Colleen A. Hanlon

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.

Poor decision-making by chronic marijuana users is associated with decreased functional responsiveness to negative consequences

Chronic marijuana users (MJ Users) perform poorly on the Iowa Gambling Task (IGT), a complex decision-making task in which monetary wins and losses guide strategy development. This functional magnetic resonance imaging (MRI) study sought to determine if the poor performance of MJ Users was related to differences in brain activity while evaluating wins and losses during the strategy development phase of the IGT. MJ Users (16) and Controls (16) performed a modified IGT in an MRI scanner. Performance was tracked and functional activity in response to early wins and losses was examined. While the MJ Users continued to perform poorly at the end of the task, there was no difference in group performance during the initial strategy development phase. During this phase, before the emergence of behavioral differences, Controls exhibited significantly greater activity in response to losses in the anterior cingulate cortex, medial frontal cortex, precuneus, superior parietal lobe, occipital lobe and cerebellum as compared to MJ Users. Furthermore, in Controls, but not MJ Users, the functional response to losses in the anterior cingulate cortex, ventral medial prefrontal cortex and rostral prefrontal cortex positively correlated with performance over time. These data suggest MJ Users are less sensitive to negative feedback during strategy development.

Parallel studies of cocaine-related neural and cognitive impairment in humans and monkeys

Cocaine users display profound impairments in executive function. Of all the components of executive function, inhibition, or the ability to withhold responding, has been studied the most extensively and may be most impaired. Consistent with these deficits, evidence from imaging studies points to dysregulation in medial and ventromedial prefrontal cortices, areas activated during performance of inhibition tasks. Other aspects of executive function including updating, shifting and decision making are also deficient in cocaine users, and these deficits are paralleled by abnormalities in patterns of prefrontal cortical activation. The extent to which cocaine plays a role in these effects, however, is not certain, and cannot be determined solely on the basis of human studies. Investigations using a non-human primate model of increasing durations of cocaine exposure revealed that initially the effects of cocaine were restricted to ventromedial and orbital prefrontal cortices, but as exposure was extended the intensity and spatial extent of the effects on functional activity also expanded rostrally and laterally. Given the spatial overlap in prefrontal pathology between human and monkey studies, these longitudinal mapping studies in non-human primates provide a unique window of understanding into the dynamic neural changes that are occurring early in human cocaine abuse.

What goes up, can come down: Novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance dependent individuals

Vulnerability to drug related cues is one of the leading causes for continued use and relapse among substance dependent individuals. Using drugs in the face of cues may be associated with dysfunction in at least two frontal-striatal neural circuits: (1) elevated activity in medial and ventral areas that govern limbic arousal (including the medial prefrontal cortex (MPFC) and ventral striatum) or (2) depressed activity in dorsal and lateral areas that govern cognitive control (including the dorsolateral prefrontal cortex (DLPFC) and dorsal striatum). Transcranial magnetic stimulation (TMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. To date however, nearly all repetitive TMS studies in addiction have focused on amplifying activity in frontal-striatal circuits that govern cognitive control. This manuscript reviews recent work using TMS as a tool to decrease craving for multiple substances and provides a theoretical model for how clinical researchers might approach target and frequency selection for TMS of addiction. To buttress this model, preliminary data from a single-blind, sham-controlled, crossover study of 11 cocaine-dependent individuals is also presented. These results suggest that attenuating MPFC activity through theta burst stimulation decreases activity in the striatum and anterior insula. It is also more likely to attenuate craving than sham TMS. Hence, while many TMS studies are focused on applying LTP-like stimulation to the DLPFC, the MPFC might be a new, efficacious, and treatable target for craving in cocaine dependent individuals.

The association between frontal-striatal connectivity and sensorimotor control in cocaine users.

BACKGROUND In addition to cognitive and emotional processing dysfunction, chronic cocaine users are also impaired at simple sensorimotor tasks. Many diseases characterized by compulsive movements, repetitive actions, impaired attention and planning are associated with dysfunction in frontal-striatal circuits. The aim of this study was to determine whether cocaine users had impaired frontal-striatal connectivity during a simple movement task and whether this was associated with sensorimotor impairment. METHODS Functional MRI data were collected from 14 non-treatment seeking cocaine users and 15 healthy controls as they performed a finger-tapping task. Functional coupling was quantified by correlating the timecourses of each pair of anatomically connected regions of interest. Behavioral performance was correlated with all functional coupling coefficients. RESULTS In controls there was a significant relationship between the primary motor cortex and the supplementary motor area (SMA), as well as the SMA and the dorsal striatum during ongoing movement. Cocaine users exhibited weaker fronto-striatal coupling than controls, while the cortical-cortical coupling was intact. Coupling strength between the SMA and the caudate was negatively correlated with reaction time in the users. CONCLUSIONS The observation that cocaine users have impaired cortical-striatal connectivity during simple motor performance, suggests that these individuals may have a fundamental deficit in information processing that influences more complex cognitive processes.

