A Research Domain Criteria Approach to Gambling Disorder and Behavioral Addictions: Decision-Making, Response Inhibition, and the Role of Cannabidiol.

Gambling Disorder (GD) has been recently re-classified in the DSM-5 under the "substance-related and addictive disorders," in light of its genetic, endophenotypic, and phenotypic resemblances to substance dependence. Diminished control is a core defining concept of psychoactive substance dependence or addiction and has given rise to the concept of "behavioral" addictions, which are syndromes analogous to substance addiction, but with a behavioral focus other than ingestion of a psychoactive substance. The main symptom clusters are represented by loss of control, craving/withdrawal, and neglect of other areas of life, whereas in a Research Domain Criteria (RDoC) perspective, GD patients exhibit deficits in the domain of "Positive valence systems," particularly in the "Approach motivation" and "Reward learning" constructs, as well as in the "Cognitive systems," primarily in the "Cognitive control" construct. In the Addictions Neuroclinical Assessment (ANA), three relevant domains for addictions emerge: "Incentive salience," "Negative Emotionality," and "Executive Function." The endocannabinoid system (ECS) may largely modulate these circuits, presenting a promising pharmaceutical avenue for treating addictions. Up to now, research on cannabidiol has shown some efficacy in Attention Deficit/Hyperactivity Disorder (ADHD), whereas in behavioral addictions its role has not been fully elucidated, as well as its precise action on RDoC domains. Herein, we review available evidence on RDoC domains affected in GD and behavioral addictions and summarize insights on the use of cannabidiol in those disorders and its potential mechanisms of action on reward, decisional, and sensorimotor processes.

Manifesto for an ECNP Neuromodulation Thematic Working Group (TWG): Non-invasive brain stimulation as a new Super-subspecialty.

Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from "mental" to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment.. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new "Super-Specialty" and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP).

Obsessive compulsive and related disorders: comparing DSM-5 and ICD-11.

Obsessive-compulsive disorder (OCD) has been recognized as mainly characterized by compulsivity rather than anxiety and, therefore, was removed from the anxiety disorders chapter and given its own in both the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the Beta Draft Version of the 11th revision of the World Health Organization (WHO) International Classification of Diseases (ICD-11). This revised clustering is based on increasing evidence of common affected neurocircuits between disorders, differently from previous classification systems based on interrater agreement. In this article, we focus on the classification of obsessive-compulsive and related disorders (OCRDs), examining the differences in approach adopted by these 2 nosological systems, with particular attention to the proposed changes in the forthcoming ICD-11. At this stage, notable differences in the ICD classification are emerging from the previous revision, apparently converging toward a reformulation of OCRDs that is closer to the DSM-5.

Better than treated as usual: Transcranial magnetic stimulation augmentation in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder, mini-review and pilot open-label trial.

OBJECTIVE: 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area has been shown to be effective in a subset of obsessive-compulsive disorder (OCD) subjects, yet these results are still to be confirmed. This preliminary study compares the efficacy of augmentation with 1 Hz rTMS over the supplementary motor area and the usual augmentation treatment (TAU; treated as usual) with antipsychotics in a sample of selective serotonin reuptake inhibitor (SSRI)-refractory OCD patients. METHOD: Fifty SSRI-refractory OCD patients consecutively admitted were studied: 25 were treated with a three-week trial of 1Hz, bilateral rTMS over the supplementary motor area and 25 with antipsychotic drugs. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; primary outcome measure), Hamilton Depression and Hamilton Anxiety scales were administered at first, second and third week of treatment. RESULTS: Y-BOCS showed a statistically significant time effect from the baseline to the third week, with a 68% of responders (Y-BOCS score reduction of ⩾ 25%), in comparison with 24.0% in the TAU group. In the rTMS group, 17.6% of patients achieved remission. CONCLUSIONS: 1 Hz rTMS over the supplementary motor area appeared to be effective in approximately 2/3 of SSRI-refractory OCD subjects, whereas in the TAU group only 1/4 of subjects were responders. The supplementary motor area might be a new target area to be further explored with neuromodulation for OCD treatment.

Transcranial magnetic stimulation for the treatment of pharmacoresistant nondelusional auditory verbal hallucinations in dementia.

Auditory verbal hallucinations (AVHs) are known as a core symptom of schizophrenia, but also occur in a number of other conditions, not least in neurodegenerative disorders such as dementia. In the last decades, Transcranial Magnetic Stimulation (TMS) emerged as a valuable therapeutic approach towards several neurological and psychiatric diseases, including AVHs. Herein we report a case of a seventy-six-years-old woman with vascular-degenerative brain disease, complaining of threatening AVHs. The patient was treated with a high-frequency temporoparietal (T3P3) rTMS protocol for fifteen days. A considerable reduction of AVHs in frequency and content (no more threatening) was observed. Although further research is needed, this seems an encouraging result.

Effect of hypoxic acclimation on anoxia tolerance in Vitis roots: response of metabolic activity and K+ fluxes.

The effect of a hypoxic pre-treatment (HPT) on improving tolerance to prolonged anoxia conditions in two contrasting Vitis species (V. riparia, anoxia tolerant; V. rupestris, anoxia sensitive) was evaluated. The energy economy of root cells was studied by measuring heat production, the activity of pyruvate decarboxylase (PDC) and alcohol dehdrogenase (ADH), ethanol and ATP production, and K(+) fluxes. The results showed that HPT is an effective tool in order to maintain a sustainable metabolic performance in both the species under anoxia conditions, especially in sensitive species such as V. rupestris. Our results showed that the improved tolerance was mainly driven by: (i) an enhanced activity of key enzymes in alcohol fermentation (ADC and PDC); (ii) the capability to maintain a higher level of respiration, evidenced by a lesser decrease in heat development and ATP production; and (iii) the maintenance of a better ion homeostasis (highlighted by measurement of K(+) fluxes) and K(+) channel functionality.

