Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action.

Well-established in the field of bioelectronic medicine, Spinal Cord Stimulation (SCS) offers an implantable, non-pharmacologic treatment for patients with intractable chronic pain conditions. Chronic pain is a widely heterogenous syndrome with regard to both pathophysiology and the resultant phenotype. Despite advances in our understanding of SCS-mediated antinociception, there still exists limited evidence clarifying the pathways recruited when patterned electric pulses are applied to the epidural space. The rapid clinical implementation of novel SCS methods including burst, high frequency and dorsal root ganglion SCS has provided the clinician with multiple options to treat refractory chronic pain. While compelling evidence for safety and efficacy exists in support of these novel paradigms, our understanding of their mechanisms of action (MOA) dramatically lags behind clinical data. In this review, we reconstruct the available basic science and clinical literature that offers support for mechanisms of both paresthesia spinal cord stimulation (P-SCS) and paresthesia-free spinal cord stimulation (PF-SCS). While P-SCS has been heavily examined since its inception, PF-SCS paradigms have recently been clinically approved with the support of limited preclinical research. Thus, wide knowledge gaps exist between their clinical efficacy and MOA. To close this gap, many rich investigative avenues for both P-SCS and PF-SCS are underway, which will further open the door for paradigm optimization, adjunctive therapies and new indications for SCS. As our understanding of these mechanisms evolves, clinicians will be empowered with the possibility of improving patient care using SCS to selectively target specific pathophysiological processes in chronic pain

Brain data:Scanning, scraping and sculpting the plastic learning brain through neurotechnology

Neurotechnology is an advancing field of research and development with significant implications for education. As 'postdigital' hybrids of biological and informational codes, novel neurotechnologies combine neuroscience insights into the human brain with advanced technical development in brain imaging, brain-computer interfaces, neurofeedback platforms, brain stimulation and other neuroenhancement applications. Merging neurobiological knowledge about human life with computational technologies, neurotechnology exemplifies how postdigital science will play a significant role in societies and education in decades to come. As neurotechnology developments are being extended to education, they present potential for businesses and governments to enact new techniques of 'neurogovernance' by 'scanning' the brain, 'scraping' it for data and then 'sculpting' the brain toward particular capacities. The aim of this article is to critically review neurotechnology developments and implications for education. It examines the purposes to which neurotechnology development is being put in education, interrogating the commercial and governmental objectives associated with it and the neuroscientific concepts and expertise that underpin it. Finally, the article raises significant ethical and governance issues related to neurotechnology development and postdigital science that require concerted attention from education researchers

Decoding Neural Signals with Computational Models: A Systematic Review of Invasive BMI

There are significant milestones in modern human's civilization in which mankind stepped into a different level of life with a new spectrum of possibilities and comfort. From fire-lighting technology and wheeled wagons to writing, electricity and the Internet, each one changed our lives dramatically. In this paper, we take a deep look into the invasive Brain Machine Interface (BMI), an ambitious and cutting-edge technology which has the potential to be another important milestone in human civilization. Not only beneficial for patients with severe medical conditions, the invasive BMI technology can significantly impact different technologies and almost every aspect of human's life. We review the biological and engineering concepts that underpin the implementation of BMI applications. There are various essential techniques that are necessary for making invasive BMI applications a reality. We review these through providing an analysis of (i) possible applications of invasive BMI technology, (ii) the methods and devices for detecting and decoding brain signals, as well as (iii) possible options for stimulating signals into human's brain. Finally, we discuss the challenges and opportunities of invasive BMI for further development in the area.Comment: 51 pages, 14 figures, review articl

A motivational model of BCI-controlled heuristic search

Several researchers have proposed a new application for human augmentation, which is to provide human supervision to autonomous artificial intelligence (AI) systems. In this paper, we introduce a framework to implement this proposal, which consists of using Brain–Computer Interfaces (BCI) to influence AI computation via some of their core algorithmic components, such as heuristic search. Our framework is based on a joint analysis of philosophical proposals characterising the behaviour of autonomous AI systems and recent research in cognitive neuroscience that support the design of appropriate BCI. Our framework is defined as a motivational approach, which, on the AI side, influences the shape of the solution produced by heuristic search using a BCI motivational signal reflecting the user’s disposition towards the anticipated result. The actual mapping is based on a measure of prefrontal asymmetry, which is translated into a non-admissible variant of the heuristic function. Finally, we discuss results from a proof-of-concept experiment using functional near-infrared spectroscopy (fNIRS) to capture prefrontal asymmetry and control the progression of AI computation of traditional heuristic search problems

