Bifrontal tDCS applied to the dorsolateral prefrontal cortex in heavy drinkers: Influence on reward-triggered approach bias and alcohol consumption.

Even though the ventromedial neural network (reward pathway) has been well documented to be a mediator for increased craving, the prefrontal cortex is receiving ever more attention for craving monitoring. In the current study, we examined whether causal modulation of the prefrontal cortex, and its associated neural network, diminishes reward-triggered approach bias (due to increased cognitive control), alcohol craving and consumption. Using a double-blind within-subjects design in a subclinical group of forty-five heavy drinkers, a single sham controlled session of bilateral transcranial direct current stimulation (tDCS) was applied to the dorsolateral prefrontal cortex (DLPFC). Following real and sham tDCS placing the anode over the right and cathode over the left DLPFC, a rewarded Go/NoGo paradigm was administrated to provoke behavioral biases (irrespective of the task goal) After the cognitive paradigm, alcohol consumption was examined using a beer taste test. Bifrontal tDCS resulted in a reduced reward-triggered approach bias and reduced alcohol consumption, but not self-reported craving. Interestingly, reward-triggered approach bias and alcohol consumption were reliably associated in the sham condition, but not in the tDCS condition. Reward-trigged approach biases might be a cognitive mechanism associated with alcohol prone behavior, and the role of the prefrontal network may be significant.

Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine: A consensus paper on the present state of the science and the road ahead.

There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

The effect of nicotine patches on craving in the brain: A functional MRI study on heavy smokers.

BACKGROUND: Smoking is a common phenomenon and kills over 6 million people every year. Many smokers try to quit smoking by using nicotine replacement therapy (NRT). Most of the time, relapse occurs in less than six months after finishing the program of NRT. We performed a single blinded study in which our aim was to figure out what the effect of the nicotine patch is on craving in the brain of smokers deprived from smoking. METHODS: Five heavy smokers (Fagerström Test for Nicotine Dependence ≥4) underwent a functional magnetic resonance imaging (fMRI) in 4 random conditions: smoking (S); smoking deprivation (SD); SD combined with a NP (SD + NP); SD combined with a placebo patch (SD + PP). Visual stimulation provoked craving in block design by randomly displaying images of smoking related scenes. After image preprocessing, a fixed-effect analysis was performed to compare average group activations. The Questionnaire for Smoking Urges (QSU) was obtained before and after each scan. RESULTS: The fMRI results showed higher activation in areas involved in craving in S compared with SD + NP, SD + PP, and SD. In the SD + NP, limbic circuit and attention area were higher activated compared with SD and SD + PP. The SD + PP and SD showed higher activation in the frontal cortex and limbic system compared with S and SD + NP. Nonsmokers showed higher limbic activation compared with SD.The QSU increased significantly after the fMRI experiment in S (P = .036).The SD had higher QSU scores compared with the S before (P = .002), and also after (P = .022) the fMRI experiment. The NP showed lower scores than the SD before the experiment (P = .046). CONCLUSION: The fMRI experiment revealed lower activity in areas associated with attention when subjects were nicotine deprived (SD + PP and SD). Areas involved with craving showed less activity when nicotine is present (S and SD + NP). The QSU showed a significant difference between SD and when nicotine is present (S and SD + NP).

Accelerated repetitive transcranial magnetic stimulation does not influence grey matter volumes in regions related to alcohol relapse: An open-label exploratory study.

The application of repetitive transcranial magnetic stimulation (rTMS) to prevent relapse in alcohol addiction is currently being evaluated. However, how rTMS may influence the related brain processes is far from clear. Here we wanted to investigate whether baseline grey matter volume (GMV) can predict relapse and whether 15 accelerated high-frequency (HF)- rTMS sessions may influence GMV in areas related to relapse. Voxel-based morphometric (VBM) measurements were used to compare baseline GMV of 22 detoxified, hospitalized, alcohol-dependent patients with 22 age and gender matched healthy control subjects. Only patients received 15 accelerated HF-rTMS sessions at the right dorsolateral prefrontal cortex (DLPFC) followed by VBM measurements. Relapse rates were assessed four weeks after the end of the stimulation protocol. At baseline, alcohol-dependent patients overall showed less GMV in diffuse brain areas compared to healthy controls. Relapsers compared to abstainers displayed larger GMV decreases, especially in brain midline structures, insular, hippocampal, and amygdalar areas. Accelerated HF-rTMS treatment had no significant effect on GMV in alcohol-dependent patients, regardless of the relapse state. Although an accelerated HF-rTMS treatment protocol did not influence GMV in alcohol-dependent patients, baseline GMV predicted future relapse.

Facing temptation: The neural correlates of gambling availability during sports picture exposure.

