Effects of alcohol on simulated driving and perceived driving impairment in binge drinkers

Background:  Binge drinking (heavy episodic alcohol use) is associated with high rates of impaired driving and myriad alcohol-related accidents. However, the underlying reasons for the heightened accident risk in this demographic group are not known. This research examined acute alcohol effects on simulated driving performance and subjective ratings of intoxication and driving ability in binge and nonbinge drinkers.
Methods:  Young social drinking college students (24 binge drinkers and 16 nonbinge drinkers) participated in this study. Participants attended a session during which they received a moderate dose of alcohol (0.65 g/kg) and a session during which they received a placebo. A simulated driving task measured participants' driving performance in response to each dose. Subjective responses to each dose were also assessed, including ratings of sedation, stimulation, and driving ability.
Results:  The acute dose of alcohol impaired multiple aspects of driving performance in both binge and nonbinge drinkers. Under alcohol, all participants had greater difficulty in maintaining their lane position, maintaining the appropriate speed and made multiple driving errors compared to placebo performance. By contrast, compared with nonbinge drinkers, binge drinkers reported feeling less sedated by the alcohol and reported having a greater ability to drive following the acute dose of alcohol.
Conclusions:  Reduced subjective intoxication and perceived driving impairment in binge drinkers may account for the greater accident risk in this demographic group. Binge drinkers may lack the internal sedation cue that helps them accurately assess that they are not able to effectively drive a vehicle after drinking.     

Functional Imaging of Cognitive Control During Acute Alcohol Intoxication

Background: The anterior cingulate and several other prefrontal and parietal brain regions are implicated in error processing and cognitive control. The effects of different doses of alcohol on activity within these brain regions during a functional magnetic resonance imaging (fMRI) task where errors are frequently committed have not been fully explored. Methods: This study examined the impact of a placebo [breath alcohol concentration (BrAC) = 0.00%], moderate (BrAC = 0.05%), and high (BrAC = 0.10%) doses of alcohol on brain hemodynamic activity during a functional MRI (fMRI) Go/No‐Go task in 38 healthy volunteers. Results: Alcohol increased reaction time and false alarm errors in a dose‐dependent manner. fMRI analyses showed alcohol decreased activity in anterior cingulate, lateral prefrontal cortex, insula, and parietal lobe regions during false alarm responses to No‐Go stimuli. Conclusions: These findings indicate that brain regions implicated in error processing are affected by alcohol and might provide a neural basis for alcohol’s effects on behavioral performance.     

Effects of family history of alcohol use disorders on spatial working memory BOLD response in adolescents

Background:  A positive family history (FH) of alcohol use disorders (AUD) has been linked to increased risk for the development of AUD, and neurocognitive factors have been postulated as important underlying mechanisms of familial alcoholism transmission.
Methods:  We used functional magnetic resonance imaging (fMRI) during a spatial working memory (SWM) and vigilance paradigm to investigate potential neurodevelopmental differences linked to familial density of AUD in 72 adolescents aged 12 to 14 years.
Results:  Youth with denser family histories of AUD showed less activation during a simple vigilance condition relative to SWM in cingulate and medial frontal gyri (β = 0.28, p  = 0.03), and a trend for more relative activity during rest (β = −0.25, p  = 0.07) in this cluster.
Conclusions:  Youth with greater familial densities of AUD may be less successful at modulating activity of the default network, potentially indicating a greater propensity for task-independent thought or reduced inhibition of task-irrelevant processing. Failure to moderate activation of the default network may have implications for cognitive efficiency and goal directed behavior in youth with dense FH. Further, aberrant activation in cingulate regions may be linked to genetic variation in GABA receptor units, suggesting a useful endophenotype for risk associated with alcohol dependence.     

