibition is related to the expectation of stop-signals.

Successful response inhibition relies on the suppression of motor cortex activity. The striatum has previously been linked to motor cortex suppression during the act of inhibition (reactive), but activation was also seen during anticipation of stop signals (proactive). More specifically, striatal activation increased with a higher stop probability. Using functional magnetic resonance imaging with specific regions of interest, we investigate for the first time whether activation in the striatum during reactive inhibition is related to previously formed expectations. We used a modified stop-signal response task in which subjects were asked trial by trial, after being presented a stop-signal probability cue, whether they actually expected a stop to occur. This enabled us to investigate the subjective expectation of a stop signal during each trial. We found that striatal activity during reactive inhibition was higher when subjects expected stop signals. These results help explain conflicting findings of previous studies on the association between striatal activation and inhibition, since we demonstrate a crucial role of the subjects' expectation of a stop signal and thus their ability to prepare for a stop in advance. In conclusion, the current results show for the first time that striatal contributions to reactive response inhibition are, in part, related to subjective anticipation.

Effort responses to suboptimal reward cues are related to striatal dopaminergic functioning.

Reward cues have been found to increase the investment of effort in tasks even when cues are presented suboptimally (i.e. very briefly), making them hard to consciously detect. Such effort responses to suboptimal reward cues are assumed to rely mainly on the mesolimbic dopamine system, including the ventral striatum. To provide further support for this assumption, we performed two studies investigating whether these effort responses vary with individual differences in markers of striatal dopaminergic functioning. Study 1 investigated the relation between physical effort responses and resting state eye-blink rate. Study 2 examined cognitive effort responses in relation to individually averaged error-related negativity. In both studies effort responses correlated with the markers only for suboptimal, but not for optimal reward cues. These findings provide further support for the idea that effort responses to suboptimal reward cues are mainly linked to the mesolimbic dopamine system, while responses to optimal reward cues also depend on higher-level cortical functions.