Executive control circuitry differentiates degree of success in weight loss following gastric‐bypass surgery

While overall success rates of bariatric surgery are high, approximately 20% of patients either regain or never lose the expected amount of weight. The purpose of this study was to determine whether, after gastric‐bypass surgery, the degree of weight loss can be differentiated based on the neural response to food cues.

Naloxone-reversible modulation of pain circuitry by left prefrontal rTMS.

A 20-minute session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) of Brodmann Area (BA) nine of the left dorsolateral prefrontal cortex (DLPFC) can produce analgesic effects on postoperative and laboratory-induced pain. This analgesia is blocked by pretreatment with naloxone, a μ-opioid antagonist. The purpose of this sham-controlled, double-blind, crossover study was to identify the neural circuitry that underlies the analgesic effects of left DLPFC rTMS, and to examine how the function of this circuit, including midbrain and medulla, changes during opioid blockade. Fourteen healthy volunteers were randomized to receive intravenous saline or naloxone immediately before sham and real left DLPFC rTMS on the same experimental visit. One week later, each participant received the novel pretreatment but the same stimulation paradigm. Using short sessions of heat on capsaicin-sensitized skin, hot allodynia was assessed during 3 Tesla functional magnetic resonance imaging (fMRI) scanning at baseline, post-sham rTMS, and post-real rTMS. Data were analyzed using whole-brain voxel-based analysis, as well as time series extractions from anatomically-defined regions of interest representing midbrain and medulla. Consistent with previous findings, real rTMS significantly reduced hot allodynia pain ratings. This analgesia was associated with elevated blood oxygenation-level dependent (BOLD) signal in BAs 9 and 10, and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and medulla during pain. Naloxone pretreatment largely abolished rTMS-induced analgesia, as well as rTMS-induced attenuation of BOLD signal response to painful stimuli throughout pain processing regions, including midbrain and medulla. These preliminary results suggest that left DLPFC rTMS drives top-down opioidergic analgesia.

Right anterior insula connectivity is important for cue‐induced craving in nicotine‐dependent smokers

The insula has been implicated in cue‐induced craving and relapse in nicotine‐dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue‐induced craving in healthy (free of axis I psychiatric disorders) nicotine‐dependent tobacco cigarette smokers. Functional magnetic resonance imaging data were collected from 63 healthy nicotine‐dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z > 2.3, P = 0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue‐induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self‐awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r2 = 0.15; P < 0.01). These data suggest that among smokers, cue‐induced craving may be a function of connectivity between two regions involved in interoception and self‐awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue‐induced craving and relapse in nicotine‐dependent smokers.

Low frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex transiently increases cue-induced craving for methamphetamine: A preliminary study

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) can temporarily interrupt or facilitate activity in a focal brain region. Several lines of evidence suggest that rTMS of the dorsolateral prefrontal cortex (DLPFC) can affect processes involved in drug addiction. We hypothesized that a single session of low-frequency rTMS of the left DLPFC would modulate cue-induced craving for methamphetamine (MA) when compared to a sham rTMS session. METHODS In this single-blind, sham-controlled crossover study, 10 non-treatment seeking MA-dependent users and 8 healthy controls were randomized to receive 15 min of sham and real (1 Hz) DLPFC rTMS in two experimental sessions separated by 1h. During each rTMS session, participants were exposed to blocks of neutral cues and MA-associated cues. Participants rated their craving after each cue block. RESULTS In MA users, real rTMS over the left DLPFC increased self-reported craving as compared to sham stimulation (17.86 ± 1.46 vs. 24.85 ± 1.57, p=0.001). rTMS had no effect on craving in healthy controls. One Hertz rTMS of the left DLPFC was safe and tolerable for all participants. CONCLUSIONS Low frequency rTMS of the left DLPFC transiently increased cue-induced craving in MA participants. These preliminary results suggest that 1 Hz rTMS of the left DLPFC may increase craving by inhibiting the prefrontal cortex or indirectly activating subcortical regions involved in craving.

Probing the Frontostriatal Loops Involved in Executive and Limbic Processing via Interleaved TMS and Functional MRI at Two Prefrontal Locations: A Pilot Study

Background The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment. Methods Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability. Results Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals. Conclusion These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations.