Stein EA, Pankiewicz J, Harsch HH, Cho J-K, Fuller SA, Hoffmann RG et al. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 155: 1009-1015

Department of Psychiatry, Biophysics Research Institute, Medical College of Wisconsin, Milwaukee 53226, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 09/1998; 155(8):1009-15. DOI: 10.1176/ajp.155.8.1009
Source: PubMed


Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates.
Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials.
Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans.
The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

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    • "Specifically, we explored the efficacy of the proposed FC-added rtfMRI-NF method at facilitating real-time control of neuronal processes involved in resisting cigarette cravings. Brain regions implicated in cigarette cravings include ACC (Hartwell et al., 2011; Kober et al., 2010; Azizian et al., 2009; Brody et al., 2007; Smolka et al., 2006; Due, Huettel, Hall, & Rubin, 2002; Ernst et al., 2001), medial pFC (Sutherland, McHugh, Pariyadath, & Stein, 2012; Hartwell et al., 2011; Brody et al., 2007; Stein et al., 1998), OFC (Lee, Kim, & Kim, 2012; Hartwell et al., 2011; Smolka et al., 2006; Due et al., 2002), posterior cingulate cortex (Lee, Kim, & Kim, 2012; Hartwell et al., 2011; Azizian et al., 2009; Brody et al., 2007), and precuneus (Lee, Kim, & Kim, 2012; Hartwell et al., 2011; Brody et al., 2007). In addition, central reward-related regions such as the ventral striatum/nucleus accumbens, dorsal striatum, and amygdala are well known for their role in addiction, and the anterior insula is especially important in nicotine addiction (Sutherland et al., 2012; Naqvi, Rudrauf, Damasio, & Bechara, 2007). "
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    ABSTRACT: Real-time fMRI (rtfMRI) neurofeedback (NF) facilitates volitional control over brain activity and the modulation of associated mental functions. The NF signals of traditional rtfMRI-NF studies predominantly reflect neuronal activity within ROIs. In this study, we describe a novel rtfMRI-NF approach that includes a functional connectivity (FC) component in the NF signal (FC-added rtfMRI-NF). We estimated the efficacy of the FC-added rtfMRI-NF method by applying it to nicotine-dependent heavy smokers in an effort to reduce cigarette craving. ACC and medial pFC as well as the posterior cingulate cortex and precuneus are associated with cigarette craving and were chosen as ROIs. Fourteen heavy smokers were randomly assigned to receive one of two types of NF: traditional activity-based rtfMRI-NF or FC-added rtfMRI-NF. Participants received rtfMRI-NF training during two separate visits after overnight smoking cessation, and cigarette craving score was assessed. The FC-added rtfMRI-NF resulted in greater neuronal activity and increased FC between the targeted ROIs than the traditional activity-based rtfMRI-NF and resulted in lower craving score. In the FC-added rtfMRI-NF condition, the average of neuronal activity and FC was tightly associated with craving score (Bonferroni-corrected p = .028). However, in the activity-based rtfMRI-NF condition, no association was detected (uncorrected p > .081). Non-rtfMRI data analysis also showed enhanced neuronal activity and FC with FC-added NF than with activity-based NF. These results demonstrate that FC-added rtfMRI-NF facilitates greater volitional control over brain activity and connectivity and greater modulation of mental function than activity-based rtfMRI-NF.
    Journal of Cognitive Neuroscience 03/2015; 27(8):1-21. DOI:10.1162/jocn_a_00802 · 4.09 Impact Factor
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    • "Rat BOLD pharmacological MRI (phMRI) is gaining popularity in studies aiming at the central effect of various pharmacological agents (Canese et al., 2009; Chen et al., 1997; Sekar et al., 2011; Stark et al., 2006). There are several human phMRI studies that verify its translational role in neuroscience (Anderson et al., 2002; Deakin et al., 2008; Stein et al., 1998). The key advantage of MRI over other imaging modalities in neuroscience is its ability to follow changes in brain neurobiology after pharmacological, electrical or environmental insult (Chang and Shyu, 2001; Reese et al., 2000; Stark et al., 2008). "
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    ABSTRACT: There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials. © The Author(s) 2015.
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    • "These associate learning processes play a critical role in the development of drug addiction (See et al., 2003). Human fMRI studies indicate that nicotine and smoking cues increase neuronal activity in the amygdala (Stein et al., 1998; Franklin et al., 2007). Nicotine also increases c-fos expression in the amygdala of rats (Shram et al., 2007). "
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    ABSTRACT: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine. Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03-0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated. A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal. These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(2). DOI:10.1093/ijnp/pyu011 · 4.01 Impact Factor
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