Development of alcohol-associated cues and cue-induced brain activation in alcoholics.

The objective of this study was to develop new standardized alcohol-associated cues and assess their effects on brain activation with functional magnetic resonance imaging (fMRI). Pictures of alcoholic and neutral beverages and affectively neutral pictures were presented to 44 abstinent alcoholics and 37 age-matched healthy control subjects. We assessed the skin conductance response, and the elicited arousal and valence. Alcoholics and control subjects did not differ in arousal, valence or skin conductance response evoked by alcohol-associated and affectively neutral stimuli, while nonalcoholic beverages were rated as more unpleasant and arousing by alcoholics compared with control subjects. In the fMRI pilot study, alcohol and abstract pictures were presented to six abstinent alcoholics and induced a significant activation of brain areas associated with visual emotional processes such as the fusiform gyrus, parts of the brain reward system (basal ganglia and orbitofrontal gyrus) and further brain regions in the frontal and parietal cortices associated with the attention network. These observations suggest that standardized pictures of alcoholic beverages can be used to assess brain circuits involved in the processing and evaluation of alcohol cues.     

Reward sensitivity modulates connectivity among reward brain areas during processing of anticipatory reward cues

Reward sensitivity, or the tendency to engage in motivated approach behavior in the presence of rewarding stimuli, may be a contributory factor for vulnerability to disinhibitory behaviors. Although evidence exists for a reward sensitivity‐related increased response in reward brain areas (i.e. nucleus accumbens or midbrain) during the processing of reward cues, it is unknown how this trait modulates brain connectivity, specifically the crucial coupling between the nucleus accumbens, the midbrain, and other reward‐related brain areas, including the medial orbitofrontal cortex and the amygdala. Here, we analysed the relationship between effective connectivity and personality in response to anticipatory reward cues. Forty‐four males performed an adaptation of the Monetary Incentive Delay Task and completed the Sensitivity to Reward scale. The results showed the modulation of reward sensitivity on both activity and functional connectivity (psychophysiological interaction) during the processing of incentive cues. Sensitivity to reward scores related to stronger activation in the nucleus accumbens and midbrain during the processing of reward cues. Psychophysiological interaction analyses revealed that midbrain–medial orbitofrontal cortex connectivity was negatively correlated with sensitivity to reward scores for high as compared with low incentive cues. Also, nucleus accumbens–amygdala connectivity correlated negatively with sensitivity to reward scores during reward anticipation. Our results suggest that high reward sensitivity‐related activation in reward brain areas may result from associated modulatory effects of other brain regions within the reward circuitry.     

Cue-induced auditory evoked potentials in alcoholism.

OBJECTIVE: Conditioning processes may convert neutral stimuli to drug-associated stimuli and create an implicit drug memory. Previous studies showed specific psychophysiological reactions to alcohol-associated stimuli differentiating alcohol-dependent subjects from healthy controls. This was shown in evoked potentials using visual and olfactory alcohol-related stimuli. METHODS: Our study examined the effects of complex alcohol-associated sounds in comparison to complex neutral sounds on electrophysiological event-related potentials and the self-report of craving. We assessed 10 detoxified alcoholics and 10 healthy controls in a cue-reactivity paradigm. RESULTS: Detoxified alcoholics demonstrated significantly higher alcohol stimulus-induced late P300 and late positive complexes. Subjective baseline craving and stimulus-induced craving only differed significantly between groups in terms of the craving dimension "relief of withdrawal symptoms". CONCLUSIONS: The results show that auditory stimuli attach importance to stimulus-induced craving in alcoholics. Therapeutic consequences will be discussed. SIGNIFICANCE: The study examined for the first time the effects of alcohol-associated auditory stimuli on alcohol craving and identifies learning processes as underlying neural mechanisms which support the assumption of an implicit addiction memory in alcoholics.     

The representation of pleasant touch in the brain and its relationship with taste and olfactory areas

Although there has been much investigation of brain pathways involved in pain, little is known about the brain mechanisms involved in processing somatosensory stimuli which feel pleasant. Employing fMRI it was shown that pleasant touch to the hand with velvet produced stronger activation of the orbitofrontal cortex than affectively neutral touch of the hand with wood. In contrast, the affectively neutral but more intense touch produced more activation of the primary somatosensory cortex than the pleasant stimulus. This indicates that part of the orbitofrontal cortex is concerned with representing the positively affective aspects of somatosensory stimuli, and in further experiments it was shown that this orbitofrontal area is different from that activated by taste and smell. The finding that three different primary or unlearned types of reinforcer (touch, taste, and smell) are represented in the orbitofrontal cortex helps to provide a firm foundation for understanding the neural basis of emotions, which can be understood in terms of states elicited by stimuli which are rewarding or punishing.     

Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving

OBJECTIVE: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D(2) receptors, and delayed recovery of D(2) receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D(2) receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli. METHOD: Multimodal imaging, with the radioligand [(18)F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D(2)-like dopamine receptors in the ventral striatum with alcohol craving and central processing of alcohol cues. RESULTS: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of D(2)-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cue-induced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI. DISCUSSION: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control.     

Exploring the motivational brain: effects of implicit power motivation on brain activation in response to facial expressions of emotion

This study tested the hypothesis that implicit power motivation (nPower), in interaction with power incentives, influences activation of brain systems mediating motivation. Twelve individuals low (lowest quartile) and 12 individuals high (highest quartile) in nPower, as assessed per content coding of picture stories, were selected from a larger initial participant pool and participated in a functional magnetic resonance imaging study during which they viewed high-dominance (angry faces), low-dominance (surprised faces) and control stimuli (neutral faces, gray squares) under oddball-task conditions. Consistent with hypotheses, high-power participants showed stronger activation in response to emotional faces in brain structures involved in emotion and motivation (insula, dorsal striatum, orbitofrontal cortex) than low-power participants.     

Neurophysiological correlates of alcohol-specific inhibition in alcohol use disorder and its association with craving and relapse

ObjectiveThis study investigates neurophysiological correlates of general and alcohol-specific inhibitory control in patients with Alcohol Use Disorder (AUD), focusing on its association with individual craving levels and with relapse at three-month follow-up.Methods59 abstinent AUD patients and 20 healthy controls performed a Go/NoGo task incorporating alcohol-related and neutral stimuli during 64-channel electroencephalography (EEG) recording, yielding four event-related potentials (ERP) per participant (NoGo-Alcohol, Go-Alcohol, NoGo-Neutral, Go-Neutral). Whole-scalp randomization-based statistics assessed effects of the factors group (patients/controls or relapsers/abstainers), craving level, response type (NoGo/Go) and picture type (alcohol/neutral) on topography and signal strength of the ERP components N2 and P3.ResultsNo differences on group level were observed between patients and controls. However, analyses incorporating individual craving indicated that the topographic difference between alcohol-related and neutral NoGo-N2 components increased with craving. Moreover, topographic differences in the alcohol-related and neutral NoGo-P3 component allowed for differentiation between relapsers and abstainers.ConclusionsIn alcohol-related contexts, the response inhibition conflict reflected in the NoGo-N2 seems enhanced in patients with high craving. The inhibition-sensitive NoGo-P3 varies in relapsers but not in abstainers between neutral and alcohol-related contexts.SignificanceIn AUD patients, neurophysiological correlates of inhibition vary with alcohol-related contexts and craving, and might be indicative of relapse risk.     

The Association of Non–Drug-Related Pavlovian-to-Instrumental Transfer Effect in Nucleus Accumbens With Relapse in Alcohol Dependence: A Replication

BackgroundThe Pavlovian-to-instrumental transfer (PIT) paradigm measures the effects of Pavlovian conditioned cues on instrumental behavior in the laboratory. A previous study conducted by our research group observed activity in the left nucleus accumbens (NAcc) elicited by a non–drug-related PIT task across patients with alcohol dependence (AD) and healthy control subjects, and the left NAcc PIT effect differentiated patients who subsequently relapsed from those who remained abstinent. In this study, we aimed to examine whether such effects were present in a larger sample collected at a later date.MethodsA total of 129 recently detoxified patients with AD (21 females) and 74 healthy, age- and gender-matched control subjects (12 females) performing a PIT task during functional magnetic resonance imaging were examined. After task assessments, patients were followed for 6 months. Forty-seven patients relapsed and 37 remained abstinent.ResultsWe found a significant behavioral non–drug-related PIT effect and PIT-related activity in the NAcc across all participants. Moreover, subsequent relapsers showed stronger behavioral and left NAcc PIT effects than abstainers. These findings are consistent with our previous findings.ConclusionsBehavioral non–drug-related PIT and neural PIT correlates are associated with prospective relapse risk in AD. This study replicated previous findings and provides evidence for the clinical relevance of PIT mechanisms to treatment outcome in AD. The observed difference between prospective relapsers and abstainers in the NAcc PIT effect in our study is small overall. Future studies are needed to further elucidate the mechanisms and the possible modulators of neural PIT in relapse in AD.     

