Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis.

Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive-emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction

Basic taste processing recruits bilateral anteroventral and middle dorsal insulae: An activation likelihood estimation meta-analysis of fMRI studies

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A core eating network and its modulations underlie diverse eating phenomena

We propose that a core eating network and its modulations account for much of what is currently known about the neural activity underlying a wide range of eating phenomena in humans (excluding homeostasis and related phenomena). The core eating network is closely adapted from a network that Kaye, Fudge, and Paulus (2009) proposed to explain the neurocircuitry of eating, including a ventral reward pathway and a dorsal control pathway. In a review across multiple literatures that focuses on experiments using functional Magnetic Resonance Imaging (fMRI), we first show that neural responses to food cues, such as food pictures, utilize the same core eating network as eating. Consistent with the theoretical perspective of grounded cognition, food cues activate eating simulations that produce reward predictions about a perceived food and potentially motivate its consumption. Reviewing additional literatures, we then illustrate how various factors modulate the core eating network, increasing and/or decreasing activity in subsets of its neural areas. These modulating factors include food significance (palatability, hunger), body mass index (BMI, overweight/obesity), eating disorders (anorexia nervosa, bulimia nervosa, binge eating), and various eating goals (losing weight, hedonic pleasure, healthy living). By viewing all these phenomena as modulating a core eating network, it becomes possible to understand how they are related to one another within this common theoretical framework. Finally, we discuss future directions for better establishing the core eating network, its modulations, and their implications for behavior

Multimodal Investigation of Peripheral and Central Nervous System Pain Mechanisms in Burning Mouth Syndrome (BMS) Using Magnetic Resonance Imaging and Psychometry (MRIBMS)