The Neural Encoding of Reward in the Striatal-Pallidal Circuitry

Humans and animals are constantly exposed to external stimuli. The ability to process reward value of a stimulus is critical to guiding appropriate behavior and essential for survival. These processes are regulated by neuronal activity and neurochemical signaling in the reward circuitry, particularly in the nucleus accumbens (NAc). The NAc receives dopaminergic inputs from the midbrain ventral tegmental area (VTA) and sends GABAergic projections to the ventral pallidum (VP). Electrophysiological studies have characterized phasic neuronal responses in the NAc that differential encode appetitive and aversive taste stimuli. Exposure to an appetitive taste stimulus evoked predominantly phasic inhibitory responses in the NAc whereas a majority of responses to an aversive taste was excitation. The work presented here focused on investigating how activity in the NAc modulate reward encoding in downstream VP, and the role of dopamine signaling in regulating neuronal responses to reward in the NAc. Using electrophysiological recording techniques, we present evidence of neural encoding of reward information in the VP. VP neurons responded to appetitive and aversive taste stimuli with primarily inhibitory and excitatory responses, respectively. Furthermore, devaluation of the appetitive stimulus resulted from cocaine-induced taste aversion conditioning revealed that the encoding of sucrose shifted from inhibition to excitation, resembling that of an aversion response. These data suggest that the VP, similar to the NAc, also encode reward information neuronally. In a subsequent study, the influence of NAc on VP reward encoding was tested by pharmacologically manipulating activity in the NAc while monitoring the neuronal activity in the VP. We demonstrate that by inhibiting activity in the NAc with a GABAergic agonist, the neural encoding to sucrose in the VP was augmented, followed by increased sucrose consumption. These findings support the notion that at least some aspect of reward information processed in VP is modulated by NAc activity. In the final study, we show that chemogenetically suppressing activity of VTA dopamine neurons inverted the response profile to sucrose from inhibition to excitation in the NAc. This elimination of inhibitory reward encoding in the NAc was accompanied by a dampened motivational state, demonstrated by subjects terminating leverpress behavior for sucrose reward quicker in a progressive ratio test on day that dopamine signaling was chemogenetically suppressed but not in control condition. Taken together, results from these studies provide insights into how reward information is represented by physiological events in the reward circuitry. We demonstrate that neuronal responses in both the NAc and the VP encode reward and correlate strongly to reward-driven motivated behavior. Furthermore, we used a chemogenetic approach to show that suppressed NAc dopamine signaling models a low motivational state that is represented by altered neuronal responses in the NAc. This endeavor to better understand the neural representation of reward may help us better understand the physiology of both normal and diseased motivational and affective states

Depressive and psychotic symptoms in schizophrenia:Focus on networks and treatment

This thesis has two main aims. First, to review and increase knowledge concerning symptom interaction in patients with schizophrenia, with a specific focus on co-occurring depressive symptoms and its neural correlates in major depressive disorder (Part I and II). Second, to review and investigate different treatment aspects and outcomes in schizophrenia (quality of life, depressive symptoms and mortality) (Part III). In sum, both network studies showed the importance of depressive symptoms in the symptom networks of patients with schizophrenia and showed the stability of such a network structure. Although the network approaches has several issues of debate, it is a promising new way of thinking about psychopathology. The network approach is an example of a new conceptualisation of psychopathology as dynamic systems that change over time. Additionally, this view on mental illness facilitates a more transdiagnostic approach, in which emotion regulation should be an important target for future studies. Given the frequent co-occurrence of depressive symptoms in patients with schizophrenia, its centrality, its correlations with suicidality and influence on quality of life, it is highly important to adequately treat co-occurring depressive symptoms and episodes. Systematically following the provided treatment guide to treat depressive symptoms or episodes might be useful. Additionally, meta-analyses showed that schizophrenia patients who do not use antipsychotics have a higher mortality risk compared to patients that use antipsychotics. In a similar way, continuous use of clozapine was related to a lower mortality risk compared to patients using other antipsychotics

