Robert Risinger

Amygdala response to both positively and negatively valenced stimuli

Human lesion and functional imaging data suggest a central role for the amygdala in the processing of negative stimuli. To determine whether the amygdalas role in affective processing extends beyond negative stimuli, subjects viewed pictures that varied in emotional content (positive vs negative valence) and arousal level (high vs low) while undergoing functional magnetic resonance imaging. Amygdala activation, relative to a low arousal and neutral valence picture baseline, was significantly increased for both positively and negatively valenced stimuli and did not differ for the two valences. There were no laterality effects. Whereas arousal level appeared to modulate the amygdala response for negative stimuli, all positively valenced pictures (both high and low in arousal) produced significant amygdala responses. These results clearly demonstrate a role for the amygdala in processing emotional stimuli that extends beyond negative and fearful stimuli.

Cocaine administration decreases functional connectivity in human primary visual and motor cortex as detected by functional MRI

Functional magnetic resonance imaging (fMRI) was conducted to observe the effects of cocaine administration on the physiological fluctuations of fMRI signal in two brain regions. Seven long‐term cocaine users with an average age of 32 years and 8 years of cocaine use history were recruited for the study. A T2*‐weighted fast echo‐planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three sets of brain images for each subject under three conditions (at rest, after saline injection, and after cocaine injection [0.57 mg/kg]). Cross‐correlation maps were constructed using the synchronous, low frequency signal from voxel time courses after filtering respiratory, cardiac, and other physiological noise. A quantitative evaluation of the changes in functional connectivity was made using spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC values in the region of primary visual cortex and 43% reduction in SCC values in the region of primary motor cortex were observed after cocaine administration. This significant reduction in SCC values in these cortical regions is a reflection of changes in neuronal activity. It is suggested that the observed changes in low frequency components after acute cocaine administration during a resting, no‐task situation may be used as a baseline reference source when assessing the effects of cocaine on task‐driven activation or on mesolimbic dopamine pathways. Magn Reson Med 43:45–51, 2000.

Neural correlates of high and craving during cocaine self-administration using BOLD fMRI.

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.

Neural responses to acute cocaine administration in the human brain detected by fMRI

An improved functional MRI (fMRI) method for the reduction of susceptibility artifacts has been utilized to measure blood oxygen level-dependent (BOLD) responses to acute cocaine administration in the human brain of cocaine users. Intravenous administration of cocaine (20 mg/70 kg) activated mesolimbic and mesocortical dopaminergic projection regions and showed temporal positive or negative BOLD responses. These results obtained from human cocaine users supported the involvement of the dopaminergic pathway in cocaine addiction from animal models. In addition, the cocaine administration also induced activations in the hierarchical brain networks in the anterior prefrontal cortex (aPFC) of the Brodmann area 10 (BA10) and orbitofrontal cortex (OFC). It is suggested that the dopaminergic pathways and the hierarchical brain networks may participate in mediating cocaine reward processes, associative learning, motivation, and memory in cocaine addiction in the human brain.

Repeated N-Acetyl Cysteine Reduces Cocaine Seeking in Rodents and Craving in Cocaine-Dependent Humans

Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine–glutamate exchange by system xc– appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine–glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof-of-concept clinical experiment. Interestingly, repeated administration (7 days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine (10 mg/kg, IP)-induced reinstatement, even though rats (N=10–12/group) were tested 24 h after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200–2400 mg/day) to cocaine-dependent human subjects (N=4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 s). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.

Expectation Modulates Human Brain Responses to Acute Cocaine: A Functional Magnetic Resonance Imaging Study

BACKGROUND Human expectation of psychoactive drugs significantly alters drug effects and behavioral responses. However, their neurophysiological mechanisms are not clear. This study investigates how cocaine expectation modulates human brain responses to acute cocaine administration. METHODS Twenty-six right-handed non-treatment-seeking regular cocaine abusers participated in this study. Changes in blood oxygenation level-dependent (BOLD) signals were measured, and online behavioral ratings during cocaine expectation and acute cocaine administration were recorded. RESULTS Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus (Brodmann area [BA] 11), frontal pole (BA 10), and anterior cingulate gyrus regions. Active engagement in the amygdala and the lateral orbitofrontal cortex (OFC; BA 47) by unexpected but not expected cocaine infusion was discovered. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus. CONCLUSIONS These results suggest that cocaine expectation modulates neural-sensitivity adaptation between the expected events and the actual outcomes but did not modulate the pharmacological characteristics of cocaine. In addition, the amygdala-lateral OFC circuitry plays an important role in mediating stimulus-outcome relations and contextual factors of drug abuse.

Peripheral blood pressure changes induced by dobutamine do not alter BOLD signals in the human brain.

In extending the use of functional MRI to neuropharmacology, a primary area of concern is that peripheral blood pressure changes induced by pharmacological agents could independently produce a change in the blood oxygenation level-dependent (BOLD) signal, resulting in difficulties distinguishing or interpreting drug-induced neural activations. In the present study, we utilized intravenous dobutamine, a beta-adrenergic receptor agonist, to increase the mean arterial blood pressure (MABP), while examining the effects of MABP changes on the BOLD signal in cocaine-dependent participants. Dobutamine infusion significantly increased the MABP from 93 +/- 8 mm Hg to 106 +/- 12 mm Hg (P < 0.0005), but did not produce a significant global BOLD signal. Yet, a few voxels in the anterior cingulate showed BOLD signal changes that paralleled the changes in blood pressure (BP). Our observations support the conclusion that following the infusion of psychoactive agents, brain BOLD signals accurately reflect neuronal activity, even in the face of relatively large peripheral cardiovascular effects that transiently increase systemic BP.

424. Executive function deficits in adults with attention deficit hyperactivity disorder (ADHD)

that S-ketamine and psilocybin produce overlapping psychotic symptoms in normal subjects that were associated with a common metabolic activation of prefrontal, limbic, striatal, and thalamic structures similarly as seen in some acute schizophrenic patients (Vollenweider 1998). In animals, behavioral effects of NMDA antagonists can be attenuated with the atypical 5-HT2A/D1,2,4 antagonist olanzapine or the 5-HT2A antagonist MDL 100907. This finding suggest that 1) 5-HT2 receptor antagonism may ameliorate ketamine-induced psychosis and 2) that serotonin via 5-HT2A receptors may modulate the glutamate system. To further explore the role of fronto-limbic pathways in acute psychotic states, the pretreatment effects of clozapine on S-ketamine and of ketanserin on psilocybin-induced metabolic hyperfrontality and associated symptoms were investigated in healthy volunteers in placebocontrolled studies using FDG-PET and statistical parametric mapping (SPM96). Drug-induced psychopathology was assessed after PET scanning using the Altered State of Consciousness Questionnaire. Pretreatment with the 5-HT2A/D2 antagonist clozapine (35 mg po) and the 5-HT2A antagonist ketanserin (50 mg), respectively, significantly reduced S-ketamineand psilocybin-induced metabolic hyperfrontality and associated psychotic symptoms. The present results strongly suggest that fronto-striato-thalamic pathways may be a common and critical substrate involved in both Sketamineand psilocybin-induced psychotic symptom formation. The finding that clozapine and ketanserin, respectively, significantly reduced S-ketamineand psilocybin-induced effects suggests that 5-HT2 receptor stimulation may be a common denominator in drug-induced and possibly also naturally occurring psychoses.