Acute neural effects of the mood stabiliser lamotrigine on emotional processing in healthy volunteers: a randomised control trial.

Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p < 0.05. Participants receiving lamotrigine were more accurate at identifying the gender of fearful (but not happy or angry) faces. A network of regions associated with emotional processing, including amygdala, insula, and the anterior cingulate cortex (ACC), was significantly less activated in the lamotrigine group compared to the placebo group across emotional facial expressions. A single dose of lamotrigine reduced activation in limbic areas in response to faces with both positive and negative expressions, suggesting a valence-independent effect. However, at a behavioural level lamotrigine appeared to reduce the distracting effect of fear on face discrimination. Such effects may be relevant to the mood stabilisation effects of lamotrigine.

A temperature-controlled cooling system for accurate quantitative post-mortem MRI.

PURPOSE: To develop a temperature-controlled cooling system to facilitate accurate quantitative post-mortem MRI and enable scanning of unfixed tissue. METHODS: A water cooling system was built and integrated with a 7T scanner to minimize temperature drift during MRI scans. The system was optimized for operational convenience and rapid deployment to ensure efficient workflow, which is critical for scanning unfixed post-mortem samples. The performance of the system was evaluated using a 7-h diffusion MRI protocol at 7T with a porcine tissue sample. Quantitative T1 , T2 , and ADC maps were interspersed with the diffusion scans at seven different time points to investigate the temperature dependence of MRI tissue parameters. The impact of temperature changes on biophysical model fitting of diffusion MRI data was investigated using simulation. RESULTS: Tissue T1 , T2 , and ADC values remained stable throughout the diffusion MRI scan using the developed cooling system, but varied substantially using a conventional scan setup without temperature control. The cooling system enabled accurate estimation of biophysical model parameters by stabilizing the tissue temperature throughout the diffusion scan, while the conventional setup showed evidence of significantly biased estimation. CONCLUSION: A temperature-controlled cooling system was developed to tackle the challenge of heating in post-mortem imaging, which shows potential to improve the accuracy and reliability of quantitative post-mortem imaging and enables long scans of unfixed tissue.

Self-modulation of motor cortex activity after stroke: a randomized controlled trial.

Real-time functional MRI neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders that are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial (ClinicalTrials.gov: NCT03775915) in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n = 12) or Sham (n = 12) neurofeedback. Assessments of brain structure, brain function and measures of upper-limb function were carried out before and 1 week after neurofeedback training. Additionally, measures of upper-limb function were repeated 1 month after neurofeedback training. Primary outcome measures were (i) changes in lateralization of motor cortex activity during movements of the stroke-affected hand throughout neurofeedback training days; and (ii) changes in motor performance of the affected limb on the Jebsen Taylor Test (JTT). Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within (P = 0.019), but not across, training days. There was no group effect on the primary behavioural outcome measure, which was average JTT performance across all subtasks (P = 0.116). Secondary analysis found improvements in the performance of the gross motor subtasks of the JTT in the Real neurofeedback group compared to Sham (P = 0.010). However, there were no improvements on the Action Research Arm Test or the Upper Extremity Fugl-Meyer score (both P > 0.5). Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1 week after neurofeedback training (P = 0.008), indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract were positively correlated with participants neurofeedback performance (P = 0.002). Therefore, here we demonstrate that chronic stroke survivors are able to use functional MRI neurofeedback to self-modulate motor cortex activity in comparison to a Sham control, and that training is associated with improvements in gross hand motor performance and with white matter structural changes.

Study Protocol: The Heart and Brain Study.

BACKGROUND: It is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart-brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives. METHODS AND DESIGN: The 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40-70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages. DISCUSSION: The study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart-brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.

Remote, Automated, and MRI-Compatible Administration of Interoceptive Inspiratory Resistive Loading.

