Family history of alcoholism mediates the frontal response to alcoholic drink odors and alcohol in at-risk drinkers

Abstract

Although a family history of alcoholism is the strongest risk factor for developing alcohol dependence, there are few studies of the association between familial alcoholism and the human brain's reward system activity. We used functional magnetic resonance imaging (fMRI) to determine how family history affects the brain's response to subjects' preferred alcoholic drink odors (AO) as compared to appetitive control odors (ApCO). Fourteen non-dependent heavy drinkers (HD) who were family history positive (FHP) participated, as did 12 HD who were family history negative (FHN). Subjects were imaged under both alcohol intoxication and placebo, using intravenous infusion and pharmacokinetic modeling to target a blood alcohol level of 50 mg%. Under placebo, HD-FHP had a larger medial frontal [AO>ApCO] effect than did HD-FHN. Alcohol intoxication dampened this response in the HD-FHP but potentiated it in the HD-FHN. This suggests that a family history of alcoholism and brain exposure to alcohol interact in heavy drinkers to differentially affect how the brain responds to alcohol cues.

Figure 1. Stimulation paradigm

Subjects sniffed alcoholic odors (subject’s two most-preferred drinks), two non-appetitive odors (from grass, leather, and Douglas fir), or appetitive control odors (grape chocolate), as well as odorless air (sham stimuli) Each stimulus was delivered over 2 s odor valve openings, with auditory commands (yellow inset) instructing subjects to sniff Following a tone, subjects signaled their ability to detect an odor (“yes” or “no”) using a button response box. Each odorant in a given class was delivered twice in alternate order (e.g., beer, whiskey, beer, whiskey) over the course of two 40 s periods, with a 10 s stimulus onset asynchrony (SOA) between single odorant pulses. Although the stimuli were grouped in classes, responses were analyzed as events (timed to each valve opening, which initial testing showed to be the most sensitive approach). Three different stimulation sequences were randomized across the subjects, such that no stimulus class was repeated without an intervening class, and any one odor class was always followed by two odorless baseline events. Three functional imaging scans per subject session were performed, for a total of 24 odor events per odorant class.

Figure 2

Stereotactically defined ROIs. Left and middle panels; Left and right medial (dark blue. cyan, respectively) and ventromedial prefrontal (yellow, burgundy). Right panel. Left and right ventral striatal (dark blue, cyan) and caudate (yellow, burgundy).

Figure 3

Perceived “high” and “intoxication” (mean ± standard error) under intravenous infusion during functional imaging. Time points are relative (1 = baseline before infusion pump start; 2= at model peak breath alcohol; 3 – 5= after each of three olfactory stimulation fMRI scans. Horizontal bar marks period of steady-state infusion (dash= placebo saline; solid= ethanol at modeled to be 50 mg%).

Figure 4

Voxel-wise heat maps (display height, p < 0.005; extent threshold. k > 25) of olfactory sensory system activation [NApO > odorless sniffing] under intravenous saline and steady-state alcohol (targeted breath level = 0.050) Circles = piriform (primary olfactory) cortex activation. Also note lateral orbitofrontal (olfactory association cortex) activation. Random effects analyses show no significant betwecn-session differences (see text for details).

Figure 5

A) Voxel-wise effects of [AO > ApCO] in subject groups under placebo and alcohol (targeted breath alcohol = 0.050) x = 2 mm right. Figure display threshold, p < 0.005, Coordinates for peak medial frontal effects exceeding p< 0.001, uncorrected, k > 10 voxels: A1[−6, 56, −6], A2[not significant], A3[no significant], A4[4,44, −6] and −10,42, −8]. B) Nature of significant Group × Odor × Condition interaction in right medial prefrontal cortex (ROI depicted in inset; text for more details). Odor effects are relative to odorless sniffing (i e., a negative value indicates a larger BOLD response to odorless sniffing than to the odorant). Left. Under placebo, AO was significantly greater than ApCO only in the HD-FHP. Right. Under alcohol, the contrast between AO and ApCO was significant in HD-FHN, but not in HD-FHP. See text for abbreviations.