Background: Tobacco use is the top preventable cause of early mortality in schizophrenia. Over 60% of people with schizophrenia (SZ) smoke, 3 times the general prevalence. The biological basis of this increased risk is not understood, and existing interventions do not target SZ- specific pathology. We therefore used a connectome-wide analysis to identify SZ-specific circuits of nicotine addiction.
Methods: We reanalyzed existing data from 2 studies: In cohort 1, 35 smokers (18 SZ, 17 control) underwent resting-state fMRI and clinical characterization. A multivariate pattern analysis of whole-connectome data was used to identify the strongest links between cigarette use and functional connectivity. In cohort 2, 12 SZ participants and 12 controls were enrolled in a randomized, controlled crossover study of transdermal nicotine patch with resting-state fMRI. We correlated change in brain network functional connectivity with nicotine dose.
Results: In cohort 1, the strongest (p<.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. This effect was entirely driven by SZ participants. In cohort 2, Nicotine reduced DMN connectivity in a dose- dependent manner (R=-0.50; 95% CI -0.75 to -0.12, p<.05). There was a significant effect of diagnosis on DMN connectivity. In the placebo condition, SZ subjects had hyperconnectivity compared to controls (p<.05). Nicotine administration normalized DMN hyperconnectivity in SZ.
Conclusions: It has been hypothesized that the biological basis of nicotine dependence is different in SZ and in non-SZ populations. We provide direct evidence in support of this hypothesis by demonstrating that 1) tobacco use is strongly linked to brain network organization only in participants with SZ and 2) nicotine normalizes network hyperconnectivity in a dose-dependent fashion. Our results suggest the high prevalence of nicotine use in SZ may be an attempt to “self-medicate” i.e. to correct a network deficit known to interfere with cognition. Future experiments will directly test if noninvasive neuromodulation of this network in SZ and controls affects cognition and nicotine use.
Over 60% of people with schizophrenia smoke cigarettes, a prevalence 3 times higher than the general population. Prior imaging studies of candidate brain circuits have not converged on a biological basis for schizophrenia’s link to nicotine dependence. We therefore employed an entirely data-driven analysis of the connectome to identify both shared and schizophrenia-specific circuits of nicotine addiction.
In this study, we reanalyzed existing data from two neuroimaging studies using a data-driven approach. In the first cohort, shown in Figure 1 and Table 1, thirty-five smokers (18 schizophrenia, 17 controls) underwent resting-state imaging and clinical characterization.
We used a multivariate pattern analysis of whole-connectome data to identify the strongest links between daily cigarette consumption and functional connectivity. We identified a parieto-occipital region (shown in Figure 2 in yellow) where increased connectivity significantly correlates with greater daily cigarette use in the schizophrenia group (in Panel B) but not in the control group (in Panel C).
We determined the spatial organization of resting state networks was strongly linked to cigarette use in schizophrenia, as in Figure 3. This was driven by individual variation in the topography of the Default Mode Network. Figure 3 shows 2 examples of individuals with either high daily cigarette use (40 cig/day) (A) or low daily cigarette use (5 cig/day) (B). In individuals with high cigarette use, the parieto-occipital region we identified (shown in green) is part of the Default Mode Network in red and not part of the Dorsal Attention Network in blue. In individuals with low cigarette use, the Default Mode Network in red is external to the green parieto-occipital region and the region is instead part of the Dorsal Attention Network in blue. This link between network topography and cigarette consumption was not observed in the control group.
Thus, nicotine consumption is linked to resting state networks. In heavy smokers, Default Mode Network topography is expanded. We had a hypothesis: we already know from previous studies that the Default Mode Network is hyperconnected in schizophrenia and that Default Mode Network hyperconnectivity is associated with impaired attention. We think that the topographic expansion we observed is a product of network dysfunction, and nicotine use is a way of self-medication of this dysfunction, thereby serving as a compensatory mechanism. If that is true, then nicotine should have a direct effect on that network, so we decided to see if that was the case.
In the second cohort (shown in Figure 4 and Table 2), 12 participants with schizophrenia and 12 controls participated in a randomized, controlled crossover study of transdermal nicotine patch with resting-state imaging. Participants were a mix of smokers and nonsmokers. We measured whole Default Mode Network functional connectivity twice: once in the placebo condition and once with nicotine patch. We then calculated average change in connectivity of the entire Default Mode Network between these two administrations and correlated network connectivity change to administered nicotine dose.
As shown in Figure 5, we observed a linear relationship between higher nicotine dose and greater reduction in Default Mode Network connectivity. We also observed a significant effect of diagnosis on Default Mode Network connectivity (shown in Figure 6). As you can see, in panel A, Default Mode Network connectivity decreases with nicotine administration in schizophrenia, but in Panel B, this pattern is not evident in controls. Panel C shows on average, subjects with schizophrenia have significantly higher Default Mode Network connectivity compared to controls in the placebo condition which was no longer significant with nicotine administration.
In summary, we have identified a novel brain basis for the high prevalence of nicotine dependence in schizophrenia. It has been hypothesized that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. We here provide direct evidence in support of this hypothesis by demonstrating that tobacco use is strongly linked to resting-state brain network organization only in participants with schizophrenia. Given that the Default Mode Network is hyperconnected in schizophrenia and that Default Mode Network hyperconnectivity is associated with impaired attention, we propose a model in Figure 7 that the high prevalence of nicotine use in schizophrenia may be a product of a hyperconnected Default Mode Network that both interferes with cognitive performance and is more sensitive to nicotine in schizophrenia compared to controls. Future experiments will directly test if modulating this network in schizophrenia and controls can affect cognition and nicotine consumption.
Live Zoom Session – April 21st
Heather Burrell Ward, MD, Adam Beermann, MA, Uzma Nawaz, MS, Mark Halko, PhD, Amy C. Janes, PhD, Lauren V. Moran, MD, Roscoe O. Brady, Jr. MD, PhD