Search

Background In cigarette smokers, the most commonly reported areas of brain activation during visual cigarette cue exposure are the prefrontal, anterior cingulate, and visual cortices. We sought to determine changes in brain activity in response to cigarette cues when smokers actively resist craving. Methods Forty-two tobacco-dependent smokers underwent functional magnetic resonance imaging, during which they were presented with videotaped cues. Three cue presentation conditions were tested: cigarette cues with subjects allowing themselves to crave (cigarette cue crave), cigarette cues with the instruction to resist craving (cigarette cue resist), and matched neutral cues. Results Activation was found in the cigarette cue resist (compared with the cigarette cue crave) condition in the left dorsal anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus. Lower magnetic resonance signal for the cigarette cue resist condition was found in the cuneus bilaterally, left lateral occipital gyrus, and right postcentral gyrus. These relative activations and deactivations were more robust when the cigarette cue resist condition was compared with the neutral cue condition. Conclusions Suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices.

Background Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. Methods We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. Results Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. Conclusions Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.

Background When nicotine-dependent human subjects abstain from cigarette smoking, they exhibit deficits in working memory. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. Our aim, therefore, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from smoking. Methods We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (≤1.5 hours abstinence) and abstinence (≥14 hours abstinence) conditions. Results Task-related activity in the left dorsal lateral prefrontal cortex (DLPFC) showed a significant interaction between test session (satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected the fact that task-related activity in the satiety condition was relatively low during performance of the 1-back task but greater at the more difficult task levels, whereas task-related activity in the abstinence condition was relatively high at the 1-back level and did not increase at the more difficult task levels. Conclusions We conclude that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety.

Background Dopamine (DA) system dysfunction is implicated in the pathophysiology of major depressive disorder (MDD). We sought to determine if cigarette smokers with a history of MDD and current mild depressive symptoms have abnormal smoking-induced DA release (measured indirectly as change in 11 C-raclopride binding potential [BP ND ]). Methods Fifty-six cigarette smokers either with ( n = 10) or without ( n = 46) a history of MDD (MDD+ and MDD−, respectively) underwent bolus-plus-continuous-infusion 11 C-raclopride positron emission tomography, during which they smoked a regular cigarette. Presmoking to postsmoking changes in 11 C-raclopride BP ND were compared between groups. Also, correlations were determined between change in BP ND and depression, anxiety, and withdrawal rating scale scores for the MDD+ group. Results The MDD+ group had a significantly greater reduction in 11 C-raclopride BP ND (−16.3%) than the MDD− group (−8.4%) (analysis of covariance [ANCOVA], p = .03). Significant negative correlations were found between depression/anxiety and change in 11 C-raclopride BP ND ( r = −.77, p r = −.74, p = .01, respectively). Conclusions MDD+ smokers have greater smoking-induced DA release than MDD− smokers, and higher depression/anxiety levels are associated with greater smoking-induced DA release. These findings support the theory that MDD+ smokers have DA system dysfunction, including heightened smoking-induced DA release.

Background Magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using MRI, we examined these regions for differences in gray matter between smokers and nonsmokers. Methods Thirty-six otherwise healthy adults (19 smokers and 17 nonsmoking control subjects) underwent three-dimensional Fourier-transform spoiled-gradient-recalled acquisition MRI of the brain. Both hand-drawn regions of interest and the computer program voxel-based morphometry were used to assess group differences in regional gray matter volumes and densities, respectively. Results Smokers had smaller gray matter volumes and lower gray matter densities than nonsmokers in the PFC bilaterally, along with smaller volumes in the left dorsal ACC and lower gray matter densities in the right cerebellum. Smokers also had negative associations between pack-year smoking history and PFC gray matter densities. Conclusions Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors.

