Logan T. Dowdle

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.

Visual cortex activation to drug cues: a meta-analysis of functional neuroimaging papers in addiction and substance abuse literature

BACKGROUND Although the visual cortex does not typically receive much attention in addiction literature, neuroimaging studies often report significant activity in visual areas when drug users are exposed to drug cues. The purpose of this meta-analysis was to investigate the frequency with which occipital cortex activity is observed during drug cue exposure and to determine its spatial distribution. METHODS A comprehensive literature search was performed of human functional neuroimaging studies of drug cue-reactivity. Fifty-five studies were used to determine the frequency with which clusters of significant visual cortex activity during visual drug cues versus non-drug cues were reported. The spatial distribution of visual cortex activations was determined via activation likelihood estimation (ALE; FDR corrected, p<0.01) in a subset of these studies (n=24). RESULTS Eighty-six percent of studies that reported fMRI results for drug versus neutral visual cues within a substance-dependent group showed significant drug-elicited activity in the visual cortex. ALE revealed clusters in the left secondary visual cortex (BA 19) and clusters in the primary visual cortex (BA 17) that were consistently activated by drug cues. CONCLUSIONS These data demonstrate that the visual cortex, often overlooked in our discussions of the neural circuitry of addiction, consistently discriminates drug cues from neutral cues in substance dependent populations. While it remains unclear whether drug cue-elicited activation in occipital cortex is related to the rewarding properties of the drug and/or attentional mechanisms, these data support further exploration.

Mobilization of Medial and Lateral Frontal-Striatal Circuits in Cocaine Users and Controls: An Interleaved TMS/BOLD Functional Connectivity Study.

The integrity of frontal-striatal circuits is an area of great interest in substance dependence literature, particularly as the field begins to develop neural circuit-specific brain stimulation treatments for these individuals. Prior research indicates that frontal-striatal connectivity is disrupted in chronic cocaine users in a baseline (resting) state. It is unclear, however, if this is also true when these circuits are mobilized by an external source. In this study, we measured the functional and structural integrity of frontal-striatal circuitry involved in limbic arousal and executive control in 36 individuals—18 cocaine-dependent individuals with a history of failed quit attempts and 18 age-matched controls. This was achieved by applying a transcranial magnetic stimulation to the medial prefrontal cortex (Brodmann area 10) and the dorsolateral prefrontal cortex (lateral Brodmann 9) while participants rested in the MRI scanner (TMS/BOLD imaging). Relative to the controls, cocaine users had a lower ventral striatal BOLD response to MPFC stimulation. The dorsal striatal BOLD response to DLPFC stimulation however was not significantly different between the groups. Among controls, DLPFC stimulation led to a reciprocal attenuation of MPFC activity (BA 10), but this pattern did not exist in cocaine users. No relationship was found between regional diffusion metrics and functional activity. Considered together these data suggest that, when engaged, cocaine users can mobilize their executive control system similar to controls, but that the ‘set point’ for mobilizing their limbic arousal system has been elevated—an interpretation consistent with opponent process theories of addiction.

A comprehensive study of sensorimotor cortex excitability in chronic cocaine users: Integrating TMS and functional MRI data

BACKGROUND Disruptions in motor control are often overlooked features of chronic cocaine users. During a simple sensorimotor integration task, for example, cocaine users activate a larger area of cortex than controls but have lower functional connectivity between the cortex and dorsal striatum, which is further correlated with poor performance. The purpose of this study was to determine whether abnormal cortical excitability in cocaine users was related to disrupted inhibitory or excitatory mechanisms, as measured by transcranial magnetic stimulation (TMS). METHODS A battery of TMS measures were acquired from 87 individuals (50 cocaine dependent, 37 controls). Functional MRI data were acquired from a subset of 28 individuals who performed a block-design finger tapping task. RESULTS TMS measures revealed that cocaine users had significantly higher resting motor thresholds and higher intracortical cortical facilitation (ICF) than controls. There was no between-group difference in either measure of cortical inhibition. Task-evoked BOLD signal in the motor cortex was significantly correlated with ICF in the cocaine users. There was no significant difference in brain-skull distance between groups. CONCLUSION These data demonstrated that cocaine users have disrupted cortical facilitation (as measured with TMS), which is related to elevated BOLD signal. Cortical inhibition, however, is largely intact. Given the relationship between ICF and glutamatergic agents, this may be a potentially fruitful and treatable target in addiction. Finally, among controls the distance from the scalp to the cortex was correlated with the motor threshold which may be a useful parameter to integrate into therapeutic TMS protocols in the future.

Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine users and alcohol users

BACKGROUND Preclinical research has demonstrated a causal relationship between medial prefrontal cortex activity and cocaine self-administration. As a step towards translating those data to a neural circuit-based intervention for patients, this study sought to determine if continuous theta burst stimulation (cTBS) to the left frontal pole (FP), would attenuate frontal-striatal activity in two substance-dependent populations. METHODS Forty-nine substance dependent individuals (25 cocaine, 24 alcohol) completed a single-blind, sham-controlled, crossover study wherein they received 6 trains of real or sham cTBS (110% resting motor threshold, FP1) each visit. Baseline evoked BOLD signal was measured immediately before and after real and sham cTBS (interleaved TMS/BOLD imaging: single pulses to left FP; scalp-to-cortex distance covariate, FWE correction p<0.05) RESULTS: Among cocaine users, real cTBS significantly decreased evoked BOLD signal in the caudate, accumbens, anterior cingulate, orbitofrontal (OFC) and parietal cortex relative to sham cTBS. Among alcohol users, real cTBS significantly decreased evoked BOLD signal in left OFC, insula, and lateral sensorimotor cortex. There was no significant difference between the groups. CONCLUSIONS These data suggest that 6 trains of left FP cTBS delivered in a single day decreases TMS-evoked BOLD signal in the OFC and several cortical nodes which regulate salience and are typically activated by drug cues. The reliability of this pattern across cocaine- and alcohol-dependent individuals suggests that cTBS may be an effective tool to dampen neural circuits typically engaged by salient drug cues. Multiday studies are required to determine it this has a sustainable effect on the brain or drug use behavior.

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review

BACKGROUND Electrical stimulation of the auricular branch of the vagus nerve (ABVN) via transcutaneous auricular vagus nerve stimulation (taVNS) may influence afferent vagal networks. There have been 5 prior taVNS/fMRI studies, with inconsistent findings due to variability in stimulation targets and parameters. OBJECTIVE We developed a taVNS/fMRI system to enable concurrent electrical stimulation and fMRI acquisition to compare the effects of taVNS in relation to control stimulation. METHODS We enrolled 17 healthy adults in this single-blind, crossover taVNS/fMRI trial. Based on parameters shown to affect heart rate in healthy volunteers, participants received either left tragus (active) or earlobe (control) stimulation at 500 μs 25 HZ for 60 s (repeated 3 times over 6 min). Whole brain fMRI analysis was performed exploring the effect of: active stimulation, control stimulation, and the comparison. Region of interest analysis of the midbrain and brainstem was also conducted. RESULTS Active stimulation produced significant increased BOLD signal in the contralateral postcentral gyrus, bilateral insula, frontal cortex, right operculum, and left cerebellum. Control stimulation produced BOLD signal activation in the contralateral postcentral gyrus. In the active vs. control contrast, tragus stimulation produced significantly greater BOLD increases in the right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid-cingulate. CONCLUSION Stimulation of the tragus activates the cerebral afferents of the vagal pathway and combined with our review of the literature suggest that taVNS is a promising form of VNS. Future taVNS/fMRI studies should systematically explore various parameters and alternative stimulation targets aimed to optimize this novel form of neuromodulation.

Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals

Transcranial magnetic stimulation (TMS) can stimulate cortical and subcortical brain regions. However, in order to reach subcortical targets, intact monosynaptic connections are required. The goal of this investigation was to evaluate the contribution of white matter integrity and gray matter volume to frontal pole TMS-evoked striatal activity in a large cohort of chronic cocaine users. 49 cocaine users received single pulses of TMS to the frontal pole while BOLD data were acquired – a technique known as interleaved TMS/fMRI. Diffusion tensor imaging and voxel-based morphometry were used to quantify white matter integrity and gray matter volume (GMV), respectively. Stepwise regression was used to evaluate the contribution of clinical and demographic variables to TMS-evoked BOLD. Consistent with previous studies, frontal pole TMS evoked activity in striatum and salience circuitry. The size of the TMS-evoked response was related to fractional anisotropy between the frontal pole and putamen and GMV in the left frontal pole and left ACC. This is the first study to demonstrate that the effect of TMS on subcortical activity is dependent upon the structural integrity of the brain. These data suggest that these structural neuroimaging data types are biomarkers for TMS-induced mobilization of the striatum.

