Effects of Smoking Status and State on Intrinsic Connectivity.

BACKGROUND: Smoking behavior during the first 24 hours of a quit attempt is a significant predictor of longer-term abstinence, yet little is known about the neurobiology of early tobacco abstinence. Specifically, the effects of acute tobacco deprivation and reinstatement on brain function-particularly at the level of large-scale network dynamics and assessed across the entire brain-remain incompletely understood. To address this gap, this study used a mixed within- and between-subjects design to assess the effects of smoking status (yes/no smoker) and state (deprived vs. satiated) on whole-brain patterns of intrinsic connectivity. METHODS: Participants included 42 tobacco smokers who underwent resting-state functional magnetic resonance imaging following overnight abstinence (deprived state) and following smoking reinstatement (satiated state, randomized order across participants). Sixty healthy control nonsmokers underwent a single resting-state scan using the same acquisition parameters. Functional connectivity data were analyzed using both a canonical network-of-interest approach and a whole-brain, data-driven approach, i.e., intrinsic connectivity distribution. RESULTS: Network-of-interest-based analyses indicated decreased functional connectivity within frontoparietal and salience networks among smokers relative to nonsmokers as well as effects of smoking state on default mode connectivity. In addition, intrinsic connectivity distribution analyses identified novel between-group differences in subcortical-cerebellar and corticocerebellar networks that were largely smoking state dependent. CONCLUSIONS: These data demonstrate the importance of considering smoking state and the utility of using both theory- and data-driven analysis approaches. These data provide much-needed insight into the functional neurobiology of early abstinence, which may be used in the development of novel treatments.

Body dissatisfaction and suicidal ideation among psychiatric inpatients with eating disorders.

The current study the relationship between eating disorders (EDs) and suicidal ideation and suicide attempt in adult inpatients. In particular, the present study investigated one potential mechanism, body dissatisfaction (BD), which may contribute to increased risk for suicide in adult ED patients. A sample of 432 psychiatric inpatients ranging from 18 to 65 years of age participated in the current study. Findings indicated that patients who have higher levels of BD also had higher levels of passive and active suicidal ideation and previous suicide attempts. Higher levels of BD were also related to increased suicidal ideation after controlling for depression and emotion dysregulation. Although additional risk factors for suicide should be investigated in adults with EDs, this study provides evidence regarding the relationship between BD and risk for suicide ideation and attempt.

The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study.

BACKGROUND: Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C-WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward. METHODS: In 12 patients with cancer and 12 healthy controls, resting-state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood oxygen level-dependent signal that can be measured using functional magnetic resonance imaging) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to juice was studied. Participants included 12 patients with histological diagnosis of incurable cancer (solid tumours), a European Cooperative Oncology Group performance status of 0-2, and a ≥5% involuntary body weight loss from pre-illness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula and brain striatum activity as measured by functional MRI during juice reward delivery events were the main outcome measures. RESULTS: After adjusting for BMI and compared with matched controls, patients with C-WL were found to have reduced RSFC between the habenula and hypothalamus (P = 0.04) and between the habenula and nucleus accumbens (P = 0.014). Patients with C-WL also had reduced juice reward responses in the striatum compared with controls. CONCLUSIONS: In patients with C-WL, reduced connectivity between both homeostatic and hedonic brain regions and the habenula and reduced juice reward were observed. Further research is needed to establish the relevance of the habenula and striatum in C-WL.

Genome-wide imaging association study implicates functional activity and glial homeostasis of the caudate in smoking addiction.

BACKGROUND: Nearly 6 million deaths and over a half trillion dollars in healthcare costs worldwide are attributed to tobacco smoking each year. Extensive research efforts have been pursued to elucidate the molecular underpinnings of smoking addiction and facilitate cessation. In this study, we genotyped and obtained both resting state and task-based functional magnetic resonance imaging from 64 non-smokers and 42 smokers. Smokers were imaged after having smoked normally ("sated") and after having not smoked for at least 12 h ("abstinent"). RESULTS: While abstinent smokers did not differ from non-smokers with respect to pairwise resting state functional connectivities (RSFCs) between 12 brain regions of interest, RSFCs involving the caudate and putamen of sated smokers significantly differed from those of non-smokers (P < 0.01). Further analyses of caudate and putamen activity during elicited experiences of reward and disappointment show that caudate activity during reward (CR) correlated with smoking status (P = 0.015). Moreover, abstinent smokers with lower CR experienced greater withdrawal symptoms (P = 0.024), which suggests CR may be related to smoking urges. Associations between genetic variants and CR, adjusted for smoking status, were identified by genome-wide association study (GWAS). Genes containing or exhibiting caudate-specific expression regulation by these variants were enriched within Gene Ontology terms that describe cytoskeleton functions, synaptic organization, and injury response (P < 0.001, FDR < 0.05). CONCLUSIONS: By integrating genomic and imaging data, novel insights into potential mechanisms of caudate activation and homeostasis are revealed that may guide new directions of research toward improving our understanding of addiction pathology.