The health risks and societal costs of cigarette smoking are well documented, but the prevalence of smoking among American adults remains high at approximately 20%. Most smokers endorse a desire to quit, but very few (only about 4–7%) will actually do so in a given year without treatment. Current commonly used treatments for tobacco dependence include nicotine replacement therapy (e.g., patch, gum, and lozenge), varenicline HCl (Chantix), bupropion HCl (Zyban), and group and/or individual psychotherapy. These treatments result in roughly 20–25% abstinence rates in smokers at 6 months or more after treatment initiation and are therefore considerably better than attempting abstinence without treatment. However, there continues to be a vital need to improve treatments for cigarette smokers wanting to quit because such a high percentage of smokers who initiate treatment will relapse within the first year. A potential new treatment option for tobacco dependence that is currently being evaluated is transcranial magnetic stimulation (TMS). TMS has proven to be a useful tool for both studying brain circuits that support behavioral and cognitive processing and some therapeutic uses. The magnetic fields of TMS systems induce small currents in cerebral tissue, leading to depolarization in the brain region adjacent to the stimulation coil (the target) and in other neurons transsynaptically (1). These fields can be characterized along many parameters, such as field strength and frequency of stimulation. For repetitive TMS (rTMS), conventional terminology refers to the pulsed fields as having slow (low frequency, ≤1 Hz) or fast (high frequency, >1 Hz) repetition frequencies, with slow stimulation frequencies leading to decreases in cortical activity and fast stimulation leading to increases. With repeated treatment sessions, these changes persist when stimulation is not occurring, presumably through neuroadaptation mechanisms. Depending on pulse parameters and neuroanatomic target, neuronal circuits can be manipulated to enhance or reduce their functional activity, with the choice related to the desired clinical effect(s). Evidence supporting the efficacy and safety of fast rTMS for the treatment of major depression led to Food and Drug Administration clearance of a system for that indication (www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm265269.htm), and a recent meta-analysis concluded that rTMS should be viewed as a useful clinical treatment method for depression (2). In the field of addiction, several reviews of the emerging use of rTMS have recently been published (3–5). When delivered to the prefrontal cortex, rTMS has been found to reduce craving for cigarettes, alcohol, cocaine, and food (5) and (in some studies) has been found to transiently reduce intake (3,4) (although not all studies have demonstrated these same effects (4,5). It has been postulated that rTMS delivered to the dorsolateral prefrontal cortex affects craving/addiction through its influence on decision making (5) and inhibitory control (3) because risky decision making and difficulty with inhibitory control are traits common to people who suffer from addiction. In addition, a possible mechanism for the effects in addiction of rTMS to frontal brain regions is that this method enhances dopamine release in mesocorticolimbic brain circuitry (3), which could alleviate substance use urges by mimicking the dopamine release associated with substance use and withdrawal, thereby diminishing the need to take additional substances. Furthermore, given the ability of brain stimulation to modulate cortical excitability, it has been hypothesized that these stimulations result in neuroadaptations and changes in synaptic plasticity in the brain reward system (5), which could be relevant for the treatment of addiction. In this month’s issue of Biological Psychiatry, Rose et al. (6) describe their innovative study in which subjective craving responses to cigarette (and neutral) cues and cigarette smoke presentation were modulated by high-frequency (10 Hz) rTMS directed at the superior frontal gyrus (SFG). Stimulation at this frequency and location increased craving in response to cigarette cues and diminished craving in response to neutral cues compared with other rTMS administrations (low frequency [1 Hz] delivered to the SFG and low frequency [1 Hz] directed at the motor cortex). High-frequency rTMS delivered to the SFG also strengthened craving alleviation in response to cigarette smoke presentation (when this smoke was delivered in a manner that simulated the participant’s own smoking pattern). Taken together, these results indicate that high-frequency rTMS directed at the SFG accentuates natural responses to cigarette-related (and neutral) cues and also to cigarette smoking itself. These results show great promise for the possibility of manipulating smoking-related symptoms and smoking behavior and could possibly guide future treatment trials of rTMS for tobacco dependence. Whereas the study by Rose et al. (6) focused on SFG function based on studies by their group, smoking-related symptoms have also been linked to SFG activity in other recent studies as well. In one such study (7), a subgroup of smokers (based on genotype) was found to have a correlation between cigarette cue-induced SFG activation and severity of nicotine dependence. In another set of studies, cigarette cue exposure delivered through a virtual reality environment was associated with increased SFG activity, and this activation was diminished from before to after cue exposure treatment of smokers (8). Additionally, in a brain-imaging study of SFG function, part of this gyrus was found to mediate the detection of unfavorable outcomes, response errors, response conflict, and decision uncertainty (9), which are functions potentially associated with addiction. Thus, the SFG has been repeatedly linked to smoking-related symptoms, may mediate certain types of smoking cessation treatment response, and holds promise as a target for TMS modulation of smoking-related symptoms. In addition to the SFG, other brain regions have been frequently linked to smoking-related symptoms (10), and future research using brain stimulation in smokers could focus on these regions as well. As for cortical structures that should be considered as potential targets for manipulation by neuromodulation, the dorsolateral prefrontal, anterior cingulate, orbitofrontal, and insular cortices all have been implicated in tobacco dependence and have demonstrated functions that could be related to addictive behavior. These regions are associated with such functions as decision making, behavioral inhibition, attention, and repetitive behavior and are therefore logical targets for neuromodulation in addiction, as has been done in the initial studies referred to in the abovementioned text. Although it would be ideal to be able to explore the potential therapeutic benefit of stimulation at each of these sites, some regions are more accessible than others, which may explain why specific surface regions (e.g., dorsolateral prefrontal cortex) have been more extensively studied than deeper regions (e.g., anterior cingulate and insular cortices). Subcortical structures that could be targets of neuromodulation treatments include the thalamus, ventral striatum (brain reward area), and brainstem. These regions have high densities of nicotinic acetylcholine (nicotine) receptors, with the thalamus being of particular interest in tobacco dependence because it has the highest density of nicotinic acetylcholine receptors in the brain and has been reported to be a relay station for cortical drive. These factors strongly implicate the thalamus as mediating at least some symptoms of tobacco dependence. The brainstem and ventral striatum are also strongly implicated in smoking behavior because the brainstem contains neurons in the ventral tegmental area that project to the ventral striatum and release dopamine in response to nicotine administration. Taken together, the research by Rose et al. (6), along with related studies, may encourage additional research focused on manipulating smoking-related symptoms and smoking behavior, with the overall goal of improving abstinence rates in smokers seeking treatment.

