Are You Being Rejected or Excluded? Insights from Neuroimaging Studies Using Different Rejection Paradigms

Rejection sensitivity is the heightened tendency to perceive or anxiously expect disengagement from others during social interaction. There has been a recent wave of neuroimaging studies of rejection. The aim of the current review was to determine key brain regions involved in social rejection by selectively reviewing neuroimaging studies that employed one of three paradigms of social rejection, namely social exclusion during a ball-tossing game, evaluating feedback about preference from peers and viewing scenes depicting rejection during social interaction. A cross the different paradigms of social rejection, there was concordance in regions for experiencing rejection, namely dorsal anterior cingulate cortex (ACC), subgenual ACC and ventral ACC. Functional dissociation between the regions for experiencing rejection and those for emotion regulation, namely medial prefrontal cortex, ventrolateral prefrontal cortex (VLPFC) and ventral striatum, was evident in the positive association between social distress and regions for experiencing rejection and the inverse association between social distress and the emotion regulation regions. The paradigms of social exclusion and scenes depicting rejection in social interaction were more adept at evoking rejection-specific neural responses. These responses were varyingly influenced by the amount of social distress during the task, social support received, self-esteem and social competence. Presenting rejection cues as scenes of people in social interaction showed high rejection sensitive or schizotypal individuals to under-activate the dorsal ACC and VLPFC, suggesting that such individuals who perceive rejection cues in others down-regulate their response to the perceived rejection by distancing themselves from the scene

Early-stage differentiation between presenile Alzheimer’s disease and frontotemporal dementia using arterial spin labeling MRI

Objective: To investigate arterial spin labeling (ASL)-MRI for the early diagnosis of and differentiation between the two most common types of presenile dementia: Alzheimer’s disease (AD) and frontotemporal dementia (FTD), and for distinguishing age-related from pathological perfusion changes. Methods: Thirteen AD and 19 FTD patients, and 25 age-matched older and 22 younger controls underwent 3D pseudo-continuous ASL-MRI at 3 T. Gray matter (GM) volume and cerebral blood flow (CBF), corrected for partial volume effects, were quantified in the entire supratentorial cortex and in 10 GM regions. Sensitivity, specificity and diagnostic performance were evaluated in regions showing significant CBF differences between patient groups or between patients and older controls. Results: AD compared with FTD patients had hypoperfusion in the posterior cingulate cortex,

Modulating Brain Rhythms of Pain using Transcranial Alternating Current Stimulation (tACS)?

Pain protects the body. However, pain can also occur for longer periods without serving protective functions. Such chronic pain conditions are difficult to treat. Thus, a better understanding of the underlying neural mechanisms and new approaches for the treatment of pain are urgently needed. Here, we investigated a causal role of oscillatory brain activity for pain and explored the potential of transcranial alternating current stimulation (tACS) as a new treatment approach for pain. To this end, we investigated whether tACS can modulate pain and pain-related autonomic activity in 29 healthy human participants using a tonic heat pain paradigm as an experimental model of chronic pain. In 6 recording sessions, participants received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. During tACS, pain ratings and autonomic responses were collected. TACS did not modulate pain intensity, the stability of pain ratings or the translation of the noxious stimulus into pain. Likewise, tACS did not change autonomic responses. Bayesian statistics further indicated a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence for tACS effects was inconclusive. Taken together, the present study did not find significant tACS effects on tonic experimental pain in healthy human participants. However, considering the conceptual plausibility of using tACS to modulate pain and the urgent need for novel pain treatments, further tACS studies are warranted. Based on the present findings, such studies might apply refined stimulation protocols targeting alpha oscillations in somatosensory cortices

Simultaneous PET-MRI assessment of central α4β2 nAChR availability in participants with obesity compared to normal weight healthy controls under baseline and stimulus conditions