Phospholipase dzeta2 drives vesicular secretion of auxin for its polar cell-cell transport in the transition zone of the root apex.

Auxin (IAA) is versatile signalling molecule of plants, currently classified as plant hormone. But there are data suggesting that auxin is acting also as plant-specific morphogen, electric-responses inducing transmitter, and as general signalling molecule used for plant-bacteria communication. Our previous data revealed that auxin is associated with secretory endosomes and also highly enriched within cell walls of cells active in transcellular auxin transport. Our present data, based on in vivo non-invasive auxin flux recordings, reveal that auxin is secreted out of synaptic-like domains specialized for efflux of auxin in root apex cells highly active in polar cell-cell transport of auxin. We obtained both genetic and pharmacological evidence that phospholipase Dzeta2 drives vesicular secretion of auxin for its polar transcellular transport in the transition zone of the root apex. Secretion of auxin via secretory vesicles has far-reaching consequences not only for our understanding of cell-cell auxin transport but also for plant sciences as a whole.

Mixture design in the optimization of a microemulsion system for the electrokinetic chromatographic determination of ketorolac and its impurities: method development and validation.

Microemulsion EKC (MEEKC) was used for the determination of ketorolac and its three impurities. The microemulsion system was optimized, for the first time in the literature, using a multivariate strategy involving a mixture design. A 13-run experimental plan covering an experimental domain defined by the components aqueous phase (10 mM borate buffer pH 9.2), oil phase (n-heptane) and surfactant/cosurfactant (SDS/n-butanol) was carried out. Good results were obtained with all microemulsions tested considering as responses analysis time and resolution, and according to the desirability function the best microemulsion system was constituted by 90.0% 10 mM borate buffer, 2.0% n-heptane, 8.0% of SDS/n-butanol in 1:2 ratio. Finally, with the aim of reducing analysis time, a response surface study was carried out in the experimental domain defined by the process variables temperature and voltage and the best values were 17 degrees C and -17 kV, respectively. Applying the optimised conditions, a complete resolution among the analytes was obtained in about 3 min using the short-end injection method. The method was validated for both drug substances and drug product and was applied to the quality control of ketorolac in coated tablets. A comparison of MEEKC, MEKC and CEC for assaying ketorolac and its related substances has been made.

Adaptative response of Vitis root to anoxia.

The effect of anoxia on the energy economy of root cells was studied by measuring heat production, ethanol and ATP production, K(+) fluxes and electrical activity in two Vitis species, V. riparia and V. rupestris, that differ in their tolerance to anoxia. Anoxia triggered a marked decrease of metabolic activity (measured by microcalorimetry) and of ATP levels in both species. In V. riparia after the first 2 h of anoxia, the decrease in the rate of heat production was not associated with a further significant decrease in ATP content, whereas in V. rupestris the ATP level continued to decrease until very low values were reached. The concomitant increase in the rate of ethanol production did not compensate for the decreased aerobic ATP supply. In V. rupestris, anoxia typically led to energy deficit and ATP imbalance, together with the subsequent disruption of ion homeostasis and cell death. In V. riparia, the strong decrease in K(+) membrane permeability together with the fast down-regulation of the electrical signals allowed the cells to avoid severe ion imbalances during prolonged anoxic episodes.

Noninvasive and continuous recordings of auxin fluxes in intact root apex with a carbon nanotube-modified and self-referencing microelectrode.

Auxin (also known as indole-3-acetic acid, IAA) represents an ancient signaling molecule of plants that also exerts bioactive actions on yeast and animal cells. Importantly, IAA emerges as a new anticancer agent due to the ability of oxidatively activated IAA to selectively kill tumor cells. IAA acts as a pheromone-like molecule in brown algae, whereas the hormone concept of IAA dominates current plant biology. However, recent advances also favor the morphogen- and transmitter-like nature of IAA in plants, making this small molecule one of the most unique molecules in the eukaryotic superkingdom. Here, we introduce new technology for the continuous measuring of IAA fluxes in living cells, tissues, and whole organs that is based on a carbon nanotube-modified and self-referencing microelectrode specific for IAA. This technique not only will advance our knowledge of how IAA regulates plant development but will also be applicable in medicine for its potential use in cancer therapy.

Different pathways of the oxygen supply in the sapwood of young Olea europaea trees.

Gaseous transport through lenticels is widely accepted to be the main pathway for oxygen supply to the parenchymatous tissues of the wood. Circumstantial evidence exists that the oxygen required for respiration by these living cells can be obtained from the transpiration stream. However, there has been no functional confirmation of this role. To address this problem and to quantify the contribution of the different pathways to the oxygen supply of the sapwood, we have developed a three-electrode miniaturized oxygen-selective sensor to be implanted into the sapwood for long-term determination of the oxygen concentration. In spring, during the active growing season, the oxygen concentration of the sapwood of young olive (Olea europaea L.) trees changed from 80-90 micromol O(2) l(-1) around midday to 20-30 micromol O(2) l(-1) in the night. These concentrations correspond to a deficit of oxygen for the sapwood between 65-70% and 88-90% of an aqueous solution saturated with air. In the daylight hours, almost all the oxygen present in the sapwood was delivered by the transpiration stream, driven by the soil-plant-atmosphere water-potential gradient. During the night the diffusion of oxygen via the sap-filled lumina of the tracheids and vessels (xylary diffusion in the aqueous phase) accounted for about 87% of all the oxygen present, whereas only the remaining 13% was assessed as supplied by radial diffusion in the aqueous or gaseous phase.