Increased habenular connectivity in opioid users is associated with an α5 subunit nicotinic receptor genetic variant.

BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence. METHODS: We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse. RESULTS: We found that habenula-striatal connectivity was stronger in opioid-using patients. Increased habenula-striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes. CONCLUSIONS: We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use. SCIENTIFIC SIGNIFICANCE: Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759).

A Novel Approach to Identifying a Neuroimaging Biomarker for Patients With Serious Mental Illness.

Serious mental illness (SMI) is disabling, and current interventions are ineffective for many. This exploratory study sought to demonstrate the feasibility of applying topological data analysis (TDA) to resting-state functional connectivity data obtained from a heterogeneous sample of 235 adult inpatients to identify a biomarker of treatment response. TDA identified two groups based on connectivity between the prefrontal cortex and striatal regions: patients admitted with greater functional connectivity between these regions evidenced less improvement from admission to discharge than patients with lesser connectivity between them. TDA identified a potential biomarker of an attenuated treatment response among inpatients with SMI. Insofar as the observed pattern of resting-state functional connectivity collected early during treatment is replicable, this potential biomarker may indicate the need to modify standard of care for a small, albeit meaningful, percentage of patients.

Life Chaos and Perceived Social Support Among Methamphetamine-Using Men Who Have Sex With Men Engaging in Transactional Sexual Encounters.

OBJECTIVE: Social support and life chaos have been inversely associated with increased risk of HIV infection. The purpose of this study was to explore among a sample of HIV-negative methamphetamine-using men who have sex with men (MSM) the association between engaging in transactional sex, life chaos, and low social support. METHODS: HIV-negative methamphetamine-using MSM completed an online questionnaire between July and October 2012 about recent substance use and sexual behavior. Bivariate and multivariate tests were used to obtain statistically significant associations between demographic characteristics, engaging in transactional sex, life chaos, and the participants' perception of their social support. RESULTS: Of the 325 participants, 23.7% reported engaging in transactional sex, 45.2% reported high life chaos, and 53.5% reported low perceived social support. Participants who engaged in transactional sex were more likely to have high life chaos than participants who did not (aOR = 1.70, 95% CI = [1.01, 2.84]); transactional sex was not associated with social support. Participants with high life chaos were more out about their sexual orientation (aOR = 2.29, 95% CI = [1.18, 4.42]) and more likely to perceive they had low social support (aOR = 3.78, 95% CI = [2.31, 6.22]) than participants with low life chaos. Non-Latinos perceived they had less social support than Latinos (aOR = 0.48, 95% CI = [0.25, 0.92]). CONCLUSIONS: Methamphetamine-using MSM engaging in transactional sex experience more life chaos than those who do not engage in transactional sex. Outness, perceived social support, and ethnicity are associated with life chaos.

Anterior cingulum white matter is altered in tobacco smokers.

BACKGROUND AND OBJECTIVES: The anterior cingulate cortex (ACC) is hypothesized to be involved in decision making and emotion regulation. Previous observations of drug dependent individuals indicate that substance dependence may be associated with cingulum white matter abnormalities. The present study evaluated cingulum white matter in cigarette smokers. METHODS: Diffusion tensor imaging (DTI) in adult tobacco smokers and healthy non-smoker controls (total N = 70) was performed in a 3T Siemens Trio MRI scanner. RESULTS: Analyses of DTI tractography of the cingulum in tobacco-smoking individuals and controls indicated that tobacco abusers have significantly reduced fractional anisotropy (FA) in the right cingulum. In addition, FA in the left cingulum white matter was negatively associated with the number of cigarettes smoked per day and the Fagerstrom test for nicotine dependence, a self-report measure of tobacco dependence severity. CONCLUSIONS: The white matter of the cingulum is altered in a non-symmetrical way in tobacco smokers. An inverse relationship between FA and reported number of cigarettes per day was observed. Previous studies have also noted altered neural connectivity in cigarette smokers using similar methods. Similar white matter differences in the cingulum have been observed in methamphetamine dependent individuals and patients with dementia, which suggests that the cingulum may be altered by mechanisms not specific to tobacco exposure. SCIENTIFIC SIGNIFICANCE: By better understanding the effects of tobacco abuse on the brain, we hope to gain insight into how drug dependence influences the neurological foundations of behavior.

Identifying diagnostically-relevant resting state brain functional connectivity in the ventral posterior complex via genetic data mining in autism spectrum disorder.

