Defining neurobiological links between substance use and mental illness

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Dr. Janes officially joined the NIDA-IRP program in October of 2021. Her efforts focused on preparing two novel lines of research for scientific and IRB review. She also focused on staff recruitment and preparation of all elements for starting a research program at the IRP. She also published 4 manuscripts, which are described below. 1. Ekhtiari H, Zare-Bidoky M,Sangchooli A, Janes AC et al (2022) A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus. Nature Protocols. This work provided a detailed discussion of the current state of fMRI cue-reactivity studies as well as provided extensive recommendations for the state of the field and how best to move forward. 2. Ward HB, Beerman A, Nawaz U, Halko MA, Janes AC, Moran LV, Brady RO. Evidence for schizophrenia-specific pathophysiology of nicotine dependence. (In Press). Frontiers in Psychiatry-Schizophrenia. A novel brain basis for the high prevalence of nicotine dependence in schizophrenia was identified. Specifically, we observed that variation in nicotine consumption is linked to the spatial organization of two resting-state networks, the default mode network (DMN) and dorsal attention network (DAN). In Cohort 1, the strongest (p < 0.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. In individuals with greater daily cigarette consumption, we observed a pathological expansion of the DMN territory into the identified parieto-occipital region, while in individuals with lower daily cigarette consumption, this region was external to the DMN. This effect was entirely driven by schizophrenia participants. Given the relationship between DMN topography and nicotine use we observed in Cohort 1, we sought to directly test the impact of nicotine on this network using an independent second cohort. In Cohort 2, nicotine reduced DMN connectivity in a dose-dependent manner (R = -0.50; 95% CI -0.75 to -0.12, p < 0.05). In the placebo condition, schizophrenia subjects had hyperconnectivity compared to controls (p < 0.05). Nicotine administration normalized DMN hyperconnectivity in schizophrenia. We provide direct evidence that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. Our results suggest the high prevalence of nicotine use in schizophrenia may be an attempt to correct a network deficit known to interfere with cognition. 3. Campbell AS, Needham BD, Meyer CR, Tan J, Contrad M, Preston GP, Bolognani F, Rao SG, Heussler H, Griffith R, Guastella AJ, Janes AC, Frederick B, Donabedian DH, Mazmania SK (In Press) Safety and target-engagement of an oral small molecule sequesterant in adolescents with Autism Spectrum Disorder: an open-label phase 1b/2a3 trial. Nature Medicine Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials. 4. Murray L, Welsh JC, Johnson CG, Kaiser RH, Farchione TJ, Janes AC (2022). Alcohol- and non-alcohol-related interference: An fMRI study of treatment-seeking adults with alcohol use Disorder. Drug and Alcohol Dependence. Epub Background: Individuals with alcohol use disorder (AUD) have difficulty diverting attention away from alcohol-related stimuli and towards non-alcohol-related goals (i.e., alcohol-related attention interference). It remains unclear whether regulatory brain function differs during alcohol and non-alcohol-related interference. This study compares brain reactivity during the alcohol and classic Stroop and whether such brain function relates to AUD severity. Methods: 46 participants with AUD completed alcohol and classic color-word Stroop tasks during fMRI. Brain activity was compared during alcohol and classic Stroop interference in the rostral and dorsal anterior cingulate cortices (rACC and dACC) and correlated with self-reported AUD severity. Exploratory whole-brain analyses were also conducted. Results: Behavioral interference (i.e., slower reaction times) was observed during alcohol and classic Stroop. rACC activity was significantly higher during the alcohol > neutral contrast versus the incongruent > congruent contrast. dACC activity did not differ between the Stroop tasks. dACC activity during incongruent > congruent was positively associated with AUD severity. Conclusions: Activity in ACC subregions differed during alcohol and non-alcohol interference. Increased alcohol-related activity in the rACC, a region linked to emotional conflict resolution, suggests an interfering effect of self-relevant alcohol cues on non-alcohol-related processing. AUD severity was related to greater dACC reactivity during classic Stroop interference, suggesting that non-drug-related cognitive control impairments are more pronounced in those with more problematic alcohol use.