Research on how humans perceive sensory inputs from their bodies ("interoception") has been rapidly gaining momentum, with interest across a host of disciplines from physiology through to psychiatry. However, studying interoceptive processes is not without significant challenges, and many methods utilized to access internal states have been largely devoted to capturing and relating naturally occurring variations in interoceptive signals (such as heartbeats) to measures of how the brain processes these signals. An alternative procedure involves the controlled perturbation of specific interoceptive axes. This is challenging because it requires non-invasive interventions that can be repeated many times within a subject and that are potent but safe. Here we present an effective methodology for instigating these perturbations within the breathing domain. We describe a custom-built circuitry that is capable of delivering inspiratory resistive loads automatically and precisely. Importantly, our approach is compatible with magnetic resonance imaging (MRI) environments, allowing for the administration of complicated experimental designs in neuroimaging as increasingly required within developing fields such as computational psychiatry/psychosomatics. We describe the experimental setup for both the control and monitoring of the inspiratory resistive loads, and demonstrate its possible utilities within different study designs. This methodology represents an important step forward from the previously utilized, manually controlled resistive loading setups, which present significant experimental burdens with prolonged and/or complicated sequences of breathing stimuli.

Maintenance of Voluntary Self-regulation Learned through Real-Time fMRI Neurofeedback.

Neurofeedback based on real-time functional magnetic resonance imaging (fMRI) is an emerging technique that allows for learning voluntary control over brain activity. Such brain training has been shown to cause specific behavioral or cognitive enhancements, and even therapeutic effects in neurological and psychiatric patient populations. However, for clinical applications it is important to know if learned self-regulation can be maintained over longer periods of time and whether it transfers to situations without neurofeedback. Here, we present preliminary results from five healthy participants who successfully learned to control their visual cortex activity and who we re-scanned 6 and 14 months after the initial neurofeedback training to perform learned self-regulation. We found that participants achieved levels of self-regulation that were similar to those achieved at the end of the successful initial training, and this without further neurofeedback information. Our results demonstrate that learned self-regulation can be maintained over longer periods of time and causes lasting transfer effects. They thus support the notion that neurofeedback is a promising therapeutic approach whose effects can last far beyond the actual training period.

Learning Control Over Emotion Networks Through Connectivity-Based Neurofeedback.

Most mental functions are associated with dynamic interactions within functional brain networks. Thus, training individuals to alter functional brain networks might provide novel and powerful means to improve cognitive performance and emotions. Using a novel connectivity-neurofeedback approach based on functional magnetic resonance imaging (fMRI), we show for the first time that participants can learn to change functional brain networks. Specifically, we taught participants control over a key component of the emotion regulation network, in that they learned to increase top-down connectivity from the dorsomedial prefrontal cortex, which is involved in cognitive control, onto the amygdala, which is involved in emotion processing. After training, participants successfully self-regulated the top-down connectivity between these brain areas even without neurofeedback, and this was associated with concomitant increases in subjective valence ratings of emotional stimuli of the participants. Connectivity-based neurofeedback goes beyond previous neurofeedback approaches, which were limited to training localized activity within a brain region. It allows to noninvasively and nonpharmacologically change interconnected functional brain networks directly, thereby resulting in specific behavioral changes. Our results demonstrate that connectivity-based neurofeedback training of emotion regulation networks enhances emotion regulation capabilities. This approach can potentially lead to powerful therapeutic emotion regulation protocols for neuropsychiatric disorders.

Negative emotions facilitate isometric force through activation of prefrontal cortex and periaqueductal gray.

Emotions are considered to modulate action readiness. Previous studies have demonstrated increased force production following exposure to emotionally arousing visual stimuli; however the neural mechanisms underlying how precise force output is controlled within varying emotional contexts remain poorly understood. To identify the neural correlates of emotion-modulated motor behaviour, twenty-two participants produced a submaximal isometric precision-grip contraction while viewing pleasant, unpleasant, neutral or blank images (without visual feedback of force output). Force magnitude was continuously recorded together with change in brain activity using functional magnetic resonance imaging. Viewing unpleasant images resulted in reduced force decay during force maintenance as compared with pleasant, neutral and blank images. Subjective valence and arousal ratings significantly predicted force production during maintenance. Neuroimaging revealed that negative valence and its interaction with force output correlated with increased activity in right inferior frontal gyrus (rIFG), while arousal was associated with amygdala and periaqueductal gray (PAG) activation. Force maintenance alone was correlated with cerebellar activity. These data demonstrate a valence-driven modulation of force output, mediated by a cortico-subcortical network involving rIFG and PAG. These findings are consistent with engagement of motor pathways associated with aversive motivation, eliciting defensive behaviour and action preparedness in response to negative emotional signals.

