Romain Duprat

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission?

Although accelerated repetitive Transcranial Magnetic Stimulation (rTMS) paradigms and intermittent Theta-burst Stimulation (iTBS) may have the potency to result in superior clinical outcomes in Treatment Resistant Depression (TRD), accelerated iTBS treatment has not yet been studied. In this registered randomized double-blind sham-controlled crossover study, spread over four successive days, 50 TRD patients received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). The accelerated iTBS treatment procedure was found to be safe and resulted in immediate statistically significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham). While only 28% of the patients showed a 50% reduction of their initial Hamilton Depression Rating Scale score at the end of the two-week procedure, this response rate increased to 38% when assessed two weeks after the end of the sham-controlled iTBS protocol, indicating delayed clinical effects. Importantly, 30% of the responders were considered in clinical remission. We found no demographic predictors for response. Our findings indicate that only four days of accelerated iTBS treatment applied to the left DLPFC in TRD may lead to meaningful clinical responses within two weeks post stimulation.

The application of tDCS in psychiatric disorders: a brain imaging view

Background Transcranial direct current stimulation (tDCS) is a non-invasive, non-convulsive technique for modulating brain function. In contrast to other non-invasive brain stimulation techniques, where costs, clinical applicability, and availability limit their large-scale use in clinical practices, the low-cost, portable, and easy-to-use tDCS devices may overcome these restrictions. Objective Despite numerous clinical applications in large numbers of patients suffering from psychiatric disorders, it is not quite clear how tDCS influences the mentally affected human brain. In order to decipher potential neural mechanisms of action of tDCS in patients with psychiatric conditions, we focused on the combination of tDCS with neuroimaging techniques. Design We propose a contemporary overview on the currently available neurophysiological and neuroimaging data where tDCS has been used as a research or treatment tool in patients with psychiatric disorders. Results Over a reasonably short period of time, tDCS has been broadly used as a research tool to examine neuronal processes in the healthy brain. tDCS has also commonly been applied as a treatment application in a variety of mental disorders, with to date no straightforward clinical outcome and not always accompanied by brain imaging techniques. Conclusion tDCS, as do other neuromodulation devices, clearly affects the underlying neuronal processes. However, research on these mechanisms in psychiatric patients is rather limited. A better comprehension of how tDCS modulates brain function will help us to define optimal parameters of stimulation in each indication and may result in the detection of biomarkers in favor of clinical response.

Transcranial Direct Current Stimulation Over the Right Frontal Inferior Cortex Decreases Neural Activity Needed to Achieve Inhibition: A Double-Blind ERP Study in a Male Population.

Inhibitory control refers to the ability to inhibit an action once it has been initiated. Impaired inhibitory control plays a key role in triggering relapse in some pathological states, such as addictions. Therefore, a major challenge of current research is to establish new methods to strengthen inhibitory control in these “high-risk” populations. In this attempt, the right inferior frontal cortex (rIFC), a neural correlate crucial for inhibitory control, was modulated using transcranial direct current stimulation (tDCS). Healthy participants (n = 31) were presented with a “Go/No-go” task, a well-known paradigm to measure inhibitory control. During this task, an event-related potential (ERP) recording (T1; 32 channels) was performed. One subgroup (n = 15) was randomly assigned to a condition with tDCS (anodal electrode was placed on the rIFC and the cathodal on the neck); and the other group (n = 16) to a condition with sham (placebo) tDCS. After one 20- minute neuromodulation session, all participants were confronted again with the same ERP Go/No-go task (T2). To ensure that potential tDCS effects were specific to inhibition, ERPs to a face-detection task were also recorded at T1 and T2 in both subgroups. The rate of commission errors on the Go/No-go task was similar between T1 and T2 in both neuromodulation groups. However, the amplitude of the P3d component, indexing the inhibition function per se, was reduced at T2 as compared with T1. This effect was specific for participants in the tDCS (and not sham) condition for correctly inhibited trials. No difference in the P3 component was observable between both subgroups at T1 and T2 for the face detection task. Overall, the present data indicate that boosting the rIFC specifically enhances inhibitory skills by decreasing the neural activity needed to correctly inhibit a response.