Introduction: Cholinergic network modulation is carried out through the neurotransmitter acetylcholine (ACh) and expression of α4β2 nicotinic acetylcholine recetors (nAChRs) in central brain regions responsible for the detection of external sensory stimuli through thalamic and basal forebrain circuits but also within mesolimbic reward signaling. Alterations in α4β2 availability could therefore contribute to pathologically increased eating behavior leading to obesity. Investigations of task-related cholinergic neurotransmission in vivo in human obesity comparing baseline versus stimulus conditions have yet to be established. Objective: Aim of this exploratory study was to investigate the neurobiological mechanisms of cholinergic signaling and its ramifications on eating behavior to possibly identify α4β2 as a pharmacological target in obesity therapy approaches. Primary outcome measure was the distribution volume calculated from PET data by VOI-based analyses. We compared α4β2 nAChR availability in OB (participants with obesity) with NW (normal weight participants) under baseline and stimulus conditions. Secondary, we explored whether changes in eating behavior measured by VAS (visual analogue scores) are correlated with changes in α4β2 nAChR availability. We also hypothesized that this relationship differs between resting state and stimulus conditions in both NW as well as OB. Materials and Methods: Study population consisted of 16 study participants with OB (N=16; mean BMI 37.8±3.18 kg/m2; 10 females; mean age 40.6±14.0; range from 20-62 years) and 14 NW (N=14; mean BMI 21.8±1.90 kg/m2; 11 females; mean age 28.1±7.58; range from 19-45 years), all mentally healthy and non-smokers. Every participant underwent simultaneous PET-MR imaging (mMR Siemens) under baseline and stimulus conditions, applying a standard set of salient food items. Calculations of VT was based on the bolus-infusion protocol. This includes investigation of VT as the ratio between mean (-)-[18F]flubatine in brain tissue and mean plasma (-)-[18F]flubatine in venous blood samples at 120 until 165 minutes post injection. During each visit VAS data were obtained. Results: No significant group differences in VT between NW and OB under baseline conditions were found, while OB showed a trend towards lower VT in the Nucleus basalis of Meynert (NBM; NW: mean VT= 11.6; OB: mean VT=10.2; mean difference= 1.35; p= 0.119). Under stimulus conditions, OB demonstrate higher thalamic VT (Thalamus; NW: mean VT= 25.1; OB: mean VT= 28.8; mean difference: -3.63; p= 0.028). Additionally, OB showed a tendency to greater VT mean differences between resting state and stimulus conditions compared with NW. Correlational analyses revealed statistically significant positive correlation (r= 0.61) between HPT and VAS “satiety” in NW and a significant negative correlation (r= -0.59) between NAc and VAS “disinhibition” in OB. Conclusion: These first in-human data suggest substantial changes in cholinergic signaling in brain circuits that process external sensory stimuli with high-incentive properties such as visual food cues in obesity. If confirmed in an extended population with larger sample size and including seed-based fMR imaging investigations, the α4β2 nAChR represent a promising target for pharmacological intervention as a non-invasive alternative to surgical procedures to combat the obesity epidemic.:2. Table of Contents 2. TABLE OF CONTENTS 2 3. ABBREVIATIONS 2 LIST OF FIGURES 4 LIST OF TABLES 6 4. INTRODUCTION 6 4.1 OBESITY AND THE CENTRAL CHOLINERGIC SYSTEM 7 4.2 CHOLINERGIC NEUROTRANSMISSION 9 4.3 STRUCTURE AND RECEPTOR KINETICS OF NACHR 11 4.4 TOPOGRAPHY OF CENTRAL NACHR 13 4.5 CHOLINERGIC NEUROMODULATION 15 4.5.1 Cholinergic Neuromodulation and Cognitive Processes 16 4.5.2 Cholinergic Neuromodulation and Reward 19 4.5.3 Cholinergic Neuromodulation and Eating Behavior 21 4.6. POSITRON EMISSION TOMOGRAPHY (PET) AS A MOLECULAR IMAGING TECHNIQUE FOR MEASURING NACHR IN VIVO 23 4.6.1 PET Imaging 23 4.6.2 Imaging of α4β2 Nicotinic Acetylcholine Receptors 23 4.6.3 (-)-[18F]flubatine: a specific α4β2 nAChR radiotracer 25 4.7 VOLUMES OF INTEREST (VOI) 33 5. OBJECTIVE 34 6. MATERIALS AND METHODS 35 6.1 ETHICS STATEMENT 35 6.2 STUDY DESIGN 35 6.3 STUDY PARTICIPANTS 36 6.4 VISUAL ANALOGUE SCALE (VAS) 38 6.5 PET/MR IMAGING 39 6.6 IMAGING DATA AND BLOOD PLASMA ANALYSIS 43 6.7 STATISTICAL ANALYSIS 45 7. RESULTS 46 7.1 EPIDEMIOLOGICAL DATA 46 7.2 BASELINE AND STIMULUS VT CALCULATIONS 47 7.3 INTRA-INDIVIDUAL VT ASSESSMENT BETWEEN BASELINE AND STIMULUS CONDITIONS 53 7.4 CORRELATIONAL ANALYSES OF VAS VERSUS VT 57 8. DISCUSSION 63 9. SUMMARY 70 10. REFERENCES 72 11. ANLAGEN 8

