Resting state functional connectivity of the nucleus accumbens in youth with a family history of alcoholism
Introduction
Adolescents with a family history of alcoholism (FHP) have elevated risk for developing alcohol use disorders (AUDs) compared to youth without a family history (FHN) of AUDs (Dawson et al., 1992, Goodwin et al., 1974, Sher et al., 1991). In an effort to understand psychological and neurobiological factors that contribute to increased vulnerability for alcohol abuse, behavioral and neuroimaging research has focused on identifying markers of risk in FHP youth. As there are various cognitive (Corral et al., 2003, Harden and Pihl, 1995, Poon et al., 2000), neurobiological (Cservenka et al., 2012, Cservenka and Nagel, 2012, Mackiewicz Seghete et al., 2013, Schweinsburg et al., 2004, Silveri et al., 2011), and psychological (Sher, 1991) abnormalities in FHP youth in the absence of heavy alcohol consumption, there is likely some heritable risk factor associated with developing an AUD. Given that adolescence is a time of heightened risk for the emergence of alcohol abuse, it is critical to examine functional brain differences between FHP and FHN youth prior to the initiation of any heavy alcohol use. By doing so, FHP-related neurobiological markers can be identified in the absence of alcohol-induced neurotoxicity, and examined during a period of active brain development, when cognitive, affective, and reward-driven systems (Casey and Jones, 2010, Ernst et al., 2006b, Galvan et al., 2006, Somerville and Casey, 2010) may contribute to addiction vulnerability.
Alcoholism is a disorder associated with dysfunctional mesolimbic reward circuitry (see Noble (1996) for review). However, there is a debate as to whether abnormalities in alcoholics' reward-related brain circuitry are a consequence of long-term alcohol abuse, or if these regions show premorbid atypical structure and/or function that contributed to the development of AUDs. The nucleus accumbens (NAcc) is a primary region of reward processing and response (Knutson et al., 2001). Structural changes, functional alterations, and neuroadapations of this region are implicated in heavy alcohol use, across human (Claus et al., 2011, Wu et al., 2010) and animal studies (Alaux-Cantin et al., 2013, Szumlinski et al., 2007). The NAcc, which is part of the mesoscorticolimbic dopamine pathway (Berendse et al., 1992, Nauta et al., 1978), has extensive functional connections to other reward-related regions, including orbitofrontal cortex (OFC), basal ganglia, and the amygdala (Cauda et al., 2011). Thus, understanding functional connectivity of the NAcc is important for identifying atypical reward-related connectivity patterns that may contribute to risk for addiction.
In alcoholics and heavy drinkers, structural studies have found reduced NAcc volume (Makris et al., 2008), while functional magnetic resonance imaging (fMRI) suggests increased blood oxygen level-dependent (BOLD) response in this region in the presence of alcohol-related cues (Claus et al., 2011, Kareken et al., 2004, Myrick et al., 2004, Wrase et al., 2007). Further, also seen in alcoholics (Beck et al., 2009, Wrase et al., 2007), adults and youth with a family history of alcoholism show blunted NAcc response during monetary reward anticipation compared to their FHN peers (Andrews et al., 2011, Yau et al., 2012). Additionally, FHP youth show increased functional connectivity of the NAcc with precuneus, somatosensory, and sensorimotor regions during reward anticipation (Weiland et al., 2013). This suggests that familial risk for alcoholism may be associated with abnormal reward processing, even in the absence of alcohol abuse. However, to our knowledge, there have been no studies published in FHP youth examining functional connectivity of the NAcc, in the absence of task-related demands (i.e., during rest).