Nowadays, sports betting has become increasingly available and easy to engage in. Here we examined the neural responses to stimuli that represent sporting events available for betting as compared to sporting events without a gambling opportunity. We used a cue exposure task in which football (soccer) fans (N = 42) viewed cues depicting scheduled football games that would occur shortly after the scanning session. In the "betting" condition, participants were instructed to choose, at the end of each block, the game (and the team) they wanted to bet on. In the "watching" condition, participants chose the game they would prefer to watch. After the scanning session, participants completed posttask rating questionnaires assessing, for each cue, their level of confidence about the team they believed would win and how much they would enjoy watching the game. We found that stimuli representing sport events available for betting elicited higher fronto-striatal activation, as well as higher insular cortex activity and functional connectivity, than sport events without a gambling opportunity. Moreover, games rated with more confidence towards the winning team resulted in greater brain activations within regions involved in affective decision-making (ventromedial prefrontal cortex), cognitive inhibitory control (medial and superior frontal gyri) and reward processing (ventral and dorsal striatum). Altogether, these novel findings offer a sensible simulation of how the high availability of sports betting in today's environment impacts on the reward and cognitive control systems. Future studies are needed to extend the present findings to a sample of football fans that includes a samilar proportion of female and male participants.

Anti-NMDA receptor encephalitis: still unknown and underdiagnosed by physicians and especially by psychiatrists?

Anti-NMDA receptor encephalitis is an autoimmune disorder confirmed by the presence of antibodies against the NMDA-receptor in serum or CSF. This case report describes a young woman with anti-NMDA receptor encephalitis, who presented with prominent psychiatric symptoms. There was a crucial delay in diagnosis and necessary treatment due to the fact that the clinical presentation was diagnosed and treated as a first psychotic episode. Physicians and especially psychiatrists, should consider the possibility of an autoimmune encephalitis in their differential diagnosis in every new onset psychotic episode with rapid progression, the presence of pathognomonic orofacial dyskinesia, the lack of psychiatric history, and the non-responding to psychopharmacological treatment. Early diagnosis and treatment is essential for recovery and may improve the prognosis.

Pseudomalabsorption of Levothyroxine: A Challenge for the Endocrinologist in the Treatment of Hypothyroidism.

BACKGROUND: Hypothyroidism due to non-compliance with levothyroxine therapy (pseudomalabsorption) is rare. The diagnosis is considered in patients with persistent severe hypothyroidism despite treatment with large doses of levothyroxine. Intestinal malabsorption, drug and dietary interference with levothyroxine absorption and nephrotic syndrome should be excluded. The diagnosis of pseudomalabsorption can be demonstrated by using "an oral 1,000 µg of levothyroxine test" showing a rapid decrease in thyroid-stimulating hormone and increase in thyroxine. There are however few data on the sensitivity and specificity of the test in large cohorts of hypothyroid patients. Treatment of pseudomalabsorption is controversial, with reports using parenteral, intramuscular or single weekly oral dosing of levothyroxine. CASES: We report 3 patients who presented with persistent clinical and biochemical signs of hypothyroidism despite replacement therapy with high doses of levothyroxine. Pseudomalabsorption was diagnosed by a systematic approach, including prior exclusion of digestive, liver and kidney diseases. A peroral challenge test was positive in all cases. Patients denied non-compliance, and a psychiatric approach was elusive. Two of the patients were treated successfully with a single supervised weekly 1,000-µg administration of levothyroxine, while non-supervised weekly administration resulted in hypothyroidism confirming pseudomalabsorption. CONCLUSIONS: Non-compliance with medical therapy should be considered in patients with treatment-refractory hypothyroidism. Supervised once weekly levothyroxine treatment is a safe and well-tolerated treatment option, obviating the need for parenteral administration of the drug. Apart from the medical treatment, there is also a need for psychiatric evaluation and care.

Accelerated HF-rTMS Protocol has a Rate-Dependent Effect on dACC Activation in Alcohol-Dependent Patients: An Open-Label Feasibility Study.

BACKGROUND: The application of accelerated high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) could be a potential treatment option for alcohol-dependent patients and may result in a faster clinical response. In this open-label HF-rTMS feasibility study, we wanted to replicate previous findings of baseline brain activation as a predictor of relapse, and to evaluate how this intervention influences the relapse neurocircuit of "treatment-seeking" alcohol-dependent patients, by means of functional magnetic resonance imaging (fMRI) cue-exposure paradigms. Because relapsing patients have a diminished resilience of the emotion regulation/cognitive control system, before HF-rTMS treatment, we expected lower neuronal activation of especially the ventromedial prefrontal cortex and anterior cingulate cortex (ACC) during the presentation of alcohol-related cues in these patients. The relapse neurocircuit should be modified after accelerated HF-rTMS treatment, only in those patients who did not relapse. METHODS: After being administered a single sham-controlled HF-rTMS session (20 Hz to 110% motor threshold), 19 alcohol-dependent patients received an accelerated HF-rTMS protocol, consisting of 14 right dorsolateral prefrontal cortical sessions spread over 3 days. Before and after stimulation, during fMRI patients were confronted with a block and an event-related alcoholic cue-exposure paradigm. Relapse was defined as the consumption of any amount of alcohol within 4 weeks after the stimulation. A region of interest analysis was performed to evaluate how HF-rTMS exerts its effect. RESULTS: After 4 weeks, 13 of 19 patients had already consumed alcohol. When abstainers were compared to patients who had relapsed, we found higher dorsal ACC (dACC) activation at baseline, but only during the blocked cue-exposure paradigm. The effects of HF-rTMS on dACC blood oxygen level-dependent response were negatively correlated with the baseline dACC activation. Due to susceptibility artifacts located at the ventral cortical aspects in 6 of our participants, reliable data were only obtained for the ACC. CONCLUSIONS: Our data indicate that higher baseline dACC activation may serve as a protective mechanism regarding relapse. For the first time, it is demonstrated that accelerated HF-rTMS treatment influences dACC activation in a rate-dependent manner: the lower the baseline dACC activation, the more dACC activity was increased after HF-rTMS treatment.