Frontal, Sensorimotor, and Posterior Parietal Regions Are Involved in Dual-Task Walking After Stroke

Background: Walking within the community requires the ability to walk while simultaneously completing other tasks. After a stroke, completing an additional task while walking is significantly impaired, and it is unclear how the functional activity of the brain may impact this. Methods: Twenty individual in the chronic stage post-stroke participated in this study. Functional near-infrared spectroscopy (fNIRS) was used to measure prefrontal, pre-motor, sensorimotor, and posterior parietal cortices during walking and walking while completing secondary verbal tasks of varying difficulty. Changes in brain activity during these tasks were measured and relationships were accessed between brain activation changes and cognitive or motor abilities. Results: Significantly larger activations were found for prefrontal, pre-motor, and posterior parietal cortices during dual-task walking. Increasing dual-task walking challenge did not result in an increase in brain activation in these regions. Higher general cognition related to lower increases in activation during the easier dual-task. With the harder dual-task, a trend was also found for higher activation and less motor impairment. Conclusions: This is the first study to show that executive function, motor preparation/planning, and sensorimotor integration areas are all important for dual-task walking post-stroke. A lack of further brain activation increase with increasing challenge suggests a point at which a trade-off between brain activation and performance occurs. Further research is needed to determine if training would result in further increases in brain activity or improved performance

Neural correlates of maladaptive pain behavior in chronic neck pain - a single case control fMRI study

Chronic neck pain patients display functional impairments like decreased range of motion, decreased strength, and reduced sensorimotor function. In patients without structural damage, the reason for the persistence of pain is not well understood. Therefore, it is assumed that in chronic pain states, memory processes play an important role. We have now detected and tested a patient that might help us to better understand the neural correlates of maladaptive pain expectation/memory. This patient displays chronic neck pain and restricted unilateral motion of the cervical spine to the left. However, when the patient is distracted, she can perform head rotations without experiencing pain and without restricting her range of movement. Based on this observation, we asked her to imagine movements shown in a video: conscious, non- distracted head rotations (pain-provoking) versus distracted head rotations (pain-free) and compared these results with an age and gender matched control volunteer. Functional magnetic resonance imaging (fMRI) showed distinct brain activation patterns that depended on the side of rotation (pain-free versus painful side) and the kind of movement (distracted versus non-distracted head rotation). Interestingly, brain areas related to the processing of pain such as primary somatosensory cortex, thalamus, insula, anterior cingulate cortex, primary motor cortex, supplementary motor area, prefrontal cortex, and posterior cingulate cortex were always more strongly activated in the non-distracted condition and when turning to the left. The age and gender matched control volunteer displayed no comparable activation of pain centers. In the patient, maladaptive pain behavior and the activity of pain-related brain areas during imagined head rotations were task-specific, indicating that the activation and/or recall of pain memories were context-dependent. These findings are important not only to improve the understanding of the neural organization of maladaptive pain behavior but also to reconsider clinical evaluation and treatment strategies. The current results therefore suggest that treatment strategies have to take into account and exploit the context in which the movement is performed

Alteraciones permanentes de los sistemas noradrenérgicos y dopaminérgicos de forma región y sexo dependiente tras exposición prenatal y postnatal al clordimeformo

