Xingbao Li

Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving

Using fMRI, our group previously found that after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. This study extends this earlier work with several improvements including imaging the entire brain (rather than the anterior half previously) and recording craving, while the subjects viewed images within the scanner. In a Philips 1.5 T MRI scanner, 10 nontreatment-seeking alcoholics and 10 age-matched healthy social drinkers were given a sip of alcohol before viewing a 12 min randomized presentation of pictures of alcoholic beverages, nonalcoholic beverages, and two different visual control tasks. During picture presentation, changes in regional brain activity were measured in 15 transverse T2*-weighted blood oxygen level dependent slices. Subjects rated their urge to drink after each picture sequence. After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. This study suggests, as did our earlier study, that alcoholics and not social drinkers, when exposed to alcohol cues, have increased brain activity in areas that reportedly subserve craving for other addictive substances.

A controlled trial of daily left prefrontal cortex TMS for treating depression

BACKGROUND Transcranial magnetic stimulation (TMS) is a new technology for noninvasively stimulating the brain. Several studies have suggested that daily stimulation of the left prefrontal cortex with TMS for 2 weeks has probable antidepressant effects. We conducted a parallel-design, double-masked, sham-controlled study to address whether 2 weeks of daily TMS over the left prefrontal cortex has antidepressant activity greater than sham. METHODS Thirty medication-free adult outpatients with nonpsychotic, major depressive (n = 21) or bipolar (n = 9) (depressed phase) disorder who were in a current major depression (Hamilton Rating Scale for Depression [HRSD] 21-item score of >18) were treated each weekday for 2 weeks. Subjects were randomly assigned to receive either daily active (20 subjects) or sham (10 subjects) stimulation. Additionally, the 20 active subjects were equally divided between slower (5 Hz) and faster (20 Hz) frequency treatment. Antidepressant response was defined as greater than a 50% improvement in the baseline HRSD. RESULTS Active TMS resulted in significantly more responders (9/20) than did sham (0/10) (chi(2) = 6.42, p <.01). The number of responders did not differ significantly between the two active cells (3/10 faster and 6/10 slower). Expressed as a percent change from baseline, active TMS subjects had significantly greater improvement on the Beck Depression Inventory as well as the Hamilton Anxiety Rating Scale than did those who received sham. CONCLUSIONS Daily left prefrontal TMS for 2 weeks significantly reduced depression symptoms greater than did sham. The two forms of active TMS treatment did not differ significantly.

Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI

Transcranial magnetic stimulation (TMS) administered over the prefrontal cortex has been shown to subtly influence neuropsychological tasks, and has antidepressant effects when applied daily for several weeks. Prefrontal TMS does not, however, produce an immediate easily observable effect, making it hard to determine if one has stimulated the cortex. Most prefrontal TMS studies have stimulated using intensity relative to the more easily determined motor threshold (MT) over motor cortex. Five healthy adults were studied in a 1.5 T MRI scanner during short trains of 1 Hz TMS delivered with a figure eight MR compatible TMS coil followed by rest epochs. In a randomized manner, left prefrontal TMS was delivered at 80%, 100% and 120% of MT interleaved with BOLD fMRI acquisition. Compared to rest, all TMS epochs activated auditory cortex, with 80% MT having no other areas of significant activation. 100% MT showed contralateral activation and 120% MT showed bilateral prefrontal activation. Higher intensity TMS, compared to lower, in general produced more activity both under the coil and contralaterally. Higher prefrontal TMS stimulation intensity produces greater local and contralateral activation. Importantly, unilateral prefrontal TMS produces bilateral effects, and TMS at 80% MT produces only minimal prefrontal cortex activation.

EFFECT OF NALTREXONE AND ONDANSETRON ON ALCOHOL CUE-INDUCED ACTIVATION OF THE VENTRAL STRIATUM IN ALCOHOL-DEPENDENT PEOPLE

CONTEXT Medication for the treatment of alcoholism is currently not particularly robust. Neuroimaging techniques might predict which medications could be useful in the treatment of alcohol dependence. OBJECTIVE To explore the effect of naltrexone, ondansetron hydrochloride, or the combination of these medications on cue-induced craving and ventral striatum activation. DESIGN Functional brain imaging was conducted during alcohol cue presentation. SETTING Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the magnetic resonance imaging suite of a major training hospital and medical research institute. PATIENTS Ninety non-treatment-seeking alcohol-dependent (by DSM-IV criteria) and 17 social drinking (< 14 drinks per week) paid volunteers recruited through advertisements at an academic center. INTERVENTIONS A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone (n = 23), 0.50 mg of ondansetron hydrochloride (n = 23), the combination of the 2 medications (n = 20), or matching placebos (n = 24). MAIN OUTCOME MEASURES Difference in brain blood oxygen level-dependent magnetic resonance when viewing alcohol pictures vs neutral beverage pictures with a particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving. RESULTS The combination treatment decreased craving for alcohol. Naltrexone with (P = .02) or without (P = .049) ondansetron decreased alcohol cue-induced activation of the ventral striatum. Ondansetron by itself was similar to naltrexone and the combination in the overall analysis but intermediate in a region-specific analysis. CONCLUSIONS Consistent with animal data that suggest that both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination, could decrease alcohol cue-induced activation of the ventral striatum, consistent with their putative treatment efficacy.

Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions.

BACKGROUND Focal prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) was originally investigated as a potential antidepressant under the assumption that in depressed patients, prefrontal cortex stimulation would produce changes in connected limbic regions involved in mood regulation. METHODS Fourteen adult patients with depression were scanned in a 1.5-T scanner using interleaved rTMS (1 Hz) applied on the left prefrontal cortex over 7.35 min. Images were analyzed with Statistical Parametric Mapping 2b and principal component analysis. RESULTS Over the left prefrontal cortex, 1-Hz TMS was associated with increased activity at the site of stimulation as well as in connected limbic regions: bilateral middle prefrontal cortex, right orbital frontal cortex, left hippocampus, mediodorsal nucleus of the thalamus, bilateral putamen, pulvinar, and insula (t = 3.85, p <.001). Significant deactivation was found in the right ventromedial frontal cortex. CONCLUSIONS In depressed patients, 1-Hz TMS at 100% motor threshold over the left prefrontal cortex induces activation underneath the coil, activates frontal-subcortical neuronal circuits, and decreases activity in the right ventromedial cortex. Further work is needed to understand whether these immediate changes vary as a function of TMS use parameters (intensity, frequency, location) and whether they relate to neurobiologic effects and antidepressant mechanisms of TMS.

Volitional reduction of anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a preliminary real-time fMRI study

Numerous research groups are now using analysis of blood oxygen level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in ‘real time’. In this study, we explored the feasibility of self‐regulation of frontal cortical activation using real‐time fMRI (rtfMRI) neurofeedback in nicotine‐dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking‐related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a ‘reduce craving’ paradigm, participants were instructed to ‘reduce’ their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate ‘increase resistance’ paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the ‘reduce craving’ task (P = 0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the ‘reduce craving’ session (P = 0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the ‘increase resistance’ session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue‐induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.

Neural Correlates of Craving and Resisting Craving for Tobacco in Nicotine Dependent Smokers

Craving is a significant factor which can lead to relapse during smoking quit attempts. Attempts to resist urges to smoke during cue‐elicited craving have been shown to activate regions in the brain associated with decision‐making, anxiety regulation and visual processing. In this study, 32 treatment‐seeking, nicotine‐dependent smokers viewed blocks of smoking and neutral cues alternating with rest periods during magnetic resonance imaging scanning in a 3T Siemens scanner (Siemens AG, Erlangen, Bavaria, Germany). While viewing cues or control images, participants were instructed either to ‘allow yourself to crave’ or ‘resist craving.’ Data were analyzed with FSL 4.1.5, focused on the smoking cues versus neutral cues contrast, using cluster thresholding (Z > 2.3 and corrected cluster threshold of P = 0.05) at the individual and group levels. During the Crave condition, activation was seen on the left anterior cingulated cortex (LACC), medial prefrontal cortex, left middle cingulate gyrus, bilateral posterior cingulated gyrus and bilateral precuneus, areas associated with attention, decision‐making and episodic memory. The LACC and areas of the prefrontal cortex associated with higher executive functioning were activated during the Resist condition. No clear distinctions between group crave and resist analyses as a whole were seen without taking into account specific strategies used to resist the urge to smoke, supporting the idea that craving is associated with some degree of resisting the urge to smoke, and trying to resist is almost always accompanied by some degree of craving. Different strategies for resisting, such as distraction, activated different regions. Understanding the underlying neurobiology of resisting craving to smoke may identify new foci for treatments.

Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex Reduces Nicotine Cue Craving

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) can noninvasively stimulate the brain and transiently amplify or block behaviors mediated through a region. We hypothesized that a single high-frequency rTMS session over the left dorsolateral prefrontal cortex (DLPFC) would reduce cue craving for cigarettes compared with a sham TMS session. METHODS Sixteen non-treatment-seeking, nicotine-dependent participants were randomized to receive either real high-frequency rTMS (10 Hz, 100% resting motor threshold, 5-sec on, 10-sec off for 15 min; 3000 pulses) or active sham (eSham) TMS over the DLPFC in two visits with 1 week between visits. The participants received cue exposure before and after rTMS and rated their craving after each block of cue presentation. RESULTS Stimulation of the left DLFPC with real, but not sham, rTMS reduced craving significantly from baseline (64.1±5.9 vs. 45.7±6.4, t = 2.69, p = .018). When compared with neutral cue craving, the effect of real TMS on cue craving was significantly greater than the effect of sham TMS (12.5±10.4 vs. -9.1±10.4; t = 2.07, p = .049). More decreases in subjective craving induced by TMS correlated positively with higher Fagerström Test for Nicotine Dependence score (r = .58, p = .031) and more cigarettes smoked per day (r = .57, p = .035). CONCLUSIONS One session of high-frequency rTMS (10 Hz) of the left DLPFC significantly reduced subjective craving induced by smoking cues in nicotine-dependent participants. Additional studies are needed to explore rTMS as an aid to smoking cessation.

Mechanisms and State of the Art of Transcranial Magnetic Stimulation

In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device with enough power to stimulate dorsal roots in the spine. They quickly realized that this machine could likely also noninvasively stimulate the superficial cortex in humans. They waited a while before using their device over a human head, fearing that the TMS pulse might magnetically “erase the hard-drive” of the human brain. Almost 10 years later, in 1994, an editorial in this journal concerned whether TMS might evolve into a potential antidepressant treatment. In the intervening years, there has been an explosion of basic and clinical research with and about TMS. Studies are now uncovering the mechanisms by which TMS affects the brain. It does not “erase the hard-drive” of the brain, and it has many demonstrated research and clinical uses. This article reviews the major recent advances with this interesting noninvasive technique for stimulating the brain, critically reviewing the data on whether TMS has anticonvulsant effects or modulates cortical-limbic loops.

Safety, tolerability, and effectiveness of high doses of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation for treatment-resistant depression in a clinical setting.

Objective: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) recently received Food and Drug Administration (FDA) approval for the treatment of depression and offers an alternative to traditional approaches. This approval was based on a study using 3000 stimuli per day (15,000 stimuli per week) in adults with unipolar depression not taking antidepressant medications. Several meta-analyses suggest a dose-response relationship with TMS. This study was carried out before US FDA approval to test the safety, tolerability, and effectiveness of adjunctive high-dose left prefrontal rTMS in a clinical setting with particular attention to safety of higher doses and potential interactions with antidepressant medications, speed of response, and effects on suicidality. Method: We enrolled 19 patients who were in a current major depressive episode with treatment-resistant unipolar or bipolar depression and treated them in their acute episode and in a maintenance fashion for 18 months. The patients received daily left prefrontal rTMS at 120% resting motor threshold, 10 Hz, 5 seconds on, and 10 seconds off and for a mean of 6800 stimuli per session (34,000 stimuli per week), more than twice the dose delivered in the pivotal FDA trial. All patients continued antidepressant medication throughout the rTMS treatment; thus rTMS was an adjunctive treatment. We measured adverse effects, depression, quality of life, suicidal ideation, and social and physical functioning. Results: These higher rTMS doses were well tolerated without significant adverse effects or adverse events. All measured dimensions showed improvement, with many showing improvement in 1 to 2 weeks. Of perhaps most importance, suicidal ideation diminished in 67% of the patients after just 1 week. Conclusions: These uncontrolled data suggest that higher doses of daily left prefrontal rTMS may safely be used in outpatients with major depressive episode even as an adjunctive treatment.