Efficacy of inflammation-based stratification for add-on celecoxib or minocycline in major depressive disorder: Protocol of the INSTA-MD double-blind placebo-controlled randomised clinical trial.

Introduction: Different lines of evidence confirm the involvement of the immune system in the pathophysiology of major depressive disorder. Up to 30% of depressed patients present with an immune-mediated subtype, characterized by peripheral inflammation (high-sensitive C-reactive protein (hsCRP) ≥ 3 mg/l) and an atypical symptom profile with fatigue, anhedonia, increased appetite, and hypersomnia. This immune-mediated subtype of MDD is associated with poorer response to first-line antidepressant treatment. Consequently, strategies for immune-targeted augmentation should be prioritised towards patients with this subtype. Meta-analyses have shown modest but heterogeneous treatment effects with immune-targeted augmentation in unstratified MDD cohorts, with celecoxib and minocycline as most promising first-line treatment options. However, no study has prospectively evaluated the effectiveness of a priori stratification by baseline inflammation levels for add-on celecoxib or minocycline in MDD. Methods: The INSTA-MD trial is a multicentre, 12-week, randomised, double-blind, placebo-controlled, parallel-group stratified clinical trial of adjunctive minocycline or celecoxib to treatment-as-usual for patients with MDD. Two hundred forty adult patients with Major Depressive Disorder who failed to remit with one or two trials of antidepressant treatment will be enrolled and allocated to high-hsCRP (hsCRP ≥3 mg/L) or low-hsCRP (hsCRP <3 mg/L) strata, where disproportional stratified sampling will ensure equally sized strata. Participants in each hsCRP stratum will be randomised to augment their ongoing antidepressant treatment with either adjunctive minocycline, celecoxib or placebo for a duration of 12 weeks, resulting in six treatment arms of each 40 participants. The primary objective is to evaluate the efficacy of immune-targeted augmentation with minocycline or celecoxib versus placebo, and the use of baseline hsCRP stratification to predict treatment response. Additionally, we will perform a head-to-head analysis between the two active compounds. The primary outcome measure is change in the Hamilton Depression Rating Scale (HDRS-17) total score. Secondary outcome measures will be response and remission rates, and change in inflammation-specific symptoms, adverse events and therapy acceptability (adherence). Further exploratory analyses will be performed with an array of peripheral inflammatory biomarkers, metabolic outcomes and physiological data. Expected impact: The aim of INSTA-MD is to advance the use of immune-targeted precision psychiatry, by supporting the implementation of targeted hsCRP screening and treatment of immune-mediated MDD as a cost-effective intervention in primary care settings. Based on previous studies, we expect immune-targeted augmentation with minocycline or celecoxib to yield a superior remission rate of 15-30% compared to treatment as usual for immune-mediated cases of MDD. By treating immune-related depression early in the treatment algorithm with repurposed first-line anti-inflammatory treatments, we can significantly improve the outcomes of these patients, and reduce the global societal and economic burden of depression. Ethics and dissemination: This protocol has been approved by the Medical Ethics Review Board (CTR - 04/08/2023). Registration details: Trial registration number NCT05644301 (Clinical trial.gov), EU-CT 2022-501692-35-00.

A subgroup of light-driven sodium pumps with an additional Schiff base counterion.

Light-driven sodium pumps (NaRs) are unique ion-transporting microbial rhodopsins. The major group of NaRs is characterized by an NDQ motif and has two aspartic acid residues in the central region essential for sodium transport. Here we identify a subgroup of the NDQ rhodopsins bearing an additional glutamic acid residue in the close vicinity to the retinal Schiff base. We thoroughly characterize a member of this subgroup, namely the protein ErNaR from Erythrobacter sp. HL-111 and show that the additional glutamic acid results in almost complete loss of pH sensitivity for sodium-pumping activity, which is in contrast to previously studied NaRs. ErNaR is capable of transporting sodium efficiently even at acidic pH levels. X-ray crystallography and single particle cryo-electron microscopy reveal that the additional glutamic acid residue mediates the connection between the other two Schiff base counterions and strongly interacts with the aspartic acid of the characteristic NDQ motif. Hence, it reduces its pKa. Our findings shed light on a subgroup of NaRs and might serve as a basis for their rational optimization for optogenetics.

[Transcranial direct current stimulation in substance use disorders: an update]. / Transcraniële gelijkstroomstimulatie bij stoornissen in het gebruik van middelen: een update.

BACKGROUND: Existing treatments for substance use disorders are often subject to drop-out or relapse. Transcranial direct current stimulation (tDCS) possibly has a positive effect on this problem. AIM: To give an updated qualitative review of existing studies investigating the clinical effects of transcranial direct current stimulation for people with a substance use disorder, considering the many recently published studies. METHOD: Extensive literature search in the electronic database PubMed. We included 43 studies on top of the 7 studies already included in the previous review of Herremans and Baeken (2017) in this journal. RESULTS: The majority of the studies showed a positive effect of transcranial direct current stimulation on clinical measures as craving and abstinence. However, there was little uniformity in used protocols. CONCLUSION: Transcranial direct current stimulation can be an effective treatment for people with a substance use disorder. Optimal parameters need to be established to make the treatment maximally effective and adapted to the individual patient.