Accelerated Intermittent Theta Burst Stimulation for Suicide Risk in Therapy-Resistant Depressed Patients: A Randomized, Sham-Controlled Trial

Objectives: We aimed to examine the effects and safety of accelerated intermittent Theta Burst Stimulation (iTBS) on suicide risk in a group of treatment-resistant unipolar depressed patients, using an extensive suicide assessment scale. Methods: In 50 therapy-resistant, antidepressant-free depressed patients, an intensive protocol of accelerated iTBS was applied over the left dorsolateral prefrontal cortex (DLPFC) in a randomized, sham-controlled crossover design. Patients received 20 iTBS sessions over 4 days. Suicide risk was assessed using the Beck Scale of Suicide ideation (BSI). Results: The iTBS protocol was safe and well tolerated. We observed a significant decrease of the BSI score over time, unrelated to active or sham stimulation and unrelated to depression-response. No worsening of suicidal ideation was observed. The effects of accelerated iTBS on mood and depression severity are reported in Duprat et al. (2016). The decrease in suicide risk lasted up to 1 month after baseline, even in depression non-responders. Conclusions: This accelerated iTBS protocol was safe. The observed significant decrease in suicide risk was unrelated to active or sham stimulation and unrelated to depression response. Further sham-controlled research in suicidal depressed patients is necessary. (Clinicaltrials.gov identifier: NCT01832805).

Subgenual Anterior Cingulate–Medial Orbitofrontal Functional Connectivity in Medication-Resistant Major Depression: A Neurobiological Marker for Accelerated Intermittent Theta Burst Stimulation Treatment?

BACKGROUND Accelerated repetitive transcranial magnetic stimulation paradigms have been shown to result in fast decreases in depressive symptoms and suicidal ideation. Although the subgenual anterior cingulate cortex (sgACC) region has been put forward as a possible biological marker, so far, no studies evaluated the clinical effects of accelerated intermittent theta burst stimulation (aiTBS) on sgACC functional connectivity (FC). METHODS Fifty patients with treatment-resistant depression were enrolled in this registered randomized double-blind sham-controlled crossover aiTBS treatment study. All received 20 iTBS sessions applied to the left dorsolateral prefrontal cortex (5 daily sessions spread over 4 days). Forty-four complete resting-state functional magnetic resonance imaging scans were collected. Baseline resting-state functional magnetic resonance imaging scans were compared with a matched healthy control group. Besides depression severity, all patients were also assessed with the Scale for Suicide Ideation and the Beck Hopelessness Scale. RESULTS Our main resting-state functional magnetic resonance imaging findings indicate that a positive sgACC FC correlation with the medial orbitofrontal cortex could distinguish aiTBS responders from nonresponders at baseline. Beneficial aiTBS treatment strengthened sgACC-medial orbitofrontal cortex FC patterns. Moreover, this increased FC pattern was associated with a decrease in feelings of hopelessness. CONCLUSIONS Clinical response to aiTBS treatment is not only characterized by stronger FC patterns between the sgACC and the medial orbitofrontal cortex, but it is also associated with decreases in hopelessness. Our observations provide a possible neurobiological explanation why accelerated repetitive transcranial magnetic stimulation paradigms may result in prompt attenuation of negative thinking in depressed patients.

Self-directedness: An indicator for clinical response to the HF-rTMS treatment in refractory melancholic depression

Although well-defined predictors of response are still unclear, clinicians refer a variety of depressed patients for a repetitive Transcranial Magnetic Stimulation (rTMS) treatment. It has been suggested that personality features such as Harm Avoidance (HA) and self-directedness (SD) might provide some guidance for a classical antidepressant treatment outcome. However, to date no such research has been performed in rTMS treatment paradigms. In this open study, we wanted to examine whether these temperament and character scores in particular would predict clinical outcome in refractory unipolar depressed patients when a typical high-frequency (HF)-rTMS treatment protocol is applied. Thirty six unipolar right-handed antidepressant-free treatment resistant depressed (TRD) patients, all of the melancholic subtype, received 10 HF-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC). All patients were classified as at least stage III TRD and were assessed with the Temperament and Character Inventory (TCI) before a HF-rTMS treatment. Only the individual scores on SD predicted clinical outcome. No other personality scales were found to be a predictor of this kind of application. Our results suggest that refractory MDD patients who score higher on the character scale SD may be more responsive to the HF-rTMS treatment.

Left prefrontal neuronavigated electrode localization in tDCS : 10-20 EEG system versus MRI-guided neuronavigation

Transcranial direct current stimulation (tDCS) involves positioning two electrodes at specifically targeted locations on the human scalp. In neuropsychiatric research, the anode is often placed over the left dorsolateral prefrontal cortex (DLPFC), while the cathode is positioned over a contralateral cephalic region above the eye, referred-to as the supraorbital region. Although the 10-20 EEG system is frequently used to locate the DLPFC, due to inter-subject brain variability, this method may lack accuracy. Therefore, we compared in forty participants left DLPFC-localization via the 10-20 EEG system to MRI-guided neuronavigation. In one participant, with individual electrode positions in close proximity to the mean electrode position across subjects, we also investigated whether distinct electrode localizations were associated with different tDCS-induced electrical field distributions. Furthermore, we aimed to examine which neural region is targeted when placing the reference-electrode on the right supraorbital region. Compared to the 10-20 EEG system, MRI-guided neuronavigation localizes the DLPFC-targeting anode more latero-posteriorly, targeting the middle prefrontal gyrus. tDCS-induced electric fields (n = 1) suggest that both localization methods induce significantly different electric fields in distinct brain regions. Considering the frequent application of tDCS as a neuropsychiatric treatment, an evaluation and direct comparison of the clinical efficacy of targeting methods is warranted.