The Impact of Accelerated Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Cue-Reactivity: An fMRI Study on Craving in Recently Detoxified Alcohol-Dependent Patients.

In alcohol-dependent patients craving is a difficult-to-treat phenomenon. It has been suggested that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) may have beneficial effects. However, exactly how this application exerts its effect on the underlying craving neurocircuit is currently unclear. In an effort to induce alcohol craving and to maximize detection of HF-rTMS effects to cue-induced alcohol craving, patients were exposed to a block and event-related alcohol cue-reactivity paradigm while being scanned with fMRI. Hence, we assessed the effect of right dorsolateral prefrontal cortex (DLPFC) stimulation on cue-induced and general alcohol craving, and the related craving neurocircuit. Twenty-six recently detoxified alcohol-dependent patients were included. First, we evaluated the impact of one sham-controlled stimulation session. Second, we examined the effect of accelerated right DLPFC HF-rTMS treatment: here patients received 15 sessions in an open label accelerated design, spread over 4 consecutive days. General craving significantly decreased after 15 active HF-rTMS sessions. However, cue-induced alcohol craving was not altered. Our brain imaging results did not show that the cue-exposure affected the underlying craving neurocircuit after both one and fifteen active HF-rTMS sessions. Yet, brain activation changes after one and 15 HF-rTMS sessions, respectively, were observed in regions associated with the extended reward system and the default mode network, but only during the presentation of the event-related paradigm. Our findings indicate that accelerated HF-rTMS applied to the right DLPFC does not manifestly affect the craving neurocircuit during an alcohol-related cue-exposure, but instead it may influence the attentional network.

Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients.

BACKGROUND: Major depression is a worldwide severe mental health problem. Unfortunately, not all depressed patients respond to pharmacotherapy or psychotherapy, even when adhering to treatment guidelines. Even though current guidelines do not in particular advocate repetitive Transcranial Magnetic Stimulation (rTMS) in refractory treatment resistant depression (TRD), using more intensive stimulation parameters might hold promise as a valuable alternative. OBJECTIVE: Consequently, in this randomized sham-controlled crossover study, we wanted to evaluate clinical outcome of intensive HF-rTMS treatment in TRD when applied to the left dorsolateral prefrontal cortex (DLPFC). METHODS: After a 2-week antidepressant washout, 20 unipolar TRD patients, at least stage III, received 20 sham-controlled high-frequency (HF)-rTMS sessions, in a crossover design. Five daily suprathreshold HF-rTMS sessions were spread over four successive days delivering in total 31,200 stimuli. RESULTS: Overall, the procedure resulted in immediate statistical significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham), suggesting possible placebo responses. On the other hand, albeit only 35% (7/20) of the patients showed a 50% reduction of their initial Hamilton Depression rating score at the end of the two-week procedure, all these patients showed a prompt clinical response after real HF-rTMS treatment, not after sham. Furthermore, a shorter duration of the current depressive episode was a predictor for beneficial clinical outcome. Unresponsiveness to former ECT could be indicative for negative clinical outcome in these kinds of patients. LIMITATIONS: Single center setup with relatively small sample size and no follow-up. CONCLUSIONS: Our findings indicate that intensive HF-rTMS treatment might have the potential to result in fast clinical response when confronted with a refractory TRD patient.

The current perspective of neuromodulation techniques in the treatment of alcohol addiction: a systematic review.

BACKGROUND: Alcohol dependency can be considered as a chronic mental disorder characterized by frequent relapses even when treated with appropriate medical or psychotherapeutic interventions. Here, the efficacy of different neuromodulation techniques in alcohol addiction, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), vagal nerve stimulation (VNS) and electroconvulsive therapy (ECT) is critically evaluated. METHODS: A broad literature search on electronic databases such as NCBI PubMed, the Web of Knowledge, the Cochrane Library was conducted. Additionally, we searched recent handbooks on neuromodulation and/or addiction. RESULTS: Studies investigating these neuromodulation techniques in alcohol addiction remain to date rather limited and especially tDCS and rTMS applications have been investigated. Overall, the clinical effects seem modest. The use of VNS and ECT has yet to be investigated in alcohol dependent patients. CONCLUSIONS: Neuromodulation techniques have only recently been subject to investigation in alcohol addiction and methodological differences between the few studies restrict clear-cut conclusions. Nevertheless, the scarce results encourage further investigation in alcohol addiction.