Increased Activation of the ACC During a Spatial Working Memory Task in Alcohol‐Dependence Versus Heavy Social Drinking

Background: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. Methods: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non‐abstinent‐dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol‐related thoughts and behavior (Obsessive–Compulsive Drinking Scale—OCDS), alcohol use of the last 90 days, and general intelligence. Results: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol‐dependent participants showed a higher task‐related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Conclusions: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task‐related activation in the dACC was only observed in alcohol‐dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self‐regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non‐alcohol‐related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol‐related thoughts.     

Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study

Patients with childhood-onset growth hormone (GH) deficiency (GHD) show impairments in mood and cognitive functioning which may resolve following GH substitution. Brain functional magnetic resonance imaging (fMRI) during performance of a memory task was used to assess the cerebral activity of such patients. Thirteen childhood-onset GHD patients (mean age 27.3 +/- 6.9 years) were included in a double-blind, placebo-controlled study. The effects of 6 months of GH replacement or placebo therapy were studied using neuropsychological tests and fMRI. One patient was excluded from the study due to noncompliance with the protocol. Six months of GH substitution in these GHD patients resulted in improved memory functioning, both for long-term and working memory. fMRI showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after GH treatment as compared with placebo treatment, indicating decreased effort and more efficient recruitment of the neural system involved. It can be concluded that GH treatment for 6 months improved the long-term as well as the working memory in patients with GHD, and this was associated with decreased brain activation in the ventrolateral prefrontal cortex. GH substitution in GHD patients is beneficial for cognitive functioning, the effects of which can be visualized by means of neuroimaging.     

Brain activation, response inhibition, and increased risk for substance use disorder

Background:  Youth at high risk for developing substance use disorders (SUDs) often exhibit differences which suggest inhibitory impairments when compared to average risk youth.
Methods:  To examine the underlying neural activity related to these impairments, functional MRI (fMRI) was employed in adolescents during an antisaccade task requiring inhibition of an eye movement response. Each subject's level of neurobehavioral disinhibition (ND) was assessed using a multi-informant, multi-method approach, which has been shown to be highly predictive of SUD onset. The fMRI data was categorized into neural regions of interest according to total frontal, parietal, occipital, and temporal lobe activation.
Results:  Results demonstrated that ND score was negatively correlated with total amount of frontal activation, but was not significantly correlated with total activation in any other neural region.
Conclusions:  These results indicate deficits in frontal activation in youth with high amounts of ND, suggesting a possible developmental delay of executive processes in high-risk youth.     

Alcohol Effects on Mood, Equilibrium, and Simulated Driving

BACKGROUND: The effects of alcohol on simple versus complex psychomotor performance were compared in 18 adults. METHODS: Subjects received ethanol doses of 0.0, 0.5, and 0.8 g/kg in a randomized, double-blind, within-subject design. Forty minutes after finishing their drinking, the subjects completed a 60-min battery of tests that included: 1) a sensory organization posturography test (EquiTest); 2) latency to apply the brake after appearance of a barrier in a driving simulator (brake reaction time); 3) visual analog subjective-effects scales (VAS); 4) the Profile of Mood States (POMS); 5) critical flicker fusion (CFF); and 6) choice reaction time (CRT). RESULTS: Alcohol dose dependently reduced composite equilibrium scores and increased brake reaction time. On the CRT task, total reaction time was significantly increased after the high dose but not the low dose. Alcohol dose dependently increased VAS "dizzy," "high," and "drug effect" ratings. The POMS and CFF were not significantly affected by alcohol. CONCLUSIONS: These data suggest that an ethanol dose that neither influences certain mood states nor impairs simple psychomotor task performance nonetheless may impair equilibrium and complex psychomotor tasks (e.g., driving).     

