Kenia M. Velasquez

The role of the habenula in drug addiction

Interest in the habenula has greatly increased in recent years. The habenula is a small brain structure located posterior to the thalamus and adjacent to the third ventricle. Despite its small size, the habenula can be divided into medial habenula (MHb) and lateral habenula (LHb) nuclei that are anatomically and transcriptionally distinct. The habenula receives inputs from the limbic system and basal ganglia primarily via the stria medullaris. The fasciculus retroflexus is the primary habenular output from the habenula to the midbrain and governs release of glutamate onto gabaergic cells in the rostromedial tegmental nucleus (RMTg) and onto the interpeduncular nucleus. The resulting GABA released from RMTg neurons inactivates dopaminergic cells in the ventral tegmental area/substantia nigra compacta. Through this process, the habenula controls dopamine levels in the striatum. Thus, the habenula plays a critical role in reward and reward-associated learning. The LHb also modulates serotonin levels and norepinephrine release, while the MHb modulates acetylcholine. The habenula is a critical crossroad that influences the brain’s response to pain, stress, anxiety, sleep, and reward. Dysfunction of the habenula has been linked to depression, schizophrenia, and the effects of drugs of abuse. This review focuses on the possible relationships between the habenula and drug abuse.

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.

Characterizing white matter changes in cigarette smokers via diffusion tensor imaging.

BACKGROUND Tobacco use remains the most preventable cause of death; however, its effects on the brain, and particularly white matter, remain elusive. Previous diffusion tensor imaging (DTI) studies have failed to yield consistent findings, with some reporting elevated measures of fractional anisotropy (FA) and others reporting lowered FA. METHODS In our study, we sought to elucidate the effects of tobacco on white matter by using enhanced imaging acquisition parameters and multiple analysis methods, including tract-based spatial statistics (TBSS) with crossing fiber measures and probabilistic tractography. RESULTS Our TBSS results revealed that chronic cigarette smokers have decreased FA in corpus callosum and bilateral anterior internal capsule, as well as specific reduced anisotropy in the two major fiber directions in a crossing fiber model. Further, our tractography results indicated that smokers have decreased FA in tracts projecting to the frontal cortex from (1) nucleus accumbens, (2) habenula, and (3) motor cortex. We also observed that smokers have greater disruptions in those regions when they had recently smoked compared to when they abstained from smoking for 24h. Our results also support previous evidence showing hemispheric asymmetry, with greater damage to the left side compared to the right. CONCLUSIONS These findings provide more conclusive evidence of white matter disruptions caused by nicotine use. By better understanding the neural disruptions correlating with cigarette smoking we can elucidate the addictive course and explore targeted treatment regimens for nicotine dependence.

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.

Prefrontal cortex, temporal cortex, and hippocampus volume are affected in suicidal psychiatric patients

Suicide is a leading cause of death in America, with over 40,000 reported suicides per year. Mental illness is a major risk factor for suicidality. This study attempts to validate findings of volumetric differences from studies on suicidality. Psychiatric inpatients classified as having mildly severe or severe depression were separated into two groups: suicide attempted in the past two months (SA; n=20), non-suicidal control group (DA; n=20); these patients were all depressed and not significantly different for age, gender, race, marital status, education level, anxiety level, and substance abuse. Healthy controls (HC; n=20) were not significantly different from the suicidal groups for age and gender. Volunteers underwent MRI to assess volumes of cortical lobes, corpus callosum, and subcortical regions of interest, including the thalamus, insula, limbic structures, and basal ganglia. The right hippocampal volume of the SA group was significantly reduced compared to healthy controls. The frontal and temporal lobe volumes of the SA group were significantly decreased compared to the DA group. These volumetric reductions confirm previous findings and support the hypothesis that fronto-temporal function may be altered in suicidal patients.

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.

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.

Effects of tobacco smoke and electronic cigarette vapor exposure on the oral and gut microbiota in humans: a pilot study

Background The use of electronic cigarettes (ECs) has increased drastically over the past five years, primarily as an alternative to smoking tobacco cigarettes. However, the adverse effects of acute and long-term use of ECs on the microbiota have not been explored. In this pilot study, we sought to determine if ECs or tobacco smoking alter the oral and gut microbiota in comparison to non-smoking controls. Methods We examined a human cohort consisting of 30 individuals: 10 EC users, 10 tobacco smokers, and 10 controls. We collected cross-sectional fecal, buccal swabs, and saliva samples from each participant. All samples underwent V4 16S rRNA gene sequencing. Results Tobacco smoking had a significant effect on the bacterial profiles in all sample types when compared to controls, and in feces and buccal swabs when compared to EC users. The most significant associations were found in the gut, with an increased relative abundance of Prevotella (P = 0.006) and decreased Bacteroides (P = 0.036) in tobacco smokers. The Shannon diversity was also significantly reduced (P = 0.009) in fecal samples collected from tobacco smokers compared to controls. No significant difference was found in the alpha diversity, beta-diversity or taxonomic relative abundances between EC users and controls. Discussion From a microbial ecology perspective, the current pilot data demonstrate that the use of ECs may represent a safer alternative compared to tobacco smoking. However, validation in larger cohorts and greater understanding of the short and long-term impact of EC use on microbiota composition and function is warranted.

Increased habenular connectivity in opioid users is associated with an α5 subunit nicotinic receptor genetic variant: Habenular Connectivity is Increased in Opioid Users

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).

Neural correlates of healing prayers, depression and traumatic memories: A preliminary study

Depression is a global health concern and when rooted in childhood adversity is particularly difficult to treat. In a previous study, we found that healing prayer was effective in reducing depressive symptoms. Subjects suffering with depression according to HAM-D scores underwent task-based brain functional MRI (fMRI) prior to and after a 6-week prayer intervention, and depression symptoms were assessed at both time points and at a 12-month follow-up. Average HAM-D scores decreased from 21.6±3.0 prior to the intervention to 4.0±2.7 immediately afterwards (14 subjects) and remained low (3.7±3.4) at 12-month follow-up (11 subjects). fMRI demonstrated increased activity in the medial prefrontal cortex during focus on the traumatic memory after the prayer intervention. Changes in activity in the left inferior frontal gyrus correlated with improvement in depressive symptoms. Activity in the precuneus region decreased after the prayer intervention when subjects focused on the negative feelings associated with the trauma. We conclude that increased activity in the prefrontal cortex after healing prayer may be associated with increased cognitive control over emotions. Healing prayer may help to dissociate the memory of the trauma from feelings associated with it, as evidenced by changes in the precuneus region.