Background The International Classification of Orofacial Pain (ICOP) has defined burning mouth syndrome (BMS-ICOP) as an intraoral burning or dysaesthetic sensation that reoccurs daily for more than two hours per day and more than three months without evidence of causative lesions upon clinical examination and investigation. The burning mouth symptoms can be caused by primary and secondary BMS. Primary BMS is idiopathic BMS or true BMS, while secondary BMS, also known as burning mouth disorder (BMD), is attributed to local factors or systemic conditions. The prevalence of BMS in women was significantly higher than in men and mainly occurred at the post-menopausal age between 50 and 80 years. This intense, continuous, spontaneous pain severely affects the patient’s oral function, health, and psychology, with high reported rates of anxiety and depression. The pathophysiology of primary BMS as defined by ICOP (BMS-ICOP) remains uncertain, and with no standardised treatment protocol, treatment outcomes are further complicated. Over the years, there have been reports of altered cerebral activities in various levels of the neuraxis in patients with BMS-ICOP, which implies that BMS pain has a central nervous system component. AimThis thesis aimed to characterise patients’ cerebral responses associated with chronic trigeminal pain following administration of two topical peripheral-acting analgesics, clonazepam mouthwash (CMW) and dental local anaesthetic (LA), and the difference between treatment responders and non-responders. Attenuating or escalating pain in response to peripheral medications will allow in-depth phenotyping of patients with BMS-ICOP and facilitate tailored medicine. This thesis also studied and described the characteristics of patients with BMS-ICOP and the psychological impact of BMS-ICOP.MethodsThis prospective, open-label study was conducted at King’s College Dental Institute and Clinical Research Facilities, King’s College London. In the first visit, 26 participants diagnosed with BMS-ICOP were clinically screened and psychologically assessed using psychometric questionnaires. Functional magnetic resonance imaging (fMRI) and pulsed-continuous arterial spin labelling (pCASL) imaging techniques were employed to provide quantitative measurements of the resting-state functional connectivity (FC) and regional cerebral blood flow (rCBF), respectively, that related to changes in the brain activity. Participants underwent a series of fMRI and pCASL scans and rated their pain intensity using the numerical rating scale (NRS, 0-10) and visual analogue scale (VAS, 0-100) before and after the administration of CMW and LA. A subgroup of 15 BMS-ICOP patients with burning pain across the tongue was selected from the initial 26 BMS-ICOP patients to receive LA intervention. In addition to it, patients’ grey matter volume (GMV) was quantified using voxel-based morphometry (VBM) analysis. Here, we performed seed-based FC and pCASL analysis of the regions of interest (ROIs), including the left hippocampus, ventromedial prefrontal cortex (vmPFC), left amygdala, thalamus, right anterior insula (RAI), and periaqueductal grey matter (PAG); given reports of perturbed functioning changes in this region in chronic pain. Treatment responders were defined as reporting 50% or greater pain reduction from baseline following analgesic administration. ResultsOverall, the cohort of patients had daily recurring and continuously hot burning pain, with a mean NRS intensity rating of 5.15, progressively worsening during the day.Although experiencing a high pain level, most patients had a low tendency to catastrophise the threat value of pain or pain-related thoughts and did not exhibit depression, anxiety, or somatic symptom disorders. When comparing the pain and control sites, more than 90% of patients showed no chairside qualitative sensory deficit to touch and two-point discrimination. Meanwhile, 42% and 20% of patients had pin-prick and thermal sensitivity changes, respectively. This similarity was also reflected in the quantitative mechanical detection threshold assessment, where there were no significant changes between the control and pain sites (p = 0.695, SE =0.06). We also did not observe any statistically significant correlation between behaviour changes and cerebral responses to pain (pre-intervention), such as anxiety (r=0.09, p=0.677, 95% CI= -0.31-0.46) and depression (r= -0.21, 95% CI= -0.55 – 0.2, p=0.314). ClonazepamRinsing with 2mg CMW for 10 minutes significantly reduced pain intensity across the participants. An acute 2mg dose was selected to provide an immediate state of pain relief effect, keeping in mind that the suggested maximum daily prescribed clonazepam dose for pain relief is 4mg/day. Patients experienced a mean pain intensity NRS score reduction of 2.67 (p<0.001), and 15 patients responded to treatment. The study found a correlation between patients’ brain GMV and resting-state FC and pain intensity before and after rinsing with CMW. These changes were seen in the brain regions responsible for pain-related cognitive and affective processing and descending pain modulation. We also demonstrated the effect of CMW, which caused a decrease in the FC in the L hippocampus and RAI ROIs. There were alterations in the FC (∆FC) following treatment that were associated with changes in pain levels, as seen in the L hippocampus and vmPFC ROIs. In attempting to predict treatment response towards clonazepam, we tested the baseline FC with changes in pain ratings, and we did not observe any significant correlation. In addition, patients with a minimum of 50% pain reduction following CMW had a lower baseline FC than non-responders in all six ROIs. Conversely, an increased FC was noted in responders between L hippocampus-brainstem/ cerebellum and vmPFC-primary motor/somatosensory cortices. Similarly, there was a reduction in post-mouthwash rCBF compared to pre-mouthwash rCBF. No significant changes were reported upon analysis of the baseline rCBF and changes in the rCBF (∆rCBF) along with pain intensity.Dental local anaesthesiaFollowing bilateral inferior alveolar nerve block, patients achieved greater pain intensity relief than CMW with a reduction of 3.73 NRS units (p<0.001, SD=1.91), with 13 patients responding to it, but two patients did not. At baseline, we also observed the FC presence between brain regions involved in cognitive and affective (emotion) pain processing and modulation, and these connectivities were associated with pain ratings and area size. Participants with a greater reduction in their pain intensity NRS (∆NRS) and VAS (∆VAS) scores after LA had weak baseline FC strength between L hippocampus-temporal lobe (p=0.024) and PAG–L amygdala (p=0.032), respectively. However, no significant association was found between the ∆FC with pain ratings and pain area size. Contrary to CMW’s pCASL analysis, no correlation was observed between LA group patients’ baseline rCBF and pain ratings and area size. However, further exploratory pCASL analysis (uncorrected initial threshold of p=0.005) showed a reduction in rCBF after LA administration in the cognitive (dorsolateral prefrontal cortex), primary motor cortex, and primary somatosensory cortex brain regions. When comparing the studies, differences in cerebral responses to pain are likely related to the context of expectancy effect and the differential in afferent nociceptive ascending trigeminothalamic inputs to the brain and descending pain inhibition modulation system.ConclusionOur cohort of patients with BMS-ICOP had a remarkable ability to engage in valued daily activities by having high pain acceptance behaviour and a low tendency to magnify the value of pain. Administration of topical peripheral analgesics during the ongoing experience of chronic pain modulated the brain’s resting state activities, such as FC and rCBF. Alterations in FC and rCBF between brain regions involved in chronic pain modulation may reflect ongoing BMS-ICOP pain symptomatology, possibly due to impaired central and/or peripheral nervous system function. Understanding the peripheral and central processes involved in BMS-ICOP pain and how analgesics alter them may provide preliminary insights into the mechanism of action of potential topical analgesics, which may be a valuable parameter in predicting treatment response and is fundamental to advancing pain medicine

