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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Biol Psychiatry. Author manuscript; available in PMC Feb 22, 2008.
Published in final edited form as:
PMCID: PMC2249755
NIHMSID: NIHMS40253

Reduced Amygdala Activation in Young Adults at High Risk of Alcoholism: Studies from the Oklahoma Family Health Patterns Project

Abstract

Background

Risk of alcoholism is higher in those with a positive family history (FH+) and in those showing behavioral disinhibition, possibly reflecting altered limbic system function.

Methods

We performed functional magnetic resonance imaging (fMRI) in 17 nonabusing young adults, 9 with FH+ and high in disinhibition versus 8 with a negative family history (FH−) and low in disinhibition. We probed limbic system reactivity with a recognition task using faces expressing fear versus geometric objects.

Results

Subjects with FH− had robust activation to the faces in the region of the right and left amygdalar complexes (p's < .05), while subjects with FH+ had no such activation (p's > .46). The blood oxygenation level-dependent (BOLD) signal in the region of the amygdala was correlated with scores on the self-report measure of temperament in the combined groups (r = .51, p < .04).

Conclusions

Behaviorally disinhibited temperament, found in many with FH+, may be associated with amygdalar hyporesponsiveness and a failure to avoid risky decisions, increasing the person's liability for alcohol abuse.

Keywords: Alcoholism, amygdala, behavioral disinhibition, fMRI, risk factors

Alcoholism affects 13% of individuals during their lifetimes (Kessler et al. 2005). Offspring of alcoholics (positive family history [FH+]) have 2 to 4 times the risk of future alcohol abuse relative to individuals with a negative family history (FH−) (Lieb et al. 2002; Merikangas et al. 1998), and twin-adoption studies implicate a genetic contribution to the disorder (Cloninger et al. 1981; Hesselbrock 1995). This calls for identifying characteristics of healthy, young individuals with FH+ that may contribute to their risk. Individuals with FH+ often display a behaviorally undercontrolled temperament (Dawes et al. 1997; Sher et al. 1991), a blunted stress cortisol response (Lovallo et al. 2000; Sorocco et al. 2006; Vanyukov et al. 1993), and reduced amygdala volumes (Hill et al. 2001), suggesting a dysregulation of neural functions underlying motivation of behavior (Koob 2003).

The Oklahoma Family Health Patterns Project (OFHP) studies nonabusing FH+ and FH− individuals in relation to behavioral undercontrol. Subjects with FH+ in this cohort score lower than FH− subjects on the California Personality Inventory Sociability Scale (CPI-So) (Gough 1994) (28.5 ± .59 vs. 32.8 ± .49, t = 5.67, p < .0001), similar to alcoholic patients (Cooney et al. 1990), indicating a predominant pattern of behavioral disinhibition among the FH+ subjects. There are no published functional magnetic resonance imaging (fMRI) studies in FH+ subjects.

Accordingly, we used an emotive face identification task shown to activate the amygdala (Hariri et al. 2002) on FH + subjects with low CPI-So scores versus FH− subjects with high CPI-So scores drawn from the parent project. We predicted deficient amygdalar responses in the FH+ subjects.

Methods and Materials

Subjects included 9 with FH+ (5 female subjects) and 8 with FH− (3 female subjects) 23.5 years of age (Table 1). Volunteers were scanned at the Research Imaging Center at the University of Texas Health Science Center San Antonio. Subjects and parents signed consent forms approved by the supervising Institutional Review Boards and were paid for participating.

Table 1
Sample Characteristics

Subjects were free of Axis I and II disorders (clusters A and C) by DSM-IV criteria (American Psychiatric Association 1994). Subjects with FH+ had a biological parent that met DSM-IV criteria for alcohol use disorders by Family History Research Diagnostic Criteria (FH-RDC) (Andreasen et al. 1977). Subjects with FH− had an absence of alcohol or substance use disorders in parents and grandparents. Subjects were excluded for possible fetal exposure to alcohol or drugs.

