Brain circuitry of compulsivity.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.Dr. Soriano-Mas is funded by a ׳Miguel Servet׳ contract from the Carlos III Health Institute (CP10/00604). Dr. Goudriaan is supported by a VIDI Innovative Research Grant (Grant no. 91713354) funded by the Dutch Scientific Research Association (NWO-ZonMW). Dr. Alonso was funded by the Instituto de Salut Carlos III-FISPI14/00413. Dr. Nakamae received Grant support from MEXT KAKENHI (Nos. 24791223 and 26461753).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.12.00

Addiction, Adolescence, and Innate Immune Gene Induction

Repeated drug use/abuse amplifies psychopathology, progressively reducing frontal lobe behavioral control, and cognitive flexibility while simultaneously increasing limbic temporal lobe negative emotionality. The period of adolescence is a neurodevelopmental stage characterized by poor behavioral control as well as strong limbic reward and thrill seeking. Repeated drug abuse and/or stress during this stage increase the risk of addiction and elevate activator innate immune signaling in the brain. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a key glial transcription factor that regulates proinflammatory chemokines, cytokines, oxidases, proteases, and other innate immune genes. Induction of innate brain immune gene expression (e.g., NF-κB) facilitates negative affect, depression-like behaviors, and inhibits hippocampal neurogenesis. In addition, innate immune gene induction alters cortical neurotransmission consistent with loss of behavioral control. Studies with anti-oxidant, anti-inflammatory, and anti-depressant drugs as well as opiate antagonists link persistent innate immune gene expression to key behavioral components of addiction, e.g., negative affect-anxiety and loss of frontal–cortical behavioral control. This review suggests that persistent and progressive changes in innate immune gene expression contribute to the development of addiction. Innate immune genes may represent a novel new target for addiction therapy

Adolescent Brain Development and the Risk for Alcohol and Other Drug Problems

Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto-subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations

Baked and Buzzed: Investigating the Influence of Co-Use of Cannabis and Alcohol on White Matter Integrity in Emerging Adults

Objective: Growing evidence suggests alcohol and cannabis use independently alter neural structure and functioning, particularly during sensitive developmental time periods such as adolescence and emerging adulthood. However, there has been minimal investigation into the effects co-occurring use of these two substances, despite preliminary evidence of unique acute and psychopharmacological changes due to using alcohol and cannabis together. Method: Data drawn from the IDEAA Consortium was utilized to assess white matter integrity as measured by FreeSurfer’s TRACULA in emerging adults (n=192; 16-27 years old). Timeline Follow-Back was used to calculate past month cannabis use, alcohol use, co-use days, binge alcohol episode, and co-use-binge days. The Stroop task was administered and normed scores were used. Multiple regressions investigated white matter integrity by past month cannabis, alcohol, and co-use days, controlling for appropriate covariates (e.g., site, gender, education, length of abstinence). Analyses were run twice, once with alcohol as measured in standard units and once with binge episodes. Follow-up brain-behavior analyses assessed whether substance use or tracts that differed significantly by substance use then related to Stroop performance. Correction for multiple comparisons was conducted using Benjamini and Hochberg’s (1995) False Discovery Rate correction method. Results: Corrected for multiple comparisons, cannabis use was significantly related to increased mean diffusivity in 12 fronto-limbic and fronto-parietal tracts. Cannabis use also associated with poorer performance on Stroop word reading. Within the MJ+ALC group, increased mean diffusivity associated with better Stroop interference performance. Discussion: The present study found cannabis use was associated with decreased white matter integrity, as measured by mean diffusivity, across fronto-parietal and fronto-limbic tracts. These results suggest a robust relationship between cannabis use and white matter integrity in this neurodevelopmentally sensitive time period. Despite our hypotheses, co-use, alcohol use, and binge drinking did not significantly predict any measures. Future research should further investigate the potential independent and interactive affects of these substances on preclinical and clinical levels. Efforts should be made to inform the public of the likely negative impact of cannabis on white matter quality