Alcohol sensitizes cerebral responses to the odors of alcoholic drinks: an fMRI study

Background:  Small, priming doses of alcohol enhance desire to drink, and thus play a role in the loss of control of alcohol consumption. Using functional magnetic resonance imaging (fMRI), we previously showed that alcoholic drink odors (AO; subjects' drinks of choice) induce greater nucleus accumbens (NAc) activity than non-appetitive odors (NApO; grass, leather) in subjects at risk for alcoholism. Here we hypothesized that priming exposure to alcohol would enhance responses to AO in the NAc and orbitofrontal cortex in comparison to NApO (grass, leather) and to the appetitive control odors (ApCO) of chocolate and grape.
Methods:  Ten hazardous drinkers (mean age = 22.7; SD = 2.9, average drinks per drinking day = 5.9, SD = 2.3; drinking days/90 days = 50.4, SD = 13.7) were scanned on a 1.5T GE Signa MR scanner during intravenous infusion of lactated Ringer's or 6% ethanol in lactated Ringer's that was pharmacokinetically modeled to achieve a constant breath alcohol concentration (BrAC) of 50 mg% throughout imaging. During scanning, subjects sniffed AO, NApO, and ApCO.
Results:  Alcohol infusion enhanced the contrast between AO and NApO in the NAc, and in orbitofrontal, medial frontal, and precuneus/posterior cingulate regions. The contrast between AO and appetitive control odors (ApCO; chocolate and grape) was similarly larger in the orbital, medial frontal, precuneus, and posterior cingulate/retrosplenial areas, with the most robust finding being a potentiated response in the posterior cingulate/retrosplenial area. The orbital region is similar to an area previously shown to manifest satiety-related decreases in activity induced by food cues.
Conclusions:  The results suggest that priming exposure to alcohol renders a limbic network more responsive to alcohol cues, potentially enhancing desire to drink.     

Insulin and insulin-like growth factor resistance in alcoholic neurodegeneration

Background:  Chronic alcohol feeding of adult Long Evans rats causes major central nervous system abnormalities that link neuronal loss and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor (IGF) signaling and increased oxidative stress.
Objectives:  We now characterize the integrity of insulin and IGF signaling mechanisms and assess molecular indices of neurodegeneration in the cerebellar vermis and anterior cingulate gyrus of human alcoholics.
Results:  Alcoholic cerebella had increased neuronal loss, gliosis, lipid peroxidation, and DNA damage relative to control. Quantitative RT-PCR studies demonstrated reduced expression of insulin, insulin receptor and IGF-II receptor in the anterior cingulate, and reduced expression of insulin, IGF-I, and their corresponding receptors in the vermis. Competitive equilibrium binding assays revealed significantly reduced specific binding to the insulin, IGF-I, and IGF-II receptors in both the anterior cingulate and vermis of alcoholic brains. These effects of chronic alcohol abuse were associated with significantly reduced expression of choline acetyltransferase, which is needed for acetylcholine biosynthesis.
Conclusions:  The results suggest that alcoholic neurodegeneration in humans is associated with insulin and IGF resistance with attendant impairment of neuronal survival mechanisms and acetylcholine homeostasis.     

Projected Alcohol Dose Influences on the Activation of Alcohol Expectancies in College Drinkers

Background:  Alcohol expectancies have been linked to drinking behavior in college students, and vary according to a number of factors, including projected dose of alcohol. Research using Multidimensional Scaling (MDS) suggests that drinking may be influenced by activation of differing expectancy dimensions in memory, yet studies have not examined expectancy activation according to projected alcohol doses.
Methods:  The present study used Individual Differences Scaling (INDSCAL) to map expectancy networks of college students ( n  = 334) who imagined varied drinking at high and low alcohol doses. Expectancy activation was modeled by dose, as well as by gender and by drinking patterns (typical quantity, blood alcohol content, heavy episodic drinking, and alcohol consequences). Expectancies were organized along positive–negative and arousal–sedation dimensions. Anticipation of a high dose of alcohol was associated with greater emphasis on the arousal–sedation dimension, whereas anticipation of a lower dose was associated with greater emphasis on the positive–negative dimension.
Results:  Across heavy, medium, and light drinkers, expectancy dimensions were most distinguishable at higher doses; activation patterns were more similar across drinking groups at lighter doses. Modest evidence for the influence of gender on activation patterns was observed. Findings were consistent across alcohol involvement indices.
Conclusions:  These data suggest that both dimensionality and context should be considered in the refinement of interventions designed to alter expectancies in order to decrease hazardous drinking.     