Introduction: Formamidines pesticides have been described to induce permanent effects on development of monoaminergic neurotransmitter systems. The mechanisms that induce these effects are not known but it has been suggested that these effects could be related to monoamino oxidase (MAO) inhibition. Chlordimeform is a formamidine pesticide, which is a very weak inhibitor of MAO although it has been described to induce permanent and sex dependent alterations of serotoninergic system. Objectives and methods: In order to confirm that formamidines induce permanent alterations of monoaminergic neurotransmitter systems regardless of MAO inhibition, the effects of maternal exposure to chlordimeform (5 mg/kg bw, orally) on brain region dopamine and noradrenaline levels of male and female offspring rats at 60 days of age were evaluated. The results showed that chlordimeform induced a significant decrease of noradrenaline and dopamine levels in the prefrontal cortex and striatum and of dopamine levels in the hippocampus, showing an interaction by sex for these regions. Results: Chlordimeform also caused a decrease of DOPAC levels in the striatum and of MHPG and HVA metabolites levels in the prefrontal cortex and striatum. Moreover, it induced an increase in the content of metabolites DOPAC and HVA in the hippocampus and an increase in the metabolite content of DOPAC in the striatum. Lastly, it increased the turnover of DA in the hippocampus and striatum and decreased the turnover of NA and DA in frontal cortex, as well as the NA in striatum. Conclusions: The present findings indicate that maternal exposure to chlordimeform altered dopaminergic and noradrenergic neurochemistry in their offspring in a region and sex dependent way, and those variations confirm that other mechanisms different from MAO inhibition are implicated.Introducción: Se ha descrito que los pesticidas formamidínicos inducen efectos permanentes en el desarrollo de los sistemas de neurotransmisores monoaminérgicos. Los mecanismos por los que se inducen estos efectos no se conocen, pero se ha sugerido que podrían estar relacionados con la inhibición de la monoamino oxidasa (MAO). El clordimeformo, es un pesticida formamidínico, del que se han descrito que induce una alteración permanente del sistema serotoninérgico región y sexo dependiente, aunque es un inhibidor muy débil de la MAO. Objetivos y métodos: Con el objetivo de confirmar que las formamidinas produce alteraciones permanentes de los neurotransmisores monoaminérgicos independientemente de la inhibición de la MAO, se evaluaron los efectos sobre los niveles de dopamina y serotonina en regiones cerebrales de ratas macho y hembra a los 60 días de edad tras la exposición maternal al clordimeformo (5 mg/kg de peso corporal). Resultados: El clordimeformo indujo una disminución significativa de los niveles de noradrenalina y dopamina en las regiones cerebrales corteza frontal, cuerpo estriado, así como de la dopamina en el hipocampo mostrando una interacción por sexo en esta regiones. El clordimeformo además, originó un descenso de los metabolitos MHPG y HVA en corteza frontal y cuerpo estriado y del metabolito DOPAC en el cuerpo estriado. También, indujo un aumento en el contenido de los metabolitos DOPAC y HVA en hipocampo y un aumento del contenido de DOPAC en el cuerpo estriado. Por ultimo aumentó la tasa de recambio de DA en el hipocampo y cuerpo estriado y disminuyó la tasa de recambio de la NA y DA en corteza frontal y así como de la NA en cuerpo estriado. Conclusiones: Los presentes resultados indican que las formamidinas y en particular el clordimeformo, inducen, tras la exposición maternal, una alteración permanente de los sistemas dopaminérgico y noradrenérgico de forma región y sexo dependiente en la descendencia, lo cual confina que estas alteraciones se deben a mecanismos distintos de la inhibición de la MAO

Whole-brain patterns of 1H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies

Acknowledgements We thank Craig Lambert for his help in processing the MRS data. The study was funded by the Sir Jules Thorn Charitable Trust (grant ref: 05/JTA) and was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University and the NIHR Biomedical Research Centre and Biomedical Research Unit in Dementia based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge.Peer reviewedPublisher PD

Resting-State Glucose Metabolism Level Is Associated with the Regional Pattern of Amyloid Pathology in Alzheimer's Disease

It has been suggested that glucose metabolism within the brain's default network is directly associated with—and may even cause—the amyloid pathology of Alzheimer's disease (AD). Here we performed 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and [11C]-labeled Pittsburgh Compound B (PIB) positron emission tomography (PET) on cognitively normal elderly subjects and on AD patients and conducted quantitative regional analysis of FDG- and PIB-PET images using an automated region of interest technique. We confirmed that resting glucose metabolism within the posterior components of the brain's default network is high in normal elderly subjects and low in AD patients, which is partially in agreement with the regional pattern of PIB uptake within the default network of AD patients. However, in several regions outside the default network, glucose metabolism was high in normal elderly subjects but was not depressed in AD patients, who exhibited significantly increased PIB uptakes in these regions. In contrast, the level of resting glucose metabolism in the default network and in regions outside the default network in normal elderly subjects was significantly correlated with the level of regional PIB uptake in AD patients. These results are discussed with experimental evidence suggesting that beta amyloid production and amyloid precursor protein regulation are dependent on neuronal activity