Behavioral disinhibition was indexed by low scores on the CPI-So scale (Lovallo et al. 2006). Groups scoring ≥30 are highly norm-abiding (research scientists, students in nursing and engineering), while scores <30 are seen in deviant groups (marijuana smokers, shoplifters, alcoholics and offspring, pathological gamblers) (Gough 1994). Table 2 shows a progressive relationship between family density of alcoholism and prevalence of low CPI-So scores in the OFHP sample (n = 175; χ2 = 10.1, p < .007). The present sample of FH+ and FH− subjects had strongly differing CPI-So scores (26.3 and 33.5, respectively).

Table 2
Family Density of Alcoholism in Relation to Behavioral Disinhibition

We probed limbic system response with a face identification task known to robustly increase blood oxygenation level-dependent (BOLD) signals in the region of the amygdala (Hariri et al. 2002). Subjects viewed trios of fearful faces (Ekman and Friesen 1976) selected from 12 such stimuli, 6 of each gender, for 5 sec, in 5 blocks of 6 trials over 5 min. To ensure attention to the faces, subjects pressed a button to indicate which bottom face was identical to the top face (Figure 1A). The sensorimotor control used geometric shapes (Figure 1B). Perceptual control blocks used sets of shapes viewed for 5 sec each. Response accuracy and reaction time were monitored.

Figure 1
Stimulus displays for emotion-matching and control tasks.

Scanning was carried out on a Siemens 3T MRI (Siemens, Munich, Germany). Functional imaging used a gradient-echo, echo-planar sequence, acquiring 30 slices (4 mm thick, 1 mm gap) parallel to the anterior commissure-posterior commissure (AC-PC) plane (repetition time/echo time [TR/TE] = 2500/30 msec, 128 × 128 × 5 mm, and field of view [FOV] = 256 mm). For anatomical reference, we acquired a higher resolution coplanar T1-weighted series (TR/TE = 500/20 msec, flip angle = 90°, 128 × 128 × 5 mm, FOV = 256 cm) and a high-quality three-dimensional (3-D) image (TR/TE = 33/12 msec, and flip angle = 60°, 1 mm isotropic). Image analyses were performed using FSL software (Smith et al. 2004) (www.fmrib.ox.ac.uk/fsl/; Oxford, UK) and in-house utilities. Images were spatially registered to the middle data point in that time series to combat motion artifacts and were smoothed using a nonlinear algorithm applied to voxels thought to be of the same tissue type (3 mm kernel) to preserve image structure.

Data were subjected to multiple regression using a prewhitening technique to account for the intrinsic temporal autocorrelation of BOLD signals. Least-squares coefficients were generated for each intracranial voxel independently for the emotion and sensorimotor control conditions, and contrasts between these coefficients were used to create the statistical images. These were spatially normalized to a standard stereotactic space to facilitate multisubject analysis based on the high-resolution anatomical image (Kochunov et al. 2002). Group maps were thresholded based on the magnitude (z ≥ 2.0) and extent (cluster p < .01) of activation.

Anatomically defined regions of interest (ROIs) were drawn bilaterally for amygdala and fusiform face areas. The amygdala ROI was an 8-mm cube centered on the maximum activation reported with the identical task: left −28, −6, −16; right 30, −4, −16 (Hariri et al. 2002). The fusiform ROI was a comparably sized region placed on a putative face-processing area (Grill-Spector et al. 2004). Regions of interest were overlaid on each subject's BOLD data to determine percent signal change from the sensorimotor control to the emotion condition. To account for amygdala volume and focus on activated voxels, analysis was confined to signal change in positive voxels.

Multisubject analyses used a mixed-effects model, with subject as a random factor, providing z-images reflecting the high- and low-risk group activation patterns and yielding between-group contrasts.

Results

Face identification activated regions implicated in facial processing: posterior fusiform gyri, inferior parietal lobules, frontal eye fields, striate and extrastriate cortex, anterior cingulate gyrus, hippocampal and parahippocampal gyri, and amygdalas (Haxby et al. 2002; Ridderinkhof et al. 2004).

A family history (FH) group × hemisphere × ROI (amygdala, fusiform) multivariate analysis of variance (MANOVA) revealed a main effect for ROI [F(1,15) = 10.63, p < .005] and an FH × ROI interaction [F (1,15) = 4.99, p < .04] (Figure 2A). The FH− group produced a greater percent signal change for facial versus geometric control stimuli for right [F(1,15) = 5.21, p < .04] and left [F(1,15) = 4.22, p < .05] amygdalas but not for either fusiform ROI (p's > .46) (Figure 3). Since hemispheres did not differ (p > .64), ROIs were then combined across hemispheres. The CPI-So scores were correlated with amygdala ROI activation (r = 0.51, p < .04, two-tailed), indicating the influence of behavioral disinhibition on amygdala hyporesponsivity.