Accurate external localization of the left frontal cortex in dogs by using pointer based frameless neuronavigation

Background In humans, non-stereotactic frameless neuronavigation systems are used as a topographical tool for non-invasive brain stimulation methods such as Transcranial Magnetic Stimulation (TMS). TMS studies in dogs may provide treatment modalities for several neuropsychological disorders in dogs. Nevertheless, an accurate non-invasive localization of a stimulation target has not yet been performed in this species. Hypothesis This study was primarily put forward to externally locate the left frontal cortex in 18 healthy dogs by means of a human non-stereotactic neuronavigation system. Secondly, the accuracy of the external localization was assessed. Animals A total of 18 healthy dogs, drawn at random from the research colony present at the faculty of Veterinary Medicine (Ghent University), were used. Methods Two sets of coordinates (X, Y, Z and X″, Y″, Z″) were compared on each dog their tomographical dataset. Results The non-stereotactic neuronavigation system was able to externally locate the frontal cortex in dogs with accuracy comparable with human studies. Conclusion and clinical importance This result indicates that a non-stereotactic neuronavigation system can accurately externally locate the left frontal cortex and paves the way to use guided non-invasive brain stimulation methods as an alternative treatment procedure for neurological and behavioral disorders in dogs. This technique could, in analogy with human guided non-invasive brain stimulation, provide a better treatment outcome for dogs suffering from anxiety disorders when compared to its non-guided alternative.

Intermittent Theta Burst Stimulation Increases Reward Responsiveness in Individuals with Higher Hedonic Capacity.

Background: Repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex (DLPFC) has been documented to influence striatal and orbitofrontal dopaminergic activity implicated in reward processing. However, the exact neuropsychological mechanisms of how DLPFC stimulation may affect the reward system and how trait hedonic capacity may interact with the effects remains to be elucidated. Objective: In this sham-controlled study in healthy individuals, we investigated the effects of a single session of neuronavigated intermittent theta burst stimulation (iTBS) on reward responsiveness, as well as the influence of trait hedonic capacity. Methods: We used a randomized crossover single session iTBS design with an interval of 1 week. We assessed reward responsiveness using a rewarded probabilistic learning task and measured individual trait hedonic capacity (the ability to experience pleasure) with the temporal experience of pleasure scale questionnaire. Results: As expected, the participants developed a response bias toward the most rewarded stimulus (rich stimulus). Reaction time and accuracy for the rich stimulus were respectively shorter and higher as compared to the less rewarded stimulus (lean stimulus). Active or sham stimulation did not seem to influence the outcome. However, when taking into account individual trait hedonic capacity, we found an early significant increase in the response bias only after active iTBS. The higher the individuals trait hedonic capacity, the more the response bias toward the rich stimulus increased after the active stimulation. Conclusion: When taking into account trait hedonic capacity, one active iTBS session over the left DLPFC improved reward responsiveness in healthy male participants with higher hedonic capacity. This suggests that individual differences in hedonic capacity may influence the effects of iTBS on the reward system.

Accelerated iTBS treatment in depressed patients differentially modulates reward system activity based on anhedonia

Abstract Objectives: Accelerated intermittent theta-burst stimulation (aiTBS) anti-depressive working mechanisms are still unclear. Because aiTBS may work through modulating the reward system and the level of anhedonia may influence this modulation, we investigated the effect of aiTBS on reward responsiveness in high and low anhedonic MDD patients. Methods: In this registered RCT (NCT01832805), 50 MDD patients were randomised to a sham-controlled cross-over aiTBS treatment protocol over the left dorsolateral prefrontal cortex (DLPFC). Patients performed a probabilistic learning task in fMRI before and after each week of stimulation. Results: Task performance analyses did not show any significant effects of aiTBS on reward responsiveness, nor differences between both groups of MDD patients. However, at baseline, low anhedonic patients displayed higher neural activity in the caudate and putamen. After the first week of aiTBS treatment, in low anhedonic patients we found a decreased neural activity within the reward system, in contrast to an increased activity observed in high anhedonic patients. No changes were observed in reward related neural regions after the first week of sham stimulation. Conclusions: Although both MDD groups showed no differences in task performance, our brain imaging findings suggest that left DLPFC aiTBS treatment modulates the reward system differently according to anhedonia severity.