Cortical substrates of cue-reactivity in multiple substance dependent populations: transdiagnostic relevance of the medial prefrontal cortex

Elevated drug-cue elicited brain activity is one of the most widely cited, transdiagnostically relevant traits of substance dependent populations. These populations, however, are typically studied in isolation. The goal of this study was to prospectively investigate the spatial topography of drug-cue reactivity in a large set of individuals dependent on either cocaine, alcohol, or nicotine. Functional MRI data was acquired from 156 substance dependent individuals (55 cocaine, 53 alcohol, and 48 nicotine) as they performed a standardized drug-cue exposure task. Clusters of significant activation to drug-cues relative to neutral cues (‘hot spots’) were isolated for each individual. K-means clustering was used to classify the spatial topography of the hotspots in the data set. The percentage of hotspots that would be reached at several distances (2–5 cm) of transcranial magnetic stimulation (TMS) were calculated. One hundred and three participants had at least one cluster of significant frontal cortex activity (66%). K-means revealed 3 distinct clusters within the medial prefrontal cortex (MPFC), left inferior frontal gyrus/insula, right premotor cortex. For the group as a whole (and for alcohol users and nicotine users independently), medial prefrontal cortex (BA 10) was the location of the greatest number of hotspots. The frontal pole was cortical location closest to the largest percentage of hotspots. While there is individual variability in the location of the cue-elicited ‘hot spot’ these data demonstrate that elevated BOLD signal to drug cues in the MPFC may be a transdiagnostic endophenotype of addiction which may also be a fruitful neuromodulation target.

Modulating Neural Circuits with Transcranial Magnetic Stimulation: Implications for Addiction Treatment Development

Although the last 50 years of clinical and preclinical research have demonstrated that addiction is a brain disease, we still have no neural circuit–based treatments for substance dependence or cue reactivity at large. Now, for the first time, it appears that a noninvasive brain stimulation technique known as transcranial magnetic stimulation (TMS), which is Food and Drug Administration approved to treat depression, may be the first tool available to fill this critical void in addiction treatment development. The goals of this review are to 1) introduce TMS as a tool to induce causal change in behavior, cortical excitability, and frontal–striatal activity; 2) describe repetitive TMS (rTMS) as an interventional tool; 3) provide an overview of the studies that have evaluated rTMS as a therapeutic tool for alcohol and drug use disorders; and 4) outline a conceptual framework for target selection when designing future rTMS clinical trials in substance use disorders. The manuscript concludes with some suggestions for methodological innovation, specifically with regard to combining rTMS with pharmacotherapy as well as cognitive behavioral training paradigms. We have attempted to create a comprehensive manuscript that provides the reader with a basic set of knowledge and an introduction to the primary experimental questions that will likely drive the field of TMS treatment development forward for the next several years.

Single pulse TMS to the DLPFC, compared to a matched sham control, induces a direct, causal increase in caudate, cingulate, and thalamic BOLD signal

BACKGROUND In the 20 years since our group established the feasibility of performing interleaved TMS/fMRI, no studies have reported direct comparisons of active prefrontal stimulation with a matched sham. Thus, for all studies there is concern about what is truly the TMS effect on cortical neurons. OBJECTIVE After developing a sham control for use within the MRI scanner, we used fMRI to test the hypothesis of greater regional BOLD responses for active versus control stimulation. METHODS We delivered 4 runs of interleaved TMS/fMRI with a limited field of view (16 slices, centered at AC-PC) to the left DLPFC (2 active, 2 control; counterbalanced) of 20 healthy individuals (F3; 20 pulses/run, interpulse interval:10-15sec, TR:1sec). In the control condition, 3 cm of foam was placed between the TMS coil and the scalp. This ensured magnetic field decay, but preserved the sensory aspects of each pulse (empirically evaluated in a subset of 10 individuals). RESULTS BOLD increases in the cingulate, thalamus, insulae, and middle frontal gyri (p < 0.05, FWE corrected) were found during both active and control stimulation. However, relative to control, active stimulation caused elevated BOLD signal in the anterior cingulate, caudate and thalamus. No significant difference was found in auditory regions. CONCLUSION(S) This TMS/fMRI study evaluated a control condition that preserved many of the sensory features of TMS while reducing magnetic field entry. These findings support a relationship between single pulses of TMS and activity in anatomically connected regions, but also underscore the importance of using a sham condition in future TMS/fMRI studies.