Exome sequencing and copy number variation analyses continue to provide novel insight to the biological bases of autism spectrum disorder (ASD). The growing speed at which massive genetic data are produced causes serious lags in analysis and interpretation of the data. Thus, there is a need to develop systematic genetic data mining processes that facilitate efficient analysis of large datasets. We report a new genetic data mining system, ProcessGeneLists and integrated a list of ASD-related genes with currently available resources in gene expression and functional connectivity of the human brain. Our data-mining program successfully identified three primary regions of interest (ROIs) in the mouse brain: inferior colliculus, ventral posterior complex of the thalamus (VPC), and parafascicular nucleus (PFn). To understand its pathogenic relevance in ASD, we examined the resting state functional connectivity (RSFC) of the homologous ROIs in human brain with other brain regions that were previously implicated in the neuro-psychiatric features of ASD. Among them, the RSFC of the VPC with the medial frontal gyrus (MFG) was significantly more anticorrelated, whereas the RSFC of the PN with the globus pallidus was significantly increased in children with ASD compared with healthy children. Moreover, greater values of RSFC between VPC and MFG were correlated with severity index and repetitive behaviors in children with ASD. No significant RSFC differences were detected in adults with ASD. Together, these data demonstrate the utility of our data-mining program through identifying the aberrant connectivity of thalamo-cortical circuits in children with ASD. Autism Res 2016, 9: 553-562. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Alterations in interhemispheric functional and anatomical connectivity are associated with tobacco smoking in humans.

Abnormal interhemispheric functional connectivity correlates with several neurologic and psychiatric conditions, including depression, obsessive-compulsive disorder, schizophrenia, and stroke. Abnormal interhemispheric functional connectivity also correlates with abuse of cannabis and cocaine. In the current report, we evaluated whether tobacco abuse (i.e., cigarette smoking) is associated with altered interhemispheric connectivity. To that end, we examined resting state functional connectivity (RSFC) using magnetic resonance imaging (MRI) in short term tobacco deprived and smoking as usual tobacco smokers, and in non-smoker controls. Additionally, we compared diffusion tensor imaging (DTI) in the same subjects to study differences in white matter. The data reveal a significant increase in interhemispheric functional connectivity in sated tobacco smokers when compared to controls. This difference was larger in frontal regions, and was positively correlated with the average number of cigarettes smoked per day. In addition, we found a negative correlation between the number of DTI streamlines in the genual corpus callosum and the number of cigarettes smoked per day. Taken together, our results implicate changes in interhemispheric functional and anatomical connectivity in current cigarette smokers.

Interhemispheric insular and inferior frontal connectivity are associated with substance abuse in a psychiatric population.

Substance abuse is highly comorbid with major psychiatric disorders. While the neural underpinnings of drug abuse have been studied extensively, most existing studies compare drug users without comorbidities and healthy, non-user controls. Such studies do not generalize well to typical patients with substance abuse disorders. Therefore, we studied a population of psychiatric inpatients (n = 151) with a range of mental illnesses. Psychiatric disorders were diagnosed via structured interviews. Sixty-five percent of patients met criteria for at least one substance use disorder. Patients were recruited for resting state functional connectivity (RSFC) and diffusion tensor imaging (DTI) experiments to examine the interhemispheric connectivity between brain regions hypothesized to be involved in drug addiction, namely: the inferior, medial, and superior frontal gyri; insula; striatum; and anterior cingulate cortex. The World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test (WHOA) questionnaire was used to further assess drug use. An association between use of tobacco, alcohol, cocaine, sedatives, and hallucinogens with increased insular interhemispheric connectivity was observed. In addition, increased inferior frontal gyrus interhemispheric connectivity was associated with amphetamine and inhalant use. Our results suggest that increased inter-hemispheric insula connectivity is associated with the use of several drugs of abuse. Importantly, psychiatric inpatients without a history of drug dependence were used as an ecologically valid control group rather than the more typical comparison between "mentally ill vs. healthy control" populations. We suggest that dysfunction of interhemispheric connectivity of the insula and to a lesser extent of the inferior frontal gyrus, are related to drug abuse in psychiatric populations.

Impaired Facilitatory Mechanisms of Auditory Attention After Damage of the Lateral Prefrontal Cortex.

There is growing evidence that auditory selective attention operates via distinct facilitatory and inhibitory mechanisms enabling selective enhancement and suppression of sound processing, respectively. The lateral prefrontal cortex (LPFC) plays a crucial role in the top-down control of selective attention. However, whether the LPFC controls facilitatory, inhibitory, or both attentional mechanisms is unclear. Facilitatory and inhibitory mechanisms were assessed, in patients with LPFC damage, by comparing event-related potentials (ERPs) to attended and ignored sounds with ERPs to these same sounds when attention was equally distributed to all sounds. In control subjects, we observed 2 late frontally distributed ERP components: a transient facilitatory component occurring from 150 to 250 ms after sound onset; and an inhibitory component onsetting at 250 ms. Only the facilitatory component was affected in patients with LPFC damage: this component was absent when attending to sounds delivered in the ear contralateral to the lesion, with the most prominent decreases observed over the damaged brain regions. These findings have 2 important implications: (i) they provide evidence for functionally distinct facilitatory and inhibitory mechanisms supporting late auditory selective attention; (ii) they show that the LPFC is involved in the control of the facilitatory mechanisms of auditory attention.