Resting state functional connectivity magnetic resonance imaging (rs-fcMRI) is a technique that characterizes the synchronous fluctuation of the BOLD timecourse at rest (Biswal et al., 1995). This technique has been used to identify distinct brain networks and the development of their functional connections (Dosenbach et al., 2007, Fair et al., 2007, Fox et al., 2005). Studies of resting state synchrony in healthy individuals indicate that the NAcc shows positive functional connectivity, or integration, with other reward and affect-related regions, such as the OFC, striatum, and amygdala (Barnes et al., 2010, Di Martino et al., 2008). In contrast, the NAcc shows negative functional connectivity, or segregation, with regions implicated in cognitive control, such as dorsolateral prefrontal and inferior parietal cortices (Barnes et al., 2010, Di Martino et al., 2008). Recently, studies in long-term abstinent alcoholics have shown that the NAcc has decreased functional connectivity with limbic regions, including the caudate and the medial dorsal and anterior nuclei of the thalamus, and increased connectivity with executive functioning brain areas, such as the dorsolateral prefrontal cortex and inferior parietal lobule (Camchong et al., 2013a, Camchong et al., 2013b). The authors interpreted these patterns of connectivity as compensatory mechanisms that allowed for continued abstinence, as they were associated with improved neuropsychological performance.
Despite these alterations in resting state synchrony observed in abstinent alcoholics, it is yet unknown whether FHP and FHN youth differ in resting state connectivity of the NAcc. This analysis is critical to differentiating consequences of long-term alcohol use from underlying risk for the development of AUDs. Thus, the goal of the current study was to use rs-fcMRI in a sample of 10–16 year old FHP and FHN youth, who had not used alcohol or other substances heavily. While healthy adults exhibit segregation of ventral striatal and fronto-parietal brain regions (Barnes et al., 2010, Di Martino et al., 2008), FHP youth and young adults have reduced functional response in these same regions (Andrews et al., 2011, Cservenka et al., 2012, Cservenka and Nagel, 2012, Mackiewicz Seghete et al., 2013, Yau et al., 2012). Interestingly, weaker NAcc response in FHP individuals during reward anticipation is related to behavioral impulsivity (Andrews et al., 2011), which could suggest interference between reward and cognitive control brain activity. Thus, we predicted that at-risk youth would have less segregation between these regions, which would suggest less distinct dissociation of reward and cognitive control brain areas. Additionally, the NAcc is typically positively functionally connected to other reward-related brain regions, such as the OFC (Barnes et al., 2010, Di Martino et al., 2008), which is essential for reward learning (Tanabe et al., 2013), and has smaller volume and increased activity to alcohol cues in those with addiction (Claus et al., 2011, Tanabe et al., 2009). Furthermore, individuals at risk for alcoholism show decreased laterality of OFC volume between right and left hemispheres (Hill et al., 2009). Given these OFC abnormalities in substance dependence and risk for alcoholism, we also hypothesized that FHP youth would have less integration between the NAcc and other reward-related brain regions, such as the OFC, suggestive of poorer within-network integration of appetitive brain regions.
Section snippets
Participants
Participants, ages 10–16 years, were recruited from the local community. FHP youth were part of an ongoing longitudinal study and matched for demographic characteristics to FHN participants. To determine eligibility, structured interviews were conducted by telephone with the youth and one of their parents [Structured Clinical Interview; (Brown et al., 1994)]. Exclusionary criteria included: lack of information on family history, family history of psychotic disorders, diagnosis of a DSM-IV
Demographics
Ninety-seven subjects were included in the final analyses of resting state functional connectivity (47 FHP, 50 FHN). Demographic characteristics of the samples are described in Table 1. Participants were well matched on age, sex ratio, race, pubertal stage, and IQ (all P>0.05). However, they differed on SES (FHN=28.56, SD=12.37, FHP=34.60, SD=14.29, U=842, Z=−2.41, P=0.016) and GPA (FHN=3.62, SD=0.39, FHP=3.41, SD=0.53, U=746, Z=−2.11, P=0.035), both of which were higher in the FHN group. For
Discussion
The goal of this study was to investigate differences in resting state synchrony of the NAcc between FHP and FHN youth, since intrinsic connectivity of this brain region may be an important neurobiological marker of AUD risk. As hypothesized, there was significantly less segregation between the NAcc and regions of the fronto-parietal network in FHP youth, which could suggest poorer dissociation of cognitive control and reward networks. There was also less integration of the right NAcc and left
Acknowledgments
Grant support for the authors of this study was provided by R01 AA017664 (Nagel), U01 AA021691 (Nagel), a pilot grant to Nagel from the Portland Alcohol Research Center (P60 AA010760 (Crabbe)), R01 MH096773 (Fair), R00 MH091238 (Fair), and the Oregon Clinical & Translational Research Institute (Fair).
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