Major depressive disorder (MDD) and substance use disorders (SUDs) are prevalent, disabling, and challenging illnesses for which new treatment options are needed, particularly in comorbid cases. ...Neuroimaging studies of the functional architecture of the brain suggest common neural substrates underlying MDD and SUDs. Intrinsic brain activity is organized into a set of functional networks, of which two are particularly relevant to psychiatry. The salience network (SN) is crucial for cognitive control and response inhibition, and deficits in SN function are implicated across a wide variety of psychiatric disorders, including MDD and SUDs. The ventromedial network (VMN) corresponds to the classic reward circuit, and pathological VMN activity for drug cues/negative stimuli is seen in SUDs/MDD. Noninvasive brain stimulation (NIBS) techniques, including rTMS and tDCS, have been used to enhance cortico–striatal–thalamic activity through the core SN nodes in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and anterior insula. Improvements in both MDD and SUD symptoms ensue, including in comorbid cases, via enhanced cognitive control. Inhibition of the VMN also appears promising in preclinical studies for quenching the pathological incentive salience underlying SUDs and MDD. Evolving techniques may further enhance the efficacy of NIBS for MDD and SUD cases that are unresponsive to conventional treatments.
The experimental manipulation of neural activity by neurostimulation techniques overcomes the inherent limitations of correlative recordings, enabling the researcher to investigate causal ...brain-behavior relationships. But only when stimulation and recordings are combined, the direct impact of the stimulation on neural activity can be evaluated. In humans, this can be achieved non-invasively through the concurrent combination of transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging (fMRI). Concurrent TMS-fMRI allows the assessment of the neurovascular responses evoked by TMS with excellent spatial resolution and full-brain coverage. This enables the functional mapping of both local and remote network effects of TMS in cortical as well as deep subcortical structures, offering unique opportunities for basic research and clinical applications. The purpose of this review is to introduce the reader to this powerful tool. We will introduce the technical challenges and state-of-the art solutions and provide a comprehensive overview of the existing literature and the available experimental approaches. We will highlight the unique insights that can be gained from concurrent TMS-fMRI, including the state-dependent assessment of neural responsiveness and inter-regional effective connectivity, the demonstration of functional target engagement, and the systematic evaluation of stimulation parameters. We will also discuss how concurrent TMS-fMRI during a behavioral task can help to link behavioral TMS effects to changes in neural network activity and to identify peripheral co-stimulation confounds. Finally, we will review the use of concurrent TMS-fMRI for developing TMS treatments of psychiatric and neurological disorders and suggest future improvements for further advancing the application of concurrent TMS-fMRI.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which is now being used in psychiatry clinics across the world as a therapeutic tool for a variety of ...neural-circuit based disorders (e.g., major depression, obsessive compulsive disorder, substance use disorders, post-traumatic stress disorder, headache, pain). The higher volume of use and publication of multiple large-scale clinical trials has provided researchers with a unique opportunity to retrospectively evaluate factors influencing TMS treatment responses in large samples of patients. While many studies have focused on TMS protocol parameters as moderators of treatment efficacy, sex/gender is another critical, often overlooked factor influencing TMS treatment outcome. Women, especially during periods of high estradiol, appear to be particularly sensitive to the therapeutic effects of rTMS. This manuscript makes a case for three potential biological explanations for these findings. Drawing on literature from cranio-facial anatomy, neuroimaging, and neuroendocrine fields, we posit that observed increases in response rates of women in clinical rTMS trials may be related to: (1) Closer proximity of the brain to the scalp at the prefrontal cortex, leading to larger TMS induced electric fields especially at the medial prefrontal cortex, (2) Greater gray matter density and gyrification in the prefrontal cortex, and (3) High levels of estradiol which facilitate cortical excitability. These biological explanations are empirical ideas which have been evaluated in laboratory studies and lend themselves to prospective evaluation in multisite clinical rTMS trials. The existing literature on this topic and these three potential biological explanations all indicate that the TMS field should routinely evaluate sex/gender (and associated biological metrics like scalp-to-cortex distance, gray matter density, estradiol/progesterone levels) as a factor that may influence treatment outcome.
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.