Perceptions about e-cigarette safety may lead to e-smoking during pregnancy.

Electronic cigarettes (e-cigarettes) are nicotine-delivery devices that are increasingly used, especially by young people. Because e-cigarettes lack many of the substances found in regular tobacco, they are often perceived as a safer smoking alternative, especially in high-risk situations such as pregnancy. However, studies suggest that it is exposure to nicotine that is most detrimental to prenatal development. The authors studied perceptions of tobacco and e-cigarette health risks using a multiple-choice survey. To study the perceived safety of e-cigarettes versus tobacco cigarettes, 184 modified Global Health Youth Surveys (WHO, http://www.who.int/tobacco/surveillance/gyts/en/ ) were completed electronically or on paper. Age range, smoking status, and perceptions about tobacco cigarettes and e-cigarettes were studied. The results verified that younger people use e-cigarettes more than older people. Tobacco cigarettes were perceived as more harmful than e-cigarettes to health in general, including lung cancer and pregnancy. Although more research is necessary, the authors postulate that the perception that e-cigarettes are safer during pregnancy may induce pregnant women to use these devices more freely. Given that nicotine is known to cause fetal harm, pregnant mothers who smoke e-cigarettes could cause even greater harm to the fetus because e-cigarettes are perceived as being safer than tobacco cigarettes. Until more data about the effects of nicotine during pregnancy are available, the authors advocate for labeling of e-cigarettes as potentially harmful, at least during pregnancy.

The medial habenula: still neglected.

The habenula is a small, bilateral brain structure located at the dorsal end of the diencephalon. This structure sends projections to the dopaminergic striatum and receives inputs from the limbic forebrain, making the habenula a unique modulator of cross-talk between these brain regions. Despite strong interest in the habenula during the seventies and eighties (Herkenham and Nauta, 1977; Beckstead, 1979; Beckstead et al., 1979; Herkenham and Nauta, 1979; Caldecott-Hazard et al., 1988), interest waned due to lack of a clearly identifiable functional role. Following Matsumoto and Hikosaka's seminal work on the lateral habenula as a predictor of negative reward in monkeys, the habenula has undergone a resurgence of scientific interest. Matsumoto and Hikosaka demonstrated an increase in habenular neuron firing when monkeys did not receive an expected juice reward (Matsumoto and Hikosaka, 2007). Studies have shown that increased habenular activity inactivates dopaminergic cells in the Rostromedial Tegmental Nucleus (RMTg) through GABAergic mechanisms (Jhou et al., 2009a,b). Additional studies link habenular activity to the regulation of serotonin and norepinephrine, suggesting the habenula modulates multiple brain systems (Strecker and Rosengren, 1989; Amat et al., 2001). These discoveries ushered in a series of new studies that have refocused attention on the lateral habenula and the importance of this small brain structure (Bianco and Wilson, 2009; Jhou et al., 2009a; Matsumoto and Hikosaka, 2009; Sartorius et al., 2010; Savitz et al., 2011). Recently, Geisler and Trimble reviewed this renewed interest in: The Lateral Habenula: No Longer Neglected (Geisler and Trimble, 2008). While the lateral habenula (LHb) has been extensively studied, the anatomically and histochemically distinct medial habenula (MHb) remains largely understudied. This short review argues that the MHb is functionally important and should be studied more aggressively.

Dynamics of anticipatory mechanisms during predictive context processing.

We employed an electroencephalography paradigm manipulating predictive context to dissociate the neural dynamics of anticipatory mechanisms. Subjects either detected random targets or targets preceded by a predictive sequence of three distinct stimuli. The last stimulus in the three-stimulus sequence (decisive stimulus) did not require any motor response but 100% predicted a subsequent target event. We showed that predictive context optimises target processing via the deployment of distinct anticipatory mechanisms at different times of the predictive sequence. Prior to the occurrence of the decisive stimulus, enhanced attentional preparation was manifested by reductions in the alpha oscillatory activities over the visual cortices, resulting in facilitation of processing of the decisive stimulus. Conversely, the subsequent 100% predictable target event did not reveal the deployment of attentional preparation in the visual cortices, but elicited enhanced motor preparation mechanisms, indexed by an increased contingent negative variation and reduced mu oscillatory activities over the motor cortices before movement onset. The present results provide evidence that anticipation operates via different attentional and motor preparation mechanisms by selectively pre-activating task-dependent brain areas as the predictability gradually increases.