Brain activity during emotionally negative pictures in schizophrenia with and without flat affect: an fMRI study

The aim of this functional magnetic resonance imaging (fMRI) study was to compare regional brain activity in schizophrenia subjects with (FA+) and without (FA-) flat affect during the viewing of emotionally negative pictures. Thirteen FA+ subjects and 11 FA- subjects were scanned while being presented with a series of emotionally negative and neutral pictures. Experientially, the viewing of the negative pictures induced a negative emotional state whose intensity was significantly greater in the FA- group than in the FA+ group. Neurally, the Negative minus Neutral contrast revealed, in the FA- group, significant loci of activation in the midbrain, pons, anterior cingulate cortex, insula, ventrolateral orbitofrontal cortex, anterior temporal pole, amygdala, medial prefrontal cortex, and extrastriate visual cortex. In the FA+ group, this contrast produced significant loci of activation in the midbrain, pons, anterior temporal pole, and extrastriate visual cortex. When the brain activity measured in the FA+ group was subtracted from that measured in the FA- group, only the lingual gyrus was significantly activated. Perhaps in FA+ subjects an amygdaloid malfunction rendered the amygdala unable to correctly evaluate the emotional meaning of the pictures presented, thus preventing effective connectivity linking the amygdala to the brain regions implicated in the physiological and experiential dimensions of emotion. Alternatively, a disturbance of effective connectivity in the neural networks linking the midbrain and the medial prefrontal system may have been responsible for the quasi absence of emotional reaction in FA+ subjects, and the abnormal functioning of the medial prefrontal cortex and anterior cingulate cortex in the FA+ group.     

Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain

The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.     

Mapping brain size and cortical gray matter changes in elderly depression.

BACKGROUND: In elderly depression, volumetric brain imaging findings suggest abnormalities of the frontal lobe, particularly the orbitofrontal cortex, and the hippocampus. No studies to date have mapped cortical abnormalities over the entire brain surface in major depression. Here, we conducted detailed spatial analyses of brain size and gray matter within the cortical mantle in elderly patients with major depression. METHODS: High-resolution, three-dimensional, structural magnetic resonance imaging data and cortical pattern matching methods were used in 24 depressed elderly patients and 19 group-matched controls to measure local brain size and proportions of gray matter at thousands of homologous cortical surface locations. RESULTS: Prominent brain size reductions were observed in the depressed subjects in the orbitofrontal cortex bilaterally. Cortical gray matter measurements revealed significant gray matter increases in the orbitofrontal cortex, adjacent to focal trend level significant decreases of gray matter in the same region. Depressed patients also exhibited significant gray matter increases in parietal cortices, as well as the left temporal cortex. CONCLUSIONS: Complex cortical changes may contribute to the brain size reduction of the orbitofrontal cortex and to the gray matter abnormalities detected in orbitofrontal cortex and temporoparietal cortices, thereby providing a potentially new window into the pathophysiology of elderly depression.     

Recovery of cortical functioning in abstinent alcohol-dependent patients: Prefrontal brain oxygenation during verbal fluency at different phases during withdrawal

Abstract

Objectives. Neurotoxic effects of alcohol consumption are well-known. There is plenty of literature on frontal lobe impairment on the behavioural and structural brain imaging level. However, only few functional imaging studies investigated altered neural patterns and even less abstinence-related neural recovery. Methods. In a cross-sectional design three patient groups (acute withdrawal, detoxified, abstinent) and healthy controls (each n = 20) performed a phonological and semantic verbal fluency task (VFT) while brain activity was measured with near-infrared spectroscopy (NIRS). Results. First, for the phonological condition withdrawal patients and detoxified patients showed less fluency-related frontal lobe activation compared to controls despite equal performance. Second, significant linear trend effects from withdrawal patients over detoxified and abstinent patients up to healthy controls indicated more normal activation patterns in the abstinent group that did not differ significantly from the controls. In the detoxified group brain activation increased with time since detoxification. Conclusions. Our results are compatible with an increase in frontal brain activity from alcohol dependence over abstinence up to normal functioning. However, as cross-sectional designs do not allow to assess causal relations, results have to be considered preliminary and longitudinal studies are needed to further elucidate recovery processes in alcohol dependence.     

Cue-induced alcohol craving. Neurobiological correlates and clinical relevance

If there is no further intervention, relapse rates in detoxified alcoholics are high, up to 85%, even after complete remission of bodily withdrawal symptoms. It has been suggested that one relevant mechanism contributing to the relapse risk is the exposure to stimuli (cues) that have regularly been associated with alcohol intake. Such stimuli can become conditioned cues that elicit alcohol craving and intake as conditioned responses. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic, and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) is associated with alcohol craving and brain activation elicited by alcohol-associated pictures. These findings point to specific indications for psychotherapeutic and additive pharmacological treatment options.     