The optimized combination of aCompCor and ICA-AROMA to reduce motion and physiologic noise in task fMRI data.

One of the main challenges in fMRI processing is filtering the task BOLD signals from the noise. Independent component analysis with automatic removal of motion artifacts (ICA-AROMA) reduces motion artifacts by identifying ICA noise components based on their location at the brain edges and cerebrospinal fluid (CSF), high frequency content and correlation with motion regressors. In anatomical component correction (aCompCor), physiological noise regressors extracted from CSF were regressed out from the fMRI time series. In this study, we compared three methods to combine aCompCor and ICA-AROMA denoising in one denoising step. In the first analysis, we regressed the temporal signals of the ICA components identified as noise by ICA-AROMA together with the noise signals determined by aCompCor from the fMRI signals. For the second and third analyses, the correlation between the temporal signals of the ICA components and the aCompCor noise signals was used as an additional criterion to identify the noise components. In the second analysis, the temporal signals of the ICA components classified as noise were regressed from the fMRI signals. In the third analysis, the noise components were removed. To compare the denoising strategies, we examined the fractional amplitude of low-frequency fluctuations (fALFF) and the overlap between the contrast maps. Our results revealed that including the aCompCor noise signals as regressors in ICA-AROMA resulted in more correctly identified noise components, higher fALFF values, and larger activation maps. Moreover, combining the temporal signals of the noise components identified by ICA-AROMA with the aCompCor signals in a noise regression matrix resulted in deactivations. These results suggest that using the correlation between the ICA component temporal signals and the aCompCor signals as noise identification criteria in ICA-AROMA is the best approach for combining both denoising methods.

Na+-dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters.

Excitatory amino acid transporters (EAATs) harness [Na+], [K+], and [H+] gradients for fast and efficient glutamate removal from the synaptic cleft. Since each glutamate is cotransported with three Na+ ions, [Na+] gradients are the predominant driving force for glutamate uptake. We combined all-atom molecular dynamics simulations, fluorescence spectroscopy, and x-ray crystallography to study Na+:substrate coupling in the EAAT homolog GltPh A lipidic cubic phase x-ray crystal structure of wild-type, Na+-only bound GltPh at 2.5-Å resolution revealed the fully open, outward-facing state primed for subsequent substrate binding. Simulations and kinetic experiments established that only the binding of two Na+ ions to the Na1 and Na3 sites ensures complete HP2 gate opening via a conformational selection-like mechanism and enables high-affinity substrate binding via electrostatic attraction. The combination of Na+-stabilized gate opening and electrostatic coupling of aspartate to Na+ binding provides a constant Na+:substrate transport stoichiometry over a broad range of neurotransmitter concentrations.

Compulsory admissions of patients with mental disorders: State of the art on ethical and legislative aspects in 40 European countries.

BACKGROUND: Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care. METHODS: The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions. RESULTS: We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures. CONCLUSIONS: We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.

[Consensus statement on the application of rTMS in depression in the Netherlands and Belgium]. / Consensusverklaring voor de toepassing van rTMS bij depressie in Nederland en België.

BACKGROUND: Since 2017, repetitive transcranial magnetic stimulation (rTMS) has become eligible for reimbursement for the treatment of therapy-resistant depression in the Dutch healthcare system.
AIM: To initiate a guideline in the Netherlands and Belgium for the safe and effective application of rTMS for the treatment of depression.
METHOD: Based on literature review, existing guidelines and consensus among Dutch rTMS experts, recommendations were developed regarding the implementation of rTMS as a treatment of depression. All available evidence was weighed and discussed among all co-authors and recommendations were reached by consensus among the group.
RESULTS: rTMS targeting the dorsolateral prefrontal cortex (DLPFC) should be seen as a first choice in the treatment of depression using high-frequency rTMS (left) or, as an alternative, low-frequency rTMS (right). Stimulation protocols should use more than 1000 pulses per session for an average of 20-30 sessions, offered in 2-5 sessions per week. Contraindications for rTMS include epilepsy, intracranial presence of (magnetisable) metals, pacemaker and cochlear implant.
CONCLUSION: rTMS, performed by competent professionals is an effective and safe treatment for depression.

Cortical motor threshold determination in dogs.