Altered Impulse Control in Alcohol Dependence: Neural Measures of Stop Signal Performance

Background: Altered impulse control has been implicated in the shaping of habitual alcohol use and eventual alcohol dependence. We sought to identify the neural correlates of altered impulse control in 24 abstinent patients with alcohol dependence (PAD), as compared to 24 demographics matched healthy control subjects (HC). In particular, we examined the processes of risk taking and cognitive control as the neural endophenotypes of alcohol dependence. Methods: To this end, functional magnetic resonance imaging (fMRI) was conducted during a stop signal task (SST), in which a procedure was used to elicit errors in the participants. The paradigm allowed trial‐by‐trial evaluation of response inhibition, error processing, and post‐error behavioral adjustment. Furthermore, by imposing on the subjects to be both fast and accurate, the SST also introduced a distinct element of risk, which participants may or may not avert during the task. Brain imaging data were analyzed with Statistical Parametric Mapping in covariance analyses accounting for group disparity in general performance. Results: The results showed that, compared to HC, PAD demonstrated longer go trial reaction time (RT) and higher stop success rate (SS%). HC and PAD were indistinguishable in stop signal reaction time (SSRT) and post‐error slowing (PES). In a covariance analysis accounting for go trial RT and SS%, HC showed greater activity in the left dorsolateral prefrontal cortex than PAD, when subjects with short and long SSRT were contrasted. By comparing PAD and HC directly during stop errors (SE), as contrasted with SS, we observed greater activity in PAD in bilateral visual and frontal cortices. Compared to HC, PAD showed less activation of the right dorsolateral prefrontal cortex during PES, an index of post‐error behavioral adjustment. Furthermore, PAD who showed higher alcohol urge at the time of the fMRI were particularly impaired in dorsolateral prefrontal activation, as compared to those with lower alcohol urge. Finally, compared to HC subjects, PAD showed less activity in cortical and subcortical structures including putamen, insula, and amygdala during risk‐taking decisions in the SST. Conclusion: These preliminary results provided evidence for altered neural processing during impulse control in PAD. These findings may provide a useful neural signature in the evaluation of treatment outcomes and development of novel pharmacotherapy for alcohol dependence.     

Disruptions in Functional Network Connectivity During Alcohol Intoxicated Driving

Background: Driving while under the influence of alcohol is a major public health problem whose neural basis is not well understood. In a recently published functional magnetic resonance imaging (fMRI) study ( Meda et al., 2009 ), our group identified 5, independent critical driving‐associated brain circuits whose inter‐regional connectivity was disrupted by alcohol intoxication. However, the functional connectivity between these circuits has not yet been explored in order to determine how these networks communicate with each other during sober and alcohol‐intoxicated states. Methods: In the current study, we explored such differences in connections between the above brain circuits and driving behavior, under the influence of alcohol versus placebo. Forty social drinkers who drove regularly underwent fMRI scans during virtual reality driving simulations following 2 alcohol doses, placebo and an individualized dose producing blood alcohol concentrations (BACs) of 0.10%. Results: At the active dose, we found specific disruptions of functional network connectivity between the frontal‐temporal‐basal ganglia and the cerebellar circuits. The temporal connectivity between these 2 circuits was found to be less correlated (p < 0.05) when driving under the influence of alcohol. This disconnection was also associated with an abnormal driving behavior (unstable motor vehicle steering). Conclusions: Connections between frontal‐temporal‐basal ganglia and cerebellum have recently been explored; these may be responsible in part for maintaining normal motor behavior by integrating their overlapping motor control functions. These connections appear to be disrupted by alcohol intoxication, in turn associated with an explicit type of impaired driving behavior.     