Given the high prevalence of individuals diagnosed with substance use disorder, along with the elevated rate of relapse following treatment initiation, investigating novel approaches and new ...modalities for substance use disorder treatment is of vital importance. One such approach involves neuromodulation which has been used therapeutically for neurological and psychiatric disorders and has demonstrated positive preliminary findings for the treatment of substance use disorder. The following article provides a review of several forms of neuromodulation which warrant consideration as potential treatments for substance use disorder. PubMed, PsycINFO, Ovid MEDLINE, and Web of Science were used to identify published articles and clinicaltrials.gov was used to identify currently ongoing or planned studies. Search criteria for Brain Stimulation included the following terminology: transcranial direct current stimulation, transcranial magnetic stimulation, theta burst stimulation, deep brain stimulation, vagus nerve stimulation, trigeminal nerve stimulation, percutaneous nerve field stimulation, auricular nerve stimulation, and low intensity focused ultrasound. Search criteria for Addiction included the following terminology: addiction, substance use disorder, substance-related disorder, cocaine, methamphetamine, amphetamine, alcohol, nicotine, tobacco, smoking, marijuana, cannabis, heroin, opiates, opioids, and hallucinogens. Results revealed that there are currently several forms of neuromodulation, both invasive and non-invasive, which are being investigated for the treatment of substance use disorder. Preliminary findings have demonstrated the potential of these various neuromodulation techniques in improving substance treatment outcomes by reducing those risk factors (e.g. substance craving) associated with relapse. Specifically, transcranial magnetic stimulation has shown the most promise with several well-designed studies supporting the potential for reducing substance craving. Deep brain stimulation has also shown promise, though lacks well-controlled clinical trials to support its efficacy. Transcranial direct current stimulation has also demonstrated promising results though consistently designed, randomized trials are also needed. There are several other forms of neuromodulation which have not yet been investigated clinically but warrant further investigation given their mechanisms and potential efficacy based on findings from other studied indications. In summary, given promising findings in reducing substance use and craving, neuromodulation may provide a non-pharmacological option as a potential treatment and/or treatment augmentation for substance use disorder. Further research investigating neuromodulation, both alone and in combination with already established substance use disorder treatment (e.g. medication treatment), warrants consideration.
•Several forms of neuromodulation are being investigated for SUD treatment.•Neuromodulation shows promise in reducing SUD risk factors for relapse (e.g. substance craving).•Further research investigating neuromodulation warrants consideration for SUD treatment.
Abstract 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. This article is part of a Special Issue entitled SI:Addiction circuits.
Theta-burst stimulation (TBS) is a form of non-invasive neuromodulation which is delivered in an intermittent (iTBS) or continuous (cTBS) manner. Although 600 pulses is the most common dose, the goal ...of these experiments was to evaluate the effect of higher per-dose pulse numbers on cortical excitability. Sixty individuals were recruited for 2 experiments. In Experiment 1, participants received 600, 1200, 1800, or sham (600) iTBS (4 visits, counterbalanced, left motor cortex, 80% active threshold). In Experiment 2, participants received 600, 1200, 1800, 3600, or sham (600) cTBS (5 visits, counterbalanced). Motor evoked potentials (MEP) were measured in 10-min increments for 60 min. For iTBS, there was a significant interaction between dose and time (F = 3.8296, p = 0.01), driven by iTBS (1200) which decreased excitability for up to 50 min (t = 3.1267, p = 0.001). For cTBS, there was no overall interaction between dose and time (F = 1.1513, p = 0.33). Relative to sham, cTBS (3600) increased excitability for up to 60 min (t = 2.0880, p = 0.04). There were no other significant effects of dose relative to sham in either experiment. Secondary analyses revealed high within and between subject variability. These results suggest that iTBS (1200) and cTBS (3600) are, respectively, the most effective doses for decreasing and increasing cortical excitability.
Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation tool currently used as a treatment in multiple psychiatric and neurologic disorders. Despite its widespread use, we have an ...incomplete understanding of the way in which acute and chronic sessions of TMS affect various neural and vascular systems. This systematic review summarizes the state of our knowledge regarding the effects TMS may be having on cerebral blood flow, glucose metabolism, and neurotransmitter release. Forty-five studies were identified. Several key themes emerged: 1) TMS transiently increases cerebral blood flow in the area under the coil; 2) TMS to the prefrontal cortex increases glucose metabolism in the anterior cingulate cortex of patients with depression; and 3) TMS to the motor cortex and prefrontal cortex decreases dopamine receptor availability in the ipsilateral putamen and caudate respectively. There is, however, a paucity of literature regarding the effects TMS may have on other neurotransmitter and neuropeptide systems of interest, all of which may shed vital light on existing biologic mechanisms and future therapeutic development. SIGNIFICANCE STATEMENT: Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation tool currently used as a treatment in multiple psychiatric and neurologic disorders. This systematic review summarizes the state of our knowledge regarding the effects TMS on cerebral blood flow, glucose metabolism, and neurotransmitter release.
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