Figure 2
Group amygdala activation patterns. Effect of FH of alcoholism on amygdala activity in healthy young adults during a face identification test using fearful face stimuli. Statistical parametric maps reflecting bilateral amygdala activation for FH− ...
Figure 3
Mean percent signal change in ROIs. Bars show mean ± SEM for ROIs comprising bilateral amygdala and fusiform gyrus. The FH+ group showed amygdala hypoactivation relative to the FH− group. In contrast, the fusiform ROIs did not differ between ...

Confounder analyses showed no effect of sex, age, or their interactions with FH group for either ROI. Family history groups did not differ in recognition accuracy or reaction times (p's > .16), ruling out attention differences. Results were not attributable to depression or frontal executive function, as Beck Depression Inventory (BDI) and Stroop Color and Word Test scores were uncorrelated with amygdala or fusiform activation (p's ≥ .09), and FH group remained significant after their inclusion as covariates (p's < .05).

Discussion

The fMRI data supported our prediction of reduced amygdala responsivity in FH+ persons who are behaviorally disinhibited, providing a perspective on risk in FH+. In human and nonhuman primates, faces are provocative social stimuli that cause robust activation of the amygdala and parahippocampal gyrus (Adolphs et al. 2005; Hariri et al. 2002; Kobatake and Tanaka 1994), further highlighting the hyporeactivity of these FH+ subjects. One study found FH+ subjects to have reduced amygdala volumes compared with FH− subjects (Hill et al. 2001). Therefore, we analyzed only activated voxels in these subjects, indicating that the reduced amygdala activation to faces in these FH+ subjects was not a function of volume differences.

A larger sample will allow a test of the dual impact of FH status and CPI-So scores on amygdala and prefrontal networks, since these work in tandem during motivated decision making (Bechara and Damasio 2002; Damasio 1994; Kringelbach 2005). We exclusively used fearful faces here, and testing a full range of facial emotions will help tease apart the effects of emotions from the impact of faces alone.

Other OFHP studies provide converging evidence of FH+ and behavioral disinhibition. Individuals with FH+ and low CPI-So scores have high interference on the Stroop task, and FH+ male subjects show high attention to financial gains in the Iowa Gambling Task (Lovallo et al. 2006), indicating mildly impaired executive cognitive functioning and appetitive response biases. Individuals with FH+ and low CPI-So scores show blunted stress cortisol responses (Sorocco et al. 2006), indicating reduced outputs from the amygdala to the hypothalamus (Herman et al. 2003; Schulkin et al. 1994), consistent with the amygdala hyporesponsiveness seen in this fMRI study.

The present data highlight the effect of disinhibitory tendencies in FH+. Deficient amygdala activation could cause inadequate signaling to prefrontal and hypothalamic areas involved in motivated behaviors. Amygdala hyporesponsiveness in persons at risk for alcoholism may therefore accompany a shift in approach-avoidance tendencies toward approach behaviors with a deficit in avoidance (Koob 2003). Such persons may fail to form aversive associations to negative consequences of alcohol intake, instead finding greater attraction to its positively hedonic aspects. The net result could be a long-term pattern of less cautious behavior and risky decisions about intake of alcohol and illicit drugs.

Acknowledgments

Supported by the Medical Research Service of the Department of Veterans Affairs, the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (NIAAA) (AA12207) (WRL) and the National Institute of Research Resources (NIRR) (RR14467) (WRL), National Alliance for Research on Schizophrenia and Depression (NARSAD) (Essel Young Investigator to DCG), and the University of Texas Health Science Center at San Antonio (UTHSCSA) General Clinical Research Center (GCRC) (M01-RR-01346).

We thank Ginger D. Haines, Kristen H. Sorocco, and Jennifer Barrett for help with subject recruitment and assessment and Tony Buchanan for his critical reading of an earlier version of the manuscript.

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