Growth hormone deficiency and memory functioning in adults visualized by functional magnetic resonance imaging

Cognitive functioning, especially memory performance, is known to be impaired in patients with childhood-onset growth hormone deficiency (CO-GHD), and growth hormone substitution has been found to counteract this memory impairment. Neuropsychological and functional magnetic resonance imagining (fMRI) data acquired during a working memory task in 13 childhood-onset GH-deficient patients were compared with 13 age, sex and education level matched healthy controls. Results demonstrated that there is no difference in the quality of the performance in the working memory task between GH-deficient patients and control subjects. However, memory speed was found to be subnormal in patients. Concerning mood, patients reported more complaints of fatigue, and less vigor. Imaging data showed that patients had increased activity in dorsolateral/ventrolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, supplementary motor and motor cortex, as well as in the thalamus and precuneus area. Increasing task load was also associated with an increase in brain activity in similar areas in patients compared to control subjects. In conclusion, this fMRI study shows that GH-deficient patients have a subnormal memory speed, but no impaired quality of memory performance, which may be due to compensatory recruitment of dorsal prefrontal brain regions. These findings indicate that the GH-IGF-1 axis contributes to prefrontal functioning in patients with CO-GHD.     

Differential neural response to alcohol priming and alcohol taste cues is associated with DRD4 VNTR and OPRM1 genotypes

Background:  Studies suggest that polymorphisms in the D4 dopamine receptor (DRD4) and opioid receptor, μ1 (OPRM1) genes are involved in differential response to the effects of alcohol and to alcohol cues. However, to date, the mechanisms that underlie these differences remain largely unknown.
Methods:  Using functional magnetic resonance imaging, hemodynamic response in mesocorticolimbic structures after exposure to alcohol tastes was contrasted with a control taste and compared between DRD4 variable number of tandem repeats (VNTR) genotypes and OPRM1 A118G genotypes. Additionally, the effects of a priming dose of alcohol on this response were examined.
Results:  The results indicated that DRD4 VNTR >7 repeat individuals (DRD4.L) had significantly greater response to alcohol cues in the orbitofrontal cortex, anterior cingulate gyrus, and striatum compared with individuals with <7 repeats (DRD4.S) prior to a priming dose of alcohol ( p  < 0.05), but not after a priming dose. In the OPRM1 comparisons, results showed that individuals with at least 1 copy of the OPRM1 + 118 G allele had greater hemodynamic response in mesocorticolimbic areas both before and after priming compared with those who were homozygous for the OPRM1 + 118 A allele. For the DRD4.L and OPRM1 + 118 G groups, brain response in the striatum was highly correlated with measures of alcohol use and behavior such that greater activity corresponded with greater frequency and quantity of alcohol use.
Conclusions:  The DRD4 VNTR and OPRM1 A118G polymorphisms are associated with functional neural changes in mesocorticolimbic structures after exposure to alcohol cues. This provides evidence for the contributions of the DRD4 and OPRM1 genes in modulating neural activity in structures that are involved in the motivation to drink.     

Blockade of cue-induced brain activation of abstinent alcoholics by a single administration of amisulpride as measured with fMRI