In humans, determining the cortical motor threshold (CMT) is a critical step in successfully applying a transcranial magnetic stimulation (TMS) treatment. Stimulus intensity, safety and efficacy of a TMS treatment are dependent of the correct assessment of the CMT. Given that TMS in dogs could serve as a natural animal model, an accurate and reliable technique for the measurement of the CMT should be available for dogs. Using a visual descending staircase paradigm (Rossini paradigm), the CMT repeatability was assessed and compared to the electromyographic (EMG) variant. The influence of a HF-rTMS treatment on the CMT was examined. Subsequently, the CMT was measured under sedation and general anaesthesia. Finally, the coil-cortex distance was associated with the CMT, weight, age and gender. During one year the CMT was measured three times, during which it remained constant, although a higher CMT was measured (40% higher machine output) when using EMG (P-value < .001) and under general anaesthesia (P-value = .005). On average, a 40% and 12% higher machine output were registered. An aHF-rTMS protocol does not influence the CMT. Males have on average a 5.2 mm larger coil cortex distance and an 11.81% higher CMT. The CMT was positively linearly associated (P-value < .05) with the weight and age of the animals. Only within female subjects, a positive linear association was found between the CMT and the coil-cortex distance (P-value = .02). Using the visual Rossini paradigm, the CMT can be reliably used over time and during a TMS treatment. It has to be kept in mind that when using EMG or assessing the CMT under general anaesthesia, a higher CMT is to be expected. As in humans, every parameter that influences the coil-cortex distance may also influence the CMT.

Changes in canine cerebral perfusion after accelerated high frequency repetitive transcranial magnetic stimulation (HF-rTMS): A proof of concept study.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for several neuropsychiatric disorders in human beings, but the neurobiological effects of rTMS in dogs have not been investigated to date. A proof of concept study was designed to evaluate the effect of rTMS on cerebral perfusion, measured with single photon emission computed tomography (SPECT), in dogs. An accelerated high frequency (aHF)-rTMS (20Hz) protocol was applied to the canine left frontal cortex. To accurately target this area, eight dogs underwent a 3 Tesla magnetic resonance imaging (MRI) scan before stimulation. The left frontal cortex was subjected to five consecutive aHF-rTMS sessions with a figure-of-eight coil designed for human beings at an intensity of 110% of the motor threshold. The dogs underwent 99mTc-d,1 hexamethylpropylene amine oxime (HMPAO) SPECT scans 1 week prior to and 1day after the stimulations. Perfusion indices (PIs) were determined semi-quantitatively; aHF-rTMS resulted in significantly increased PIs in the left frontal cortex and the subcortical region, whereas no significant differences were noted for the other regions. Behaviour was not influenced by the stimulation sessions. As has been observed in human beings, aHF-rTMS applied to the left frontal cortex alters regional cerebral perfusion in dogs.

[Non-invasive brain stimulation techniques in psychiatric disorders: influential factors and combination of interventions]. / Niet-invasieve hersenstimulatie bij psychiatrische stoornissen: beïnvloedende factoren en combinatie van interventies.

BACKGROUND: The causal influence of cortico-subcortical connectivity by means of brain stimulation seems to be an effective biological treatment in psychiatric patients. AIM: To review the working mechanisms and moderating factors of two non-invasive brain stimulation techniques (NIBS), namely repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). METHOD: We reviewed the current literature on the use of nibs in neuropsychiatric disorders. RESULTS: First of all, stimulation parameters (location of the stimulation, intensity and duration of the stimulation, number of sessions) are important for the effect of nibs. Secondly, it is important to consider the non-specific neuroplasticity that results from NIBS. Thirdly, recent studies suggest that NIBS should be combined with neurobehavioral interventions, namely cognitive interventions, for the purpose of modulating specific neural processes (i.e. specific neuroplasticity). CONCLUSION: If we want to improve the NIBS treatment in neuropsychiatric patients, we need to consider the factors that influence the patients' response to treatment with rTMS and tDCS.

[Brain stimulation: the most direct form of neurostimulation]. / Hersenstimulatie: de meest directe vorm van neuromodulatie.

BACKGROUND: Brain stimulation is the most direct form of neuromodulation. Direct brain stimulation is an older procedure that has taken various forms, but 'non-invasive brain stimulation' is a more recent development. AIM: To provide an overview of the current arsenal of non-invasive brain stimulation techniques. METHOD: We discuss the underlying principles, the pros and cons, and the applicability of non-invasive brain stimulation in experimental research and treatment of neuropsychiatric disorders. RESULTS: Non-invasive brain stimulation is a direct form of neuromodulation, which is not invasive, harmful or painful. Its effects are in principle temporary, which makes the technique suitable for experimental research. At the same time, temporary effects can have lasting clinical consequences, if they target neuroplasticity to aid rehabilitation or alleviate symptoms. CONCLUSION: Whereas the value of non-invasive brain stimulation for research purposes is undisputed, its efficacy and value as a treatment for neuropsychiatric disorders are still being debated. Nevertheless, the accumulated evidence about the clinical efficacy of the treatment for certain disorders is sufficiently compelling to start thinking about European regulations and standard medical insurance coverage.