Gender differences in the neural network of facial mimicry of smiles--An rTMS study.

Under theories of embodied emotion, exposure to a facial expression triggers facial mimicry. Facial feedback is then used to recognize and judge the perceived expression. However, the neural bases of facial mimicry and of the use of facial feedback remain poorly understood. Furthermore, gender differences in facial mimicry and emotion recognition suggest that different neural substrates might accompany the production of facial mimicry, and the processing of facial feedback, in men and women. Here, repetitive transcranial magnetic stimulation (rTMS) was applied to the right primary motor cortex (M1), the right primary somatosensory cortex (S1), or, in a control condition, the vertex (VTX). Facial mimicry of smiles and emotion judgments were recorded in response to video clips depicting changes from neutral or angry to happy facial expressions. While in females rTMS over M1 and S1 compared to VTX led to reduced mimicry and, in the case of M1, delayed detection of smiles, there was no effect of TMS condition for males. We conclude that in female participants M1 and S1 play a role in the mimicry and in the use of facial feedback for accurate processing of smiles.

Brain systems underlying encounter expectancy bias in spider phobia.

Spider-phobic individuals are characterized by exaggerated expectancies to be faced with spiders (so-called encounter expectancy bias). Whereas phobic responses have been linked to brain systems mediating fear, little is known about how the recruitment of these systems relates to exaggerated expectancies of threat. We used fMRI to examine spider-phobic and control participants while they imagined visiting different locations in a forest after having received background information about the likelihood of encountering different animals (spiders, snakes, and birds) at these locations. Critically, imagined encounter expectancies modulated brain responses differently in phobics as compared with controls. Phobics displayed stronger negative modulation of activity in the lateral prefrontal cortex, precuneus, and visual cortex by encounter expectancies for spiders, relative to snakes or birds (within-participants analysis); these effects were not seen in controls. Between-participants correlation analyses within the phobic group further corroborated the hypothesis that these phobia-specific modulations may underlie irrationality in encounter expectancies (deviations of encounter expectancies from objective background information) in spider phobia; the greater the negative modulation a phobic participant displayed in the lateral prefrontal cortex, precuneus, and visual cortex, the stronger was her bias in encounter expectancies for spiders. Interestingly, irrationality in expectancies reflected in frontal areas relied on right rather than left hemispheric deactivations. Our data accord with the idea that expectancy biases in spider phobia may reflect deficiencies in cognitive control and contextual integration that are mediated by right frontal and parietal areas.

The neural basis of age-related changes in motor imagery of gait: an fMRI study.

BACKGROUND: Aging is often associated with modifications of gait. Recent studies have revealed a strong relationship between gait and executive functions in healthy and pathological aging. We hypothesized that modification of gait due to aging may be related to changes in frontal lobe function. METHODS: Fourteen younger (27.0±3.6 years) and 14 older healthy adults (66.0±3.5 years) performed a motor imagery task of gait as well as a matched visual imagery task. Task difficulty was modulated to investigate differential activation for precise control of gait. Task performance was assessed by recording motor imagery latencies, eye movements, and electromyography during functional magnetic resonance imaging scanning. RESULTS: Our results showed that both healthy older and young adults recruited a network of brain regions comprising the bilateral supplementary motor cortex and primary motor cortex, right prefrontal cortex, and cerebellum, during motor imagery of gait. We observed an age-related increase in brain activity in the right supplementary motor area (BA6), the right orbitofrontal cortex (BA11), and the left dorsolateral frontal cortex (BA10). Activity in the left hippocampus was significantly modulated by task difficulty in the elderly participants. Executive functioning correlated with magnitude of increases in right primary motor cortex (BA4) during the motor imagery task. CONCLUSIONS: Besides demonstrating a general overlap in brain regions recruited in young and older participants, this study shows age-related changes in cerebral activation during mental imagery of gait. Our results underscore the importance of executive function (dorsolateral frontal cortex) and spatial navigation or memory function (hippocampus) in gait control in elderly individuals.