Neural and cognitive biomarkers of binge and heavy drinking

BACKGROUND: Theories suggest two motivations that drive people to consume alcohol at pathological levels: (1) seeking of short-term pleasurable effects and (2) alleviation of unpleasant states. The former is associated with binge drinking (BD; i.e. high intake during fewer occasions) and the latter with heavy drinking (HD; substantial intake during more occasions). Although direct comparisons have not been made, BD has been associated with impairments in top-down executive control (related to frontal-parietal regions) and HD has been linked to bottom-up changes in internal mentation (related to the default mode network anatomical structure and function). This dissertation compares the two drinking patterns with the goal of testing for differential neurocognitive and neuroanatomical characteristics that would be indicative of two disorder subtypes. METHODS: The sample consisted of adult participants with a history of adolescent onset: BD (N = 16), HD (N = 15), and Healthy Controls (HC; N = 21). All groups were equated on age, education, amount of lifetime alcohol consumed (BD and HD groups), as well as other factors. The study compared group performance on an affective go/no go task and group differences in brain volume and cortical thickness based on structural MRI. RESULTS: Behavioral results showed a higher number of errors for the HD group, in comparison to other groups. Volumetric results indicated a smaller bilateral ventral diencephalon in both BD and HD, in comparison to the HC, and smaller bilateral globus pallidus in BD only. Cortical thickness analyses revealed a thinner left superior parietal region (overlapping with the dorsal attention and fronto-parietal networks) in BD, whereas a left medial occipito-parietal region was thicker in HD (overlapping mainly with the visual network). CONCLUSION: These data, interpreted in the context of prior studies, suggest that BD findings might be indicative of an executive control dysregulation that could contribute to continued BD. HD findings might be indicative of tissue damage due to frequent drinking. Prior research has found the occipital region to have the highest concentration γ-Aminobutyric acid receptors that are affected by alcohol, which might explain the thicker occipital region findings in the HD group

The Relation of Impulsivity and Obesity: A Neuroimaging Analysis

The current study examined the relation of impulsivity and obesity in three neuroimaging studies using MRI techniques to test the hypothesis that deficits in brain regions responsible for inhibitory control are associated with obesity. The first study used voxel-based morphometry (VBM) to explore volumetric differences in lean, overweight, and obese women (N=83) and found that BMI was negatively correlated with grey matter (GM) in the insula, frontal operculum, and inferior frontal gyrus. BMI was positively correlated with white matter (WM) in the fusiform gyrus, parahippocampal gyrus, Rolandic operculum, and dorsal striatum. Genetic alleles for dopamine expression moderated these relations. Additionally, less GM in the superior frontal gyrus predicted future increases in BMI. The second study used VBM to examine differences between lean adolescents at risk versus not at risk for obesity (N=54). There were no regional GM or WM differences based on risk status. There were also no regional differences that predicted weight gain over 1-year follow-up. Additionally, genetic alleles for dopamine expression did not moderate any of these regions. These findings suggest that volumetric differences may emerge after excessive weight gain. Finally, the third study used a psychophysiological interaction analysis to test functional connectivity between prefrontal and limbic regions as a function of BMI in lean, overweight, and obese women (N=37) during a go/no-go task. There was no functional connectivity found in seed regions in relation to BMI. Implications for intervention and future research are discussed

Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats

Background and Purpose: Substance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse. Experimental Approach: The effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. Key Results: Systemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism

Relevance of cannabinoids in preclinical models of psychiatric disorders

Throughout this thesis, we are going to navigate through the history of cannabis, from its first use thousands of years ago, to its exponential growth in use and knowledge during the last third of the last century. The endocannabinoid system was a cutting-edge discovery, which initiated interest in cannabinoids both in their effects on the human body, and in their interaction with other neural systems, such as the dopaminergic reward system. Not much later, the implications of cannabis in adolescence were postulated, opening a wide range of possibilities in the study of cannabinoids. Consequently, researchers began to wonder whether cannabinoids might influence the consumption of other drugs and, the possible interactions with other endogenous systems, such as the opioid system, and their association with the onset of psychiatric disorders, such as schizophrenia. In this sense, preclinical models have provided a great impulse for the understanding of such processes and effects of cannabinoids. Nevertheless, it is important to note that the field of cannabinoid research is rapidly evolving, and although substantial progress has been made, many questions remain to be answered.Programa de Doctorado en Ciencia y Tecnología Biomédica por la Universidad Carlos III de MadridPresidente: Juan Nàcher Roselló.- Secretaria: Raquel Abalo Delgado.- Vocal: Miguel Ángel Morcillo Alons