Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC-extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = -0.56, p = 0.025 uncorrected) and morning smoking severity (R = -0.59, p = 0.016 uncorrected). These results suggest that the dmPFC-extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

Low versus high level of response to alcohol affects amygdala functional connectivity during processing of emotional stimuli.

BACKGROUND: Low levels of response (low LR) to alcohol predict heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies of emotion processing have shown that low LR individuals exhibit lower activation in task-related brain regions following both placebo and alcohol administration, but these studies did not examine functional brain networks that might contribute to the phenomena. The current study expands upon the earlier results by evaluating whether functional connectivity differences between the amygdala and other brain regions modulated by emotional face processing are associated with LR. Based on prior findings, we hypothesized that low LR is related to lower functional connectivity in fronto-amygdalar functional circuits, which underlie the processing of emotional stimuli. METHODS: Secondary analyses were conducted on data from a double-blind, placebo-controlled, within-subjects, cross-over study in 108 18-to-25-year-old low and high LR sex-matched pairs without alcohol use disorder at baseline. Participants performed modified emotional faces processing tasks after receiving placebo or approximately 0.7 ml/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between left and right amygdalae and related brain circuits using LR-by-alcohol general linear models. The data included 54 sex-matched pairs with 216 fMRI scans comprising alcohol and placebo conditions. RESULTS: Compared with individuals with high LR, low LR subjects demonstrated lower functional connectivity between the amygdala and the frontal lobes, insula, and parietal regions, while processing angry and happy faces. Interactions showed lower connectivity following alcohol in low LR and higher connectivity in high LR groups. CONCLUSIONS: Low LR individuals demonstrated lower functional connectivity in response both to placebo and a modest dose of ethanol. Attenuated connectivity among low LR individuals when processing emotional faces may contribute to an impaired ability to recognize alcohol intoxication in social situations and to appraise angry and happy emotions irrespective of whether alcohol is consumed.

The antiepileptic activity of Safranal in kindling model of epilepsy in male rats

Abstract Recent studies suggested that safranal exerts anticonvulsant properties. The present study aimed to investigate the effect of safranal on epileptic activities in the amygdala electrical kindling model in male rats. Animals were implanted with a recording electrode on the skull and a tripolar in the amygdala. After 10 days of recovery, the afterdischarge (AD) threshold of each animal was determined and stimulated once daily the AD threshold for full kindling development. Then, parameters including afterdischarge duration (ADD), stage 4 latency (S4L), stage 5 duration (S5D), and stimulation threshold were determined before and after injection of safranal (0.05, 0.1, 0.2 ml/ kg; i.p). While the dose of 0.05 ml/kg had no significant effect, the dose of 0.1 ml/kg increased the AD threshold as well as S4L and decreased the S5D (P<0.05). Injection of 0.2 ml/kg of the safranal significantly decreased the ADD and S5D (P<0.05) and 83.3% of animals had no stage 4 and stage 5 of kindling (P<0.001). Based on the obtained data safranal has anticonvulsant effects dosedependently. It seems that a dose of 0.2 ml/kg is the minimum effective dose. Further investigation is warranted to conduct the clinical implications for the treatment of epileptic disorders

Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; An fMRI study.

BACKGROUND: Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. METHODS: This study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.

Association of Inflammatory Activity With Larger Neural Responses to Threat and Reward Among Children Living in Poverty.