Background: Symptoms of major depressive disorder (MDD) have been linked to regional brain function through imaging studies of symptom provocation in normal control subjects and baseline studies of subjects with MDD. We examined associations between change in depressive symptom factors and change in regional brain metabolism from before to after treatment of MDD. Methods: Thirty-nine outpatients with MDD underwent 18F-fluorodeoxyglucose positron emission tomography scanning before and after treatment with either paroxetine or interpersonal psychotherapy. Associations were determined between changes in regional brain metabolism and changes in four Hamilton Depression Rating Scale factors (anxiety/somatization [ANX], psychomotor retardation [PR], cognitive disturbance [COGN], and sleep disturbance) and two corresponding Profile of Mood States subscales (tension [TENS] and fatigue [FATIG]). Results: Improvement in ANX, PR, TENS, and FATIG factors was associated with decreasing ventral frontal lobe metabolism. Improvement in ANX and TENS was also associated with decreasing ventral anterior cingulate gyrus (AC) and anterior insula activity, whereas improvement in PR was associated with increasing dorsal AC activity. COGN improvement was associated with increasing dorsolateral prefrontal cortex metabolism. Conclusions: Brain regions that show significant relationships with symptom provocation in normal control subjects have similar relationships with MDD symptoms as they improve with treatment.

Background: The frequent comorbidity of major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) suggests a fundamental relationship between them. We sought to determine whether MDD and OCD have unique cerebral metabolic patterns that remain the same when they coexist as when they occur independently. Methods: [ 18 F]-fluorodeoxyglucose positron emission tomography (PET) brain scans were obtained on 27 subjects with OCD alone, 27 with MDD alone, 17 with concurrent OCD+MDD, and 17 normal control subjects, all in the untreated state. Regional cerebral glucose metabolism was compared between groups. Results: Left hippocampal metabolism was significantly lower in subjects with MDD alone and in subjects with concurrent OCD+MDD than in control subjects or subjects with OCD alone. Hippocampal metabolism was negatively correlated with depression severity across all subjects. Thalamic metabolism was significantly elevated in OCD alone and in MDD alone. Subjects with concurrent OCD+MDD had significantly lower metabolism in thalamus, caudate, and hippocampus than subjects with OCD alone. Conclusions: Left hippocampal dysfunction was associated with major depressive episodes, regardless of primary diagnosis. Other cerebral metabolic abnormalities found in OCD and MDD occurring separately were not seen when the disorders coexisted. Depressive episodes occurring in OCD patients may be mediated by different basal ganglia-thalamic abnormalities than in primary MDD patients.