BACKGROUND: Once alcohol dependence is established, alcohol-associated cues may induce dopamine release in the reward system, which is accompanied by alcohol craving and may lead to relapse. In cocaine addicts, dopamine release in the thalamus was positively correlated with cocaine craving. We tested the effects of the atypical dopamine D(2/3) blocker amisulpride on cue-induced brain activation in a functional magnetic resonance imaging (fMRI) paradigm. METHODS: Alcohol-associated and neutral pictures were presented in a block design to 10 male abstinent alcoholics (1-3 weeks after detoxification) and 10 healthy men during fMRI. The fMRI scans were acquired before and 2 hours after the oral application of 400 mg amisulpride. Before and after each scan, alcohol craving was measured with visual analogue scales. RESULTS: Before the application of amisulpride, alcohol versus control cues elicited a higher blood oxygen level-dependent (BOLD) signal in the left frontal and orbitofrontal lobe, left cingulate gyrus, bilateral parietal lobe, and bilateral hippocampus in alcoholics compared with healthy controls. After amisulpride, alcoholics showed a reduced activation in the right thalamus compared with the first scan. Alcoholics no longer showed significant differences in their cue-elicited BOLD response after amisulpride medication compared with medication-free controls. Self-reported craving was not affected by amisulpride medication. CONCLUSIONS: Amisulpride medication was associated with reduced cue-induced activation of the thalamus, a brain region closely connected with frontostriatal circuits that regulate behavior and may influence relapse risk.     

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects

Background:  Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders.
Methods:  Participants were adolescents aged 15 to 17 who met criteria for AUD ( n  = 14), and demographically similar healthy controls ( n  = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups.
Results:  After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes ( p  = 0.09) than controls, and significant interactions between group and gender were observed ( p  < 0.001 to p  < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes.
Conclusions:  Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.     

Effects of a moderate evening alcohol dose. II: performance

BACKGROUND: This second of a pair of papers investigates the effects of a moderate dose of alcohol and staying up late on driving simulation performance and simple visual reaction time (RT) at a known circadian phase in well-rested young adults. METHODS: Twenty-nine adults (9 males), ages 21 to 25 years, spent 1 week on an at-home stabilization schedule of 8.5 to 9 hours, followed by 3 nonconsecutive nights in-lab: adaptation, placebo, and alcohol. Performance task practice occurred on 3 occasions before the study. Alcohol (vodka; 0.54 g/kg men; 0.49 g/kg women mixed with tonic) was consumed over 30 minutes ending 1 hour before normal bedtime; the same quantity of beverage was given on placebo. Driving simulation (with drive-only and dual-task drive and subtract components) and psychomotor vigilance task (PVT) testing occurred before and after alcohol/placebo ingestion. Breath alcohol concentration (BrAC) readings were taken before all test sessions. Saliva samples were taken approximately every 30 minutes to determine circadian phase. RESULTS: Driving simulation and PVT variables significantly deteriorated with increasing time awake. Driving simulator lane variability was worse with alcohol compared with placebo at 15.5 hours awake. No PVT variable showed an effect of alcohol. CONCLUSIONS: Driving simulation performance deteriorated with extended waking and with alcohol; driving was most impaired at the peak alcohol level. The PVT, less complex than the driving simulation, did not show effects of alcohol, a finding consistent with previous literature that disruptive effects of low alcohol concentrations increase with task complexity. Overall, simulated driving performance is significantly impaired late at night when even a moderate dose of alcohol is consumed.     

Brain activation elicited by affectively positive stimuli is associated with a lower risk of relapse in detoxified alcoholic subjects