OBJECTIVE: Children exposed to severe, chronic stress are vulnerable to mental and physical health problems across the lifespan. To explain how these problems develop, the neuroimmune network hypothesis suggests that early-life stress initiates a positive feedback loop between peripheral inflammatory cells and networked brain regions involved in threat and reward processing. The authors sought to test this hypothesis by studying a sample of urban children from diverse socioeconomic backgrounds. METHODS: The authors examined the basic predictions of the neuroimmune network hypothesis in 207 children (mean age=13.9 years, 63% female; 33% Black; 30% Hispanic), focusing on poverty as a stressor. The children had fasting blood drawn to quantify five inflammatory biomarkers-C-reactive protein, tumor necrosis factor-α, and interleukins-6, -8, and -10-which were averaged to form a composite score. Children also completed two functional MRI tasks, which measured amygdala responsivity to angry facial expressions and ventral striatum responsivity to monetary rewards. RESULTS: Poverty status and neural responsivity interacted statistically to predict inflammation. Among children living in poverty, amygdala threat responsivity was positively associated with inflammation, and the same was true for ventral striatum responsivity to reward. As children's socioeconomic conditions improved, these brain-immune associations became weaker. In sensitivity analyses, these patterns were robust to alternative measures of socioeconomic status and were independent of age, sex, racial and ethnic identity, and pubertal status. The associations were also condition specific; no interactions were apparent for amygdala responsivity to neutral faces, or striatal responsivity to monetary losses. CONCLUSIONS: These findings suggest that childhood poverty is associated with accentuated neural-immune signaling, consistent with the neuroimmune network hypothesis.

Plastic changes in amygdala subregions by voluntary running contribute to exercise-induced hypoalgesia in neuropathic pain model mice.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic pain, but exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. Since a growing body of evidence implicated the amygdala (Amyg) as a critical node in emotional affective aspects of chronic pain, we hypothesized that the Amyg may play important roles to produce EIH effects. Here, using partial sciatic nerve ligation (PSL) model mice, we investigated the effects of voluntary running (VR) on the basal amygdala (BA) and the central nuclei of amygdala (CeA). The present study indicated that VR significantly improved heat hyperalgesia which was exacerbated in PSL-Sedentary mice, and that a significant positive correlation was detected between total running distances after PSL-surgery and thermal withdrawal latency. The number of activated glutamate (Glu) neurons in the medal BA (medBA) was significantly increased in PSL-Runner mice, while those were increased in the lateral BA in sedentary mice. Furthermore, in all subdivisions of the CeA, the number of activated gamma-aminobutyric acid (GABA) neurons was dramatically increased in PSL-Sedentary mice, but these numbers were significantly decreased in PSL-Runner mice. In addition, a tracer experiment demonstrated a marked increase in activated Glu neurons in the medBA projecting into the nucleus accumbens lateral shell in runner mice. Thus, our results suggest that VR may not only produce suppression of the negative emotion such as fear and anxiety closely related with pain chronification, but also promote pleasant emotion and hypoalgesia. Therefore, we conclude that EIH effects may be produced, at least in part, via such plastic changes in the Amyg.

Amygdala stimulation ameliorates memory impairments and promotes c-Fos activity in fimbria-fornix-lesioned rats.

Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: ß = 0.20, p = 0.01) and subclinical CVD (VI: ß = 0.31, p < 0.001; NCB: ß = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study.

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.

Variability in nicotine conditioned place preference and stress-induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine.

Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex-specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2-adrenergic receptor agonist, may provide sex-sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress-induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress-induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress-induced reinstatement in both male and female mice, but with different nicotine dose-response patterns. In addition, we explored the variability in nicotine-dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress-induced reinstatement. In groups that showed significant stress-induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex-dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex-dependent relationships between initial chamber preference and stress-induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.

Pathoetiology and pathophysiology of borderline personality: Role of prenatal factors, gut microbiome, mu- and kappa-opioid receptors in amygdala-PFC interactions.

The pathoetiology and pathophysiology of borderline personality disorder (BPD) have been relatively under-explored. Consequently, no targetted pharmaceutical treatments or preventative interventions are available. The current article reviews the available data on the biological underpinnings of BPD, highlighting a role for early developmental processes, including prenatal stress and maternal dysbiosis, in BPD pathoetiology. Such factors are proposed to drive alterations in the infant's gut microbiome, in turn modulating amygdala development and the amygdala's two-way interactions with other brain regions. Alterations in opioidergic activity, including variations in the ratio of the mu-and kappa-opioid receptors seem a significant aspect of BPD pathophysiology, contributing to its comorbidities with depression, anxiety, impulsivity and addiction. Stress and dysphoria are commonly experienced in people classed with BPD. A growing body of data, across a host of medical conditions, indicate that stress and mood dysregulation may be intimately associated with gut dysbiosis and increased gut permeability, coupled to heightened levels of oxidative stress and immune-inflammatory activity. It urgently requires investigation as to the relevance of such gut changes in the course of BPD symptomatology. Accumulating data indicates that BPD symptom exacerbations may be linked to cyclical variations in estrogen, in turn decreasing serotonin and local melatonin synthesis, and thereby overlapping with the pathophysiology of migraine and endometriosis, which also have a heightened association with BPD. Future research directions and treatment implications are indicated.

Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission.

An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPARγ manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPARγ deletion (PPARγ(-/-)) and their littermate wild-type (PPARγ(+/+)) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPARγ during nicotine withdrawal. Brain site-specific microinjections of the PPARγ agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPARγ by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPARγ(+/+)) mice. This effect was blocked by the PPARγ antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPARγ increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPARγ in nicotine withdrawal and indicates that activation of PPARγ may offer an interesting strategy for smoking cessation.SIGNIFICANCE STATEMENT Smoking cessation leads the occurrence of physical and affective withdrawal symptoms representing a major burden to quit tobacco use. Here, we show that activation of PPARγ prevents the expression of both somatic and affective signs of nicotine withdrawal. At molecular levels results show that PPARγ expression increases in GABAergic cells in the hippocampus and in GABA- and glutamate-positive cells in the basolateral amygdala. Hippocampal microinjections of pioglitazone reduce the insurgence of the physical withdrawal signs, whereas anxiety linked to protracted abstinence is attenuated by pioglitazone injected into the amygdala. Our results demonstrate the implication of neuronal PPARγ in nicotine withdrawal and suggest that PPARγ agonism may represent a promising treatment to aid smoking cessation.

Experimental Characterization of the Chronic Constriction Injury-Induced Neuropathic Pain Model in Mice.

Number of ligations made in the chronic constriction injury (CCI) neuropathic pain model has raised serious concerns. We compared behavioural responses, nerve morphology and expression of pain marker, c-fos among CCI models developed with one, two, three and four ligations. The numbers of ligation(s) on sciatic nerve shows no significant difference in displaying mechanical and cold allodynia, and mechanical and thermal hyperalgesia throughout 84 days. All groups underwent similar levels of nerve degeneration post-surgery. Similar c-fos level in brain cingulate cortex, parafascicular nuclei and amygdala were observed in all CCI models compared to sham-operated group. Therefore, number of ligations does not impact intensity of pain symptoms, pathogenesis and neuronal activation. A single ligation is sufficient to develop neuropathic pain, in contrast to the established model of four ligations. This study dissects and characterises the CCI model, ascertaining a more uniform animal model to surrogate actual neuropathic pain condition.

Retrospectively reported childhood physical abuse, systemic inflammation, and resting corticolimbic connectivity in midlife adults.

Childhood abuse confers risk for psychopathology and pathophysiology in midlife through intermediate pathways that remain unclear. Systemic inflammation was tested in the present study as one pathway that may link physical abuse in childhood to the adult functioning of corticolimbic brain circuits broadly implicated in risk for poor mental and physical health. Midlife adults (N = 303; 30-51 years of age; 149 women) without psychiatric, immune, or cardiovascular diagnoses provided retrospective reports of childhood physical abuse. Functional connectivity between corticolimbic brain areas (amygdala, hippocampus, ventromedial prefrontal cortex [vmPFC], anterior cingulate cortex [ACC]) was measured at rest using functional magnetic resonance imaging. Circulating levels of interleukin(IL)-6, a pro-inflammatory cytokine previously linked to childhood abuse and corticolimbic functionality, were measured via blood draw. Consistent with prior studies, retrospectively reported childhood physical abuse was associated positively with circulating IL-6, and negatively with connectivity between the amygdala and vmPFC. IL-6 was also associated negatively with several corticolimbic functional connections, including amygdala-vmPFC connectivity. Moreover, path analyses revealed an indirect effect of IL-6 that partially explained the association between childhood physical abuse and adult amygdala-vmPFC connectivity. Consistent with recent neurobiological models of early life influences on disease risk across the lifespan, associations between childhood physical abuse and adulthood corticolimbic circuit functionality may be partially explained by inflammatory processes.