The influence of individual motor imagery ability on cerebral recruitment during gait imagery.

Motor imagery (MI) is often used in combination with neuroimaging techniques to study the cognitive control of gait. However, imagery ability (IA) varies widely across individuals, potentially influencing the pattern of cerebral recruitment during MI. The aim of the current study was to investigate this effect of IA on the neural correlates of gait control using functional magnetic resonance imaging (fMRI). Twenty healthy young subjects were subdivided into a good and bad imagers group, on the basis of their performance on two mental chronometry tests. For the whole group, MI activated a bilateral network of areas highly consistent with previous studies, encompassing primary motor cortex (BA 4), supplementary motor area, and other frontal and parietal areas, anterior insula, and cerebellum. Compared to bad imagers, good imagers showed higher activation in the right BA 4, left prefrontal cortex (BA 10), right thalamus, and bilateral cerebellum. Good imagers thus appear better able to recruit motor areas during MI, but also activate a prefrontal executive area (BA 10), which integrates information from the body and the environment and participates in higher-order gait control. These differences were found even though the two groups did not differ in other imagery abilities according to a standard questionnaire for vividness of motor and visual imagery. Future studies on MI should take into account these effects, and control for IA when comparing different populations, using appropriate measures. A better understanding of the neural mechanisms that underlie MI ability is crucial to accurately evaluate locomotor skills in clinical measures and neurorehabilitation techniques.

Persistent affective biases in human amygdala response following implicit priming with negative emotion concepts.

To what extent do past experiences shape our behaviors, perceptions, and thoughts even without explicit knowledge of these influences? Behavioral research has demonstrated that various cognitive processes can be influenced by conceptual representations implicitly primed during a preceding and unrelated task. Here we investigated whether emotion processing might also be influenced by prior incidental exposure to negative semantic material and which neural substrates would mediate these effects. During a first (priming) task, participants performed a variant of the hangman game with either negative or neutral emotion-laden words. Subsequently, they performed a second, unrelated visual task with fearful and neutral faces presented at attended or unattended locations. Participants were generally not aware of any relationships between the two tasks. We found that priming with emotional words enhanced amygdala sensitivity to faces in the subsequent visual task, while decreasing discriminative responses to threat. Furthermore, the magnitude of the induced bias in behavior and amygdala activation was predicted by the effectiveness of semantic access observed in the priming task. This demonstrates that emotional processing can be modulated by implicit influence of environmental information processed at an earlier time, independently of volitional control.

Associative and semantic memory deficits in amnestic mild cognitive impairment as revealed by functional magnetic resonance imaging.

OBJECTIVE: To identify the neural underpinnings of cognitive deficits associated with memory problems in amnestic mild cognitive impairment (aMCI). BACKGROUND: Functional magnetic resonance imaging (fMRI) is increasingly used to assess patients with aMCI and could potentially help predict conversion to Alzheimer disease, but imaging results so far have been inconsistent in identifying brain activation patterns in aMCI. There is an immediate need to identify the neural substrates of different memory components that are affected by aMCI. METHODS: We used fMRI to study 13 patients with aMCI and 15 healthy age-matched controls during an associative memory encoding and recognition task. The picture-pair memory task encompassed different types of recognition trials to investigate recollection versus familiarity, and manipulated the relationship between paired pictures to investigate semantic processing. RESULTS: Brain activation during both encoding and recognition was lower in patients than controls, with greatest implications in the medial temporal lobe during encoding. Patients also had much greater impairment of associative recollection than recognition based on familiarity, along with a failure to recruit regions that normally respond to violations of learned associations. Finally, patients' impaired semantic encoding was reflected by deficient activation of a left frontotemporal network responsible for elaborate semantic processes. CONCLUSIONS: We show that a simple fMRI task may be sensitive to deficits in different memory components in aMCI and could thus prove useful in the development of an fMRI tool to assess and monitor patients.