BACKGROUND: Stimuli that are regularly associated with alcohol intake (AI) may acquire incentive salience, while other reinforcers can be devalued. We assessed whether brain activation elicited by (1) alcohol associated, (2) affectively positive, and (3) negative versus neutral stimuli is associated with the subsequent risk of relapse. METHODS: Twelve detoxified alcoholic subjects (6 women and 6 men) and 12 age-matched and gender-matched healthy control subjects were assessed with functional magnetic resonance imaging (fMRI) and a fast single-event paradigm using standardized affective and alcohol-associated pictures. Patients were followed for 6 months and AI was recorded. RESULTS: In alcoholic subjects, compared with healthy control subjects, (1) alcohol-related versus neutral visual stimuli elicited increased activation in the prefrontal (PFC; BA 6 and 10) and cingulate cortex (BA 23 and 24), precuneus and adjacent parietal cortex; (2) positive versus neutral stimuli elicited increased activation in the anterior cingulate cortex (ACC; BA 24), PFC (BA 10), ventral striatum and thalamus; and (3) negative versus neutral stimuli elicited increased activation in the PFC (BA 10). Seven alcoholic subjects relapsed. Within the follow-up period of 6 months, the number of subsequent drinking days (DD) and the amount of AI were inversely correlated with brain activation elicited by positive versus neutral stimuli in the thalamus (DD: r=-0.63, p=0.03; AI: r=-0.63, p=0.03) and in the ventral striatum (DD: r=-0.60, p=0.04; AI: r=-0.48, p=0.11). CONCLUSIONS: In this study, brain activation elicited by briefly presented alcohol-associated stimuli was not associated with the prospective risk of relapse. Unexpectedly, alcoholic subjects displayed increased limbic brain activation during the presentation of affectively positive but not negative stimuli, which may reflect a protective factor in detoxified alcoholic subjects.     

Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is a disorder of intestinal hypersensitivity and altered motility, exacerbated by stress. Functional magnetic resonance imaging (fMRI) during painful rectal distension in IBS has demonstrated greater activation of the anterior cingulate cortex (ACC), an area relevant to pain and emotions. Tricyclic antidepressants are effective for IBS. The aim of this study was to determine if low dose amitriptyline reduces ACC activation during painful rectal distension in IBS to confer clinical benefits. Secondary aims were to identify other brain regions altered by amitriptyline, and to determine if reductions in cerebral activation are greater during mental stress. METHODS: Nineteen women with painful IBS were randomised to amitriptyline 50 mg or placebo for one month and then crossed over to the alternate treatment after washout. Cerebral activation during rectal distension was compared between placebo and amitriptyline groups by fMRI. Distensions were performed alternately during auditory stress and relaxing music. RESULTS: Rectal pain induced significant activation of the perigenual ACC, right insula, and right prefrontal cortex. Amitriptyline was associated with reduced pain related cerebral activations in the perigenual ACC and the left posterior parietal cortex, but only during stress. CONCLUSIONS: The tricyclic antidepressant amitriptyline reduces brain activation during pain in the perigenual (limbic) anterior cingulated cortex and parietal association cortex. These reductions are only seen during stress. Amitriptyline is likely to work in the central nervous system rather than peripherally to blunt pain and other symptoms exacerbated by stress in IBS.     

Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study

Background:  Topiramate was recently reported to be efficacious in reducing drinking rates and craving among individuals with alcohol dependence in a randomized controlled trial, but dose effects could not be determined. This laboratory study systematically examined the dose-dependent effects of topiramate on cue-elicited craving and other putative mechanisms of its pharmacotherapeutic effects on drinking.
Methods:  Male and female heavy drinkers ( n  = 61) were randomized to 1 of 3 medication conditions (200 mg/d; 300 mg/d; placebo) in a double-blind study. Participants reached the target dose after a 32-day titration period, then were stabilized for approximately 1 week. All then participated in a laboratory assessment of alcohol cue reactivity and of the subjective effects of a moderate dose of alcohol.
Results:  Both doses of topiramate reduced the frequency of heavy drinking during the titration period as compared to placebo. However, topiramate did not affect self-reported craving for alcohol during the titration period, during the cue reactivity protocol, or in response to the alcohol challenge procedure. Topiramate reduced the stimulating effects of alcohol ingestion compared to placebo, but only in the 200 mg group.
Conclusions:  The results of this study support previous findings that topiramate reduces drinking, but the behavioral mechanism underlying this effect does not appear to be attenuation of craving for alcohol as measured using the approaches employed in this study. Rather, the results tentatively suggest that topiramate may exert its beneficial effects by altering the subjective experiences of alcohol consumption. Limitations of the current study are discussed and complementary methods are recommended for future studies, such as the use of behavioral economic paradigms and ecological momentary assessment.