The epileptogenic zone in pharmaco-resistant temporal lobe epilepsy with amygdala enlargement.

Temporal lobe epilepsy with amygdala enlargement (TLE-AE) has been considered a subtype of TLE. We evaluated the epileptogenic zone in patients with TLE-AE, who underwent intracranial video-EEG (ivEEG) and/or intraoperative electrocorticography (ioECoG) as well as epilepsy surgery. Eleven patients with TLE-AE were enrolled and investigated based on seizure profile, volumetric MRI, the Wechsler Memory Scale-Revised (WMS-R), the location of seizure onset zone (SOZ) and irritative zone (IZ) based on ivEEG (n=8), the location of interictal epileptiform discharges (IEDs) based on ioECoG (11), surgical procedure, and seizure outcome. The mean age at seizure onset was 34.9 years (range: 23-57). The mean duration of seizures was 5.0 years (range: 1-10). The number of AEDs was 2.3 (range: 1-5). The mean seizure frequency was nine per month (range: 1-30/month). All patients presented with focal impaired awareness seizures with (n=9) and without (2) secondary generalized convulsions. Volumetric MRI analysis showed unilateral enlarged amygdala with statistical significance (p<0.01). None of the patients' hippocampi had any abnormality based on MRI. Pre-operative mean verbal, visual, and delayed recall scores based on the WMS-R were over 100. The SOZ and IZ were identified in both the amygdala and hippocampus in seven patients and in only the amygdala in one patient based on ivEEG. IEDs were identified in the hippocampus in six patients and in both the amygdala and hippocampus in four patients based on ioECoG. All 11 patients underwent anterior temporal lobectomy, including amygdala resection, with multiple hippocampal transections (dominant hemisphere: seven patients) and resection (non-dominant hemisphere: three patients). Nine (81.8%) of 11 patients achieved seizure freedom with a mean follow-up of 26 months (range: 12-47). Post-operative WMS-R results did not show any significant deterioration, with a mean follow-up of 15 months (range: 12-24). The resected amygdala showed no histopathological abnormality. The epileptogenic zone of TLE-AE involves both the amygdala and hippocampus. ivEEG may be needed to explore the SOZ in normal hippocampus in addition to enlarged amygdala. Amygdala resection and multiple hippocampal transections may control the epileptogenic limbic system and save memory function in patients with TLE-AE.

Stress-Associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease.

BACKGROUND: Lower socioeconomic status (SES) associates with a higher risk of major adverse cardiac events (MACE) via mechanisms that are not well understood. OBJECTIVES: Because psychosocial stress is more prevalent among those with low SES, this study tested the hypothesis that stress-associated neurobiological pathways involving up-regulated inflammation in part mediate the link between lower SES and MACE. METHODS: A total of 509 individuals, median age 55 years (interquartile range: 45 to 66 years), underwent clinically indicated whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging and met pre-defined inclusion criteria, including absence of known cardiovascular disease or active cancer. Baseline hematopoietic tissue activity, arterial inflammation, and in a subset of 289, resting amygdalar metabolism (a measure of stress-associated neural activity) were quantified using validated 18F-fluorodeoxyglucose positron emission tomography/computed tomography methods. SES was captured by neighborhood SES factors (e.g., median household income and crime). MACE within 5 years of imaging was adjudicated. RESULTS: Over a median 4.0 years, 40 individuals experienced MACE. Baseline income inversely associated with amygdalar activity (standardized ß: -0.157 [95% confidence interval (CI): -0.266 to -0.041]; p = 0.007) and arterial inflammation (ß: -0.10 [95% CI: -0.18 to -0.14]; p = 0.022). Further, income associated with subsequent MACE (standardized hazard ratio: 0.67 [95% CI: 0.47 to 0.96]; p = 0.029) after multivariable adjustments. Mediation analysis demonstrated that the path of: ↓ neighborhood income to ↑ amygdalar activity to ↑ bone marrow activity to ↑ arterial inflammation to ↑ MACE was significant (ß: -0.01 [95% CI: -0.06 to -0.001]; p < 0.05). CONCLUSIONS: Lower SES: 1) associates with higher amygdalar activity; and 2) independently predicts MACE via a serial pathway that includes higher amygdalar activity, bone marrow activity, and arterial inflammation. These findings illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

Food Addiction Symptoms and Amygdala Response in Fasted and Fed States.