The Effect of Appetite on Pain

Hunger and pain are powerful homeostatic drives, which compete for a behavioural response when experienced simultaneously. This thesis set out to explore neural mechanisms underpinning this competition, and how appetitive visual and olfactory stimuli may modulate the effect of homeostatic energy manipulations on pain. Using well-established techniques including EEG source analysis and resting state fMRI, we consistently employed a within-subjects fasting vs. satiation paradigm to investigate the effects of appetite on subjective pain perception and neural pain processing. Pain stimuli which selectively activated nociceptive Aδ fibres were presented concurrently with appetitive stimuli, and the neural nociceptive responses were mapped with high-density (128-channel) EEG recordings and fMRI functional connectivity. Based on the results of previous research, we hypothesised that fasting would suppress subjective and neural pain processing, and that visual and olfactory appetitive stimuli may augment this effect. We first found that a relatively short overnight fast was sufficient to induce significant changes in resting state functional connectivity in areas that underlie both hunger / satiety and pain: insula cortex, hypothalamus, and regions of prefrontal cortex. Source analysis of EEG data revealed a small group of brain regions whose pain-related activation was suppressed by hunger and / or appetitive stimuli: anterior cingulate cortex, operculo-insular cortex, parahippocampal cortex, and cerebellum. Functional connectivity analysis of fMRI data further uncovered a widely-distributed network of brain areas whose pain-induced connectivity was enhanced by fasting or satiety. Of particular interest was a small network of areas involved in stimulus saliency processing (anterior insula, anterior cingulate cortex, and prefrontal cortex), which was stronger during fasting; presumably advantageous when searching for food. Lastly, in an experiment using a bread odour, we found that the suppressive effect of appetitive stimuli on nociception is not just confined to the visual modality. Brief, strong pain can also be suppressed by an appetitive odour during fasting. We conclude that fasting reliably interferes with pain processing, and that ambient appetitive stimuli might be of use in situations where short-lasting pain is likely to occur

From a systems view to spotting a hidden island : A narrative review implicating insula function in alcoholism

Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.Peer reviewe

Impact of Exercise on Brain Responses to Visual Food Cues: An fMRI Study

On the basis of a strong body of data, the Institute of Medicine currently recommends at least 60 minutes of exercise per day to prevent body weight gain overtime. Previous studies have shown that there is no compensatory increase in food intake with this dose of exercise. Ultimately, the brain decides whether to alter food intake. Surprisingly, no published studies have assessed the impact of exercise on brain activation. Using functional magnetic resonance imaging (fMRI) and an appetite questionnaire, we investigated the effects of a single bout of aerobic exercise on brain responses to visual food cues and subjective appetite responses. After an overnight fast, 30 (17M, 13W), healthy, habitually active subjects (22.0±3.8 years, 23.6±2.4 kg/m2, 44.3±8.3 mL∙kg-1∙min-1) either rested or exercised for 60 minutes, in a counterbalanced crossover design. Immediately after each condition, blood oxygen dependent levels were determined in response to visual food cues of different energy value during an fMRI scan. Exercise showed significantly greater activation (P \u3c .005, uncorrected) in regions implicated in food inhibition (superior frontal gyrus, medial surface), and visual attention (precuneus, superior temporal gyrus, middle temporal gyrus and fusiform gyrus) regions. However, exercise did show a greater activation in a food reward region (medial orbitofrontal cortex). The rest condition only showed greater activation in a visual center (fusiform gyrus) and the midbrain. In addition, relative to no-exercise, subjective appetite responses were suppressed following the exercise bout. Taken altogether, these data suggest exercise may impact the brain in a direction expected to suppress food intake and increase food attention, which is in line with previous behavioral, biological and fMRI data. These findings may explain, at least partially, why aerobic exercise does not lead to a compensatory increase in food intake

Neural Basis of Social and Perceptual Decision-making in Humans

We make decisions in every moment of our lives. How the brain forms those decisions has been an active topic of inquiry in the field of brain science in recent years. In this dissertation, I discuss our recent neuroimaging studies in trying to uncover the functional architecture of the human brain during social and perceptual decision-making processes. Our decisions in social context vary tremendously with many factors including emotion, reward, social norms, treatments from others, cooperation, and dependence to others. We studied the neural basis of social decision-making processes with a functional magnetic resonance imaging (fMRI) experiment using three economic exchange games with undercompensating, nearly equal, and overcompensating offers. Refusals of undercompensating offers recruited the right dorsolateral prefrontal cortex (dlPFC). Accepting of overcompensating offers recruited the brain reward pathway consisting of the caudate, the cingulate cortex, and the thalamus. Protesting of decisions activated the network consisting of the right dlPFC, the left ventrolateral prefrontal cortex, and midbrain in the substantia nigra. These findings suggested that social decisions are the results of coordination between evaluated fairness norms, self-interest, and reward. In the topic of perceptual decision-making, we contributed to answering how diverse cortical structures are involved in relaying and processing of sensory information to make a sense of environment around us. We conducted two fMRI experiments. In the first experiment, we used an audio-visual (AV) synchrony and asynchrony perceptual categorization task. In the second experiment, we used a face-house categorization task. Stimuli in the second experiment included three levels of noise in face and house images. In AV, we investigated the effective connectivity within the salience network consisting of the anterior insulae and anterior cingulate cortex. In face-house, we discovered that the BOLD activity in the dlPFC, the bidirectional connectivity between the fusiform face area (FFA) and the parahippocampal place area (PPA), and the feedforward connectivity from these regions to the dlPFC increased with the noise level – thus with difficulty of decision-making. These results support that the FFA-PPA-dlPFC network plays an important role for relaying and integrating competing sensory information to arrive at perceptual decisions of face and house