Real-time fMRI links subjective experience with brain activity during focused attention.

Recent advances in brain imaging have improved the measure of neural processes related to perceptual, cognitive and affective functions, yet the relation between brain activity and subjective experience remains poorly characterized. In part, it is a challenge to obtain reliable accounts of participant's experience in such studies. Here we addressed this limitation by utilizing experienced meditators who are expert in introspection. We tested a novel method to link objective and subjective data, using real-time fMRI (rt-fMRI) to provide participants with feedback of their own brain activity during an ongoing task. We provided real-time feedback during a focused attention task from the posterior cingulate cortex, a hub of the default mode network shown to be activated during mind-wandering and deactivated during meditation. In a first experiment, both meditators and non-meditators reported significant correspondence between the feedback graph and their subjective experience of focused attention and mind-wandering. When instructed to volitionally decrease the feedback graph, meditators, but not non-meditators, showed significant deactivation of the posterior cingulate cortex. We were able to replicate these results in a separate group of meditators using a novel step-wise rt-fMRI discovery protocol in which participants were not provided with prior knowledge of the expected relationship between their experience and the feedback graph (i.e., focused attention versus mind-wandering). These findings support the feasibility of using rt-fMRI to link objective measures of brain activity with reports of ongoing subjective experience in cognitive neuroscience research, and demonstrate the generalization of expertise in introspective awareness to novel contexts.

Maternal separation with early weaning: a novel mouse model of early life neglect.

BACKGROUND: Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. RESULTS: In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. CONCLUSIONS: These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.

Craving to quit: psychological models and neurobiological mechanisms of mindfulness training as treatment for addictions.

Humans suffer heavily from substance use disorders and other addictions. Despite much effort that has been put into understanding the mechanisms of the addictive process, treatment strategies have remained suboptimal over the past several decades. Mindfulness training, which is based on ancient Buddhist models of human suffering, has recently shown preliminary efficacy in treating addictions. These early models show remarkable similarity to current models of the addictive process, especially in their overlap with operant conditioning (positive and negative reinforcement). Further, they may provide explanatory power for the mechanisms of mindfulness training, including its effects on core addictive elements, such as craving, and the underlying neurobiological processes that may be active therein. In this review, using smoking as an example, we will highlight similarities between ancient and modern views of the addictive process, review studies of mindfulness training for addictions and their effects on craving and other components of this process, and discuss recent neuroimaging findings that may inform our understanding of the neural mechanisms of mindfulness training.

Mindfulness training for smoking cessation: moderation of the relationship between craving and cigarette use.

BACKGROUND: Smoking is the leading cause of preventable death in the US, while abstinence rates remain modest. Smoking has been shown to be perpetuated by operant conditioning, notably negative reinforcement (e.g., smoking to relieve negative affective states). Mindfulness training (MT) shows promise for smoking cessation, by potentially altering an individual's tendency to smoke in response to craving. The purpose of this study was to examine the effects of MT and mindfulness practice on the relationship between smoking and craving after receiving four weeks of MT. METHODS: 33 adults received MT as part of a randomized trial for smoking cessation. Individuals in the MT condition recorded formal and informal mindfulness practice during treatment using daily diaries. RESULTS: Analyses showed that strong correlations between craving and smoking at baseline (r=0.582) were attenuated at the end of treatment (r=0.126). Mindfulness home practice significantly predicted cigarette use (formal: B=-1.21, p=0.007; informal: B=-1.52, p<0.0001) and informal practice moderated the relationship between craving and smoking at the end of treatment (B=0.52, p=0.03). CONCLUSIONS: These findings suggest that MT may be effective as a treatment for smoking cessation and that informal mindfulness practice predicts a decoupling of the association between craving and smoking.

Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity.

OBJECTIVE: Sodium-dependent and chloride-dependent gamma-aminobutyric acid (GABA) transporter 1 (SLC6A1) is the target of a number of drugs of clinical importance and is a major determinant of synaptic GABA concentrations. We resequenced the human SLC6A1 gene previously and discovered a novel 21 bp insertion in the predicted promoter region that creates a second tandem copy of the sequence. Here we sought to determine the functional relevance of this variation. METHODS: We used reporter assays, mobility shift assays, quantitative PCR, and proteomics methods as well as postmortem expression analysis for this work. RESULTS: Reporter assays showed that the insertion allele significantly increases promoter activity in multiple cell lines. The zinc finger transcription factor ZNF148 was found to significantly transactivate the promoter and increase expression when overexpressed but could not account for the differences in activity between the two alleles of the promoter. Copy number of the insertion sequence was associated with exponentially increasing activity of a downstream promoter, suggesting that the insertion sequence has enhancer activity when present in multiple copies. SLC6A1 promoter genotype was found to predict SLC6A1 RNA expression in human postmortem hippocampal samples. These results suggest that the insertion polymorphism leads to increased SLC6A1 promoter activity because, in part, of creation of an enhancer element when present as multiple copies. Genotyping individuals from Tanzania in this study suggested that the insertion allele has its origin in Africa. CONCLUSION: On account of the effect of the insertion on promoter activity, this relatively common polymorphism may prove useful in predicting clinical response to pharmacological modulators of SLC6A1 as well as GABAergic function in individuals of African descent.