Few studies have investigated the underlying neural substrates of food addiction (FA) in humans using a recognised assessment tool. In addition, no studies have investigated subregions of the amygdala (basolateral (BLA) and central amygdala), which have been linked to reward-seeking behaviours, susceptibility to weight gain, and promoting appetitive behaviours, in the context of FA. This pilot study aimed to explore the association between FA symptoms and activation in the BLA and central amygdala via functional magnetic resonance imaging (fMRI), in response to visual food cues in fasted and fed states. Females (n = 12) aged 18-35 years completed two fMRI scans (fasted and fed) while viewing high-calorie food images and low-calorie food images. Food addiction symptoms were assessed using the Yale Food Addiction Scale. Associations between FA symptoms and activation of the BLA and central amygdala were tested using bilateral masks and small-volume correction procedures in multiple regression models, controlling for BMI. Participants were 24.1 ± 2.6 years, with mean BMI of 27.4 ± 5.0 kg/m2 and FA symptom score of 4.1 ± 2.2. A significant positive association was identified between FA symptoms and higher activation of the left BLA to high-calorie versus low-calorie foods in the fasted session, but not the fed session. There were no significant associations with the central amygdala in either session. This exploratory study provides pilot data to inform future studies investigating the neural mechanisms underlying FA.

Hippocampal high frequency oscillations in unilateral and bilateral mesial temporal lobe epilepsy.

OBJECTIVE: The main aim of this study was to investigate the potential differences in terms of interictal high frequency oscillations (HFOs) between both hippocampi in unilateral (U-MTLE) and bilateral mesial temporal lobe epilepsy (B-MTLE). METHODS: Sixteen patients with MTLE underwent bilateral hippocampal depth electrode implantation as part of epilepsy surgery evaluation. Interictal HFOs were detected automatically. The analyses entail comparisons of the rates and spatial distributions of ripples and fast ripples (FR) in hippocampi and amygdalae, with respect to the eventual finding of hippocampal sclerosis (HS). RESULTS: In U-MTLE, higher ripple and FR rates were found in the hippocampi ipsilateral to the seizure onset than in the contralateral hippocampi. Non-epileptic hippocampi in U-MTLE were distinguished by significantly lower ripple rate than in the remaining analyzed hippocampi. There were not differences between the hippocampi in B-MTLE. In the hippocampi with proven HS, higher FR rates were observed in the ventral than in the dorsal parts. CONCLUSIONS: Non-epileptic hippocampi in U-MTLE demonstrated significantly lower ripple rates than those epileptic in U-MTLE and B-MTLE. SIGNIFICANCE: Low interictal HFO occurrence might be considered as a marker of the non-epileptic hippocampi in MTLE.

Anterior nucleus of paraventricular thalamus mediates chronic mechanical hyperalgesia.

Pain-related diseases are the top leading causes of life disability. Identifying brain regions involved in persistent neuronal changes will provide new insights for developing efficient chronic pain treatment. Here, we showed that anterior nucleus of paraventricular thalamus (PVA) plays an essential role in the development of mechanical hyperalgesia in neuropathic and inflammatory pain models in mice. Increase in c-Fos, phosphorylated extracellular signal-regulated kinase, and hyperexcitability of PVA neurons were detected in hyperalgesic mice. Direct activation of PVA neurons using optogenetics and pharmacological approaches were sufficient to induce persistent mechanical hyperalgesia in naive animals. Conversely, inhibition of PVA neuronal activity using DREADDs (designer receptors exclusively activated by designer drugs) or inactivation of PVA extracellular signal-regulated kinase at the critical time window blunted mechanical hyperalgesia in chronic pain models. At the circuitry level, PVA received innervation from central nucleus of amygdala, a known pain-associated locus. As a result, activation of right central nucleus of amygdala with blue light was enough to induce persistent mechanical hyperalgesia. These findings support the idea that targeting PVA can be a potential therapeutic strategy for pain relief.