Influence of ventral tegmental area input on cortico‐subcortical networks underlying action control and decision making

It is argued that the mesolimbic system has a more general function in processing all salient events, including and extending beyond rewards. Saliency was defined as an event that is unexpected due to its frequency of occurrence and elicits an attentional‐behavioral switch. Using functional magnetic resonance imaging (fMRI), signals were measured in response to the modulation of salience of rewarding and nonrewarding events during a reward‐based decision making task, the so called desire‐reason dilemma paradigm (DRD). Replicating previous findings, both frequent and infrequent, and therefore salient, reward stimuli elicited reliable activation of the ventral tegmental area (VTA) and ventral striatum (vStr). When immediate reward desiring contradicted the superordinate task‐goal, we found an increased activation of the VTA and vStr when the salient reward stimuli were presented compared to the nonsalient reward stimuli, indicating a boosting of activation in these brain regions. Furthermore, we found a significantly increased functional connectivity between the VTA and vStr, confirming the boosting of vStr activation via VTA input. Moreover, saliency per se without a reward association led to an increased activation of brain regions in the mesolimbic reward system as well as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC). Finally, findings uncovered multiple increased functional interactions between cortical saliency‐processing brain areas and the VTA and vStr underlying detection and processing of salient events and adaptive decision making.     

Common and distinct brain activation to threat and safety signals in social phobia

BACKGROUND: Little is known about the functional neuroanatomy underlying the processing of emotional stimuli in social phobia. OBJECTIVES: To investigate specific brain activation that is associated with the processing of threat and safety signals in social phobics. METHODS: Using functional magnetic resonance imaging, brain activation was measured in social phobic and nonphobic subjects during the presentation of angry, happy and neutral facial expressions under free viewing conditions. RESULTS: Compared to controls, phobics showed increased activation of extrastriate visual cortex regardless of facial expression. Angry, but not neutral or happy, faces elicited greater insula responses in phobics. In contrast, both angry and happy faces led to increased amygdala activation in phobics. CONCLUSIONS: The results support the hypothesis that the amygdala is involved in the processing of negative and positive stimuli. Furthermore, social phobics respond sensitively not only to threatening but also to accepting faces and common and distinct neural mechanisms appear to be associated with the processing of threat versus safety signals.     

Acute effect of methadone maintenance dose on brain FMRI response to heroin-related cues

OBJECTIVE: Environmental drug-related cues have been implicated as a cause of illicit heroin use during methadone maintenance treatment of heroin dependence. The authors sought to identify the functional neuroanatomy of the brain response to visual heroin-related stimuli in methadone maintenance patients. METHOD: Event-related functional magnetic resonance imaging was used to compare brain responses to heroin-related stimuli and matched neutral stimuli in 25 patients in methadone maintenance treatment. Patients were studied before and after administration of their regular daily methadone dose. RESULTS: The heightened responses to heroin-related stimuli in the insula, amygdala, and hippocampal complex, but not the orbitofrontal and ventral anterior cingulate cortices, were acutely reduced after administration of the daily methadone dose. CONCLUSIONS: The medial prefrontal cortex and the extended limbic system in methadone maintenance patients with a history of heroin dependence remains responsive to salient drug cues, which suggests a continued vulnerability to relapse. Vulnerability may be highest at the end of the 24-hour interdose interval.     

Abnormal structural and functional brain connectivity in gray matter heterotopia

Purpose: Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. Methods: Eleven patients were studied using diffusion tensor tractography and resting‐state functional connectivity MRI with bold oxygenation level–dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting‐state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. Key Findings: A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). Significance: Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico‐cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.     

Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study

Objective:  To investigate neural activity in prefrontal cortex and amygdala during bipolar depression.
Methods:  Eleven bipolar I depressed and 17 normal subjects underwent functional magnetic resonance imaging (fMRI) while performing a task known to activate prefrontal cortex and amygdala. Whole brain activation patterns were determined using statistical parametric mapping (SPM) when subjects matched faces displaying neutral or negative affect (match condition) or matched a geometric form (control condition). Contrasts for each group for the match versus control conditions were used in a second-level random effects analysis.
Results:  Random effects between-group analysis revealed significant attenuation in right and left orbitofrontal cortex (BA47) and right dorsolateral prefrontal cortex (DLPFC) (BA9) in bipolar depressed subjects. Additionally, random effects analysis showed a significantly increased activation in left lateral orbitofrontal cortex (BA10) in the bipolar depressed versus control subjects. Within-group contrasts demonstrated significant amygdala activation in the controls and no significant amygdala activation in the bipolar depressed subjects. The amygdala between-group difference, however, was not significant.
Conclusions:  Bipolar depression is associated with attenuated bilateral orbitofrontal (BA47) activation, attenuated right DLPFC (BA9) activation and heightened left orbitofrontal (BA10) activation. BA47 attenuation has also been reported in mania and may thus represent a trait feature of the disorder. Increased left prefrontal (BA10) activation may be a state marker to bipolar depression. Our findings suggest dissociation between mood-dependent and disease-dependent functional brain abnormalities in bipolar disorder.     

Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen‐level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO ‐ R OFC, R AMYG ‐ R OFC, and R AMYG ‐ R HIPP. Overall, our findings demonstrated sex‐dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex‐dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733–3744, 2016. © 2016 Wiley Periodicals, Inc .