RAPID-ACTING ANTIDEPRESSANT DRUGS: AN EMERGING APPROACH FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

In questa tesi viene proposta ed elaborata l'evoluzione terapeutica contro la depressione resistente ai trattamenti convenzionali, con un'attenzione maggiore a una nuova e promettente classe di farmaci denominata Rapid-Acting-Antidepressant. Inizialmente, viene offerta una presentazione in cui vengono definiti i vari tipi di depressione diagnosticabili, con le rispettive caratterizzazioni e sintomi, per poi delineare le terapie attualmente prescritte contro questa condizione. In seguito, viene introdotta una nuova ipotesi chiamata ipotesi glutammatergica, in quanto si ritiene che la presenza di un'aumentata concentrazione del neurotrasmettitore glutammato sia coinvolta nella manifestazione dei sintomi nei pazienti depressi. Questo neurotrasmettitore eccitatorio è il più abbondante nel sistema nervoso centrale dei mammiferi adulti e possiede un ruolo importante nell'neuroplasticità. In base alla neurotrasmissione, i recettori glutammatergici possono essere suddivisi in: metabotropici (mGluR), che sono recettori accoppiati a proteine G implicati nella plasticità sinaptica, nell'eccitabilità e nella connettività neuronale; e ionotropici (iGluR), che sono canali cationici dipendenti dal ligando. I recettori ionotropici sono proteine di membrana composte da quattro subunità che costituiscono il canale ionico che consente l'afflusso di cationi calcio in seguito al legame con il glutammato. Le subunità sono essenziali per la sinaptogenesi, il rimodellamento sinaptico che dipende dalle variazioni della potenza sinaptica. Nella depressione, vi è una sovrastimolazione di questi recettori causata da alte concentrazioni di glutammato che porta a una condizione di eccitotossicità. Le terapie farmacologiche basate su questa teoria mirano all'inibizione dei recettori N-metil-D-aspartato (NMDA). Il principale capostipite dal punto di vista farmacologico è la ketamina, diffusa come anestetico locale, che ha dimostrato un'attività antidepressiva rapida e prolungata. Tuttavia, la ketamina non può essere considerata un farmaco sicuro perché la sua somministrazione richiede un trattamento ambulatoriale del paziente, a causa della comparsa di effetti collaterali dissociativi e del potenziale di abuso. Per questo motivo, la ricerca si è concentrata sullo sviluppo di altri composti attivi. Oltre alla ketamina, altri antagonisti dei recettori NMDA sono: la memantina, un farmaco prescritto per la malattia di Alzheimer; la norketamina, un derivato della ketamina; l'MK-801, il destrometorfano, il destrometadone e la lanicemina. Tuttavia, esistono anche altri farmaci con un diverso meccanismo d'azione, come il rapastinel, un agonista parziale dei recettori NMDA. Oltre al sistema glutammatergico, negli ultimi anni è stato dimostrato il coinvolgimento di altri sistemi, tra cui il sistema serotoninergico, il sistema colinergico e l'asse ipotalamo-ipofisi-surrene. Ognuno di questi sistemi ha almeno un candidato farmaco in fase di sperimentazione clinica per il trattamento del disturbo depressivo maggiore. In conclusione, questo lavoro di tesi propone un confronto tra le terapie attualmente prescritte e i nuovi approcci terapeutici per la depressione, confrontandone le caratteristiche principali.In this thesis, therapeutic evolution against depression resistant to conventional treatment is proposed and elaborated with a greater focus on a new and promising class of drugs called Rapid-Acting-Antidepressant. Initially, a presentation is offered in which the various types of diagnosable depression are defined along with their respective characterizations and symptoms, and then the currently prescribed therapies against this condition are outlined. Continuing, a new hypothesis called the glutamatergic hypothesis is introduced as it is believed that the presence of increased concentration of the neurotransmitter glutamate is involved in the manifestation of symptoms in depressed patients. This excitatory neurotransmitter is the most abundant in the adult mammalian central nervous system and possesses an important role inneuroplasticity. Based on neurotransmission, glutamatergic receptors can be divided into: metabotropic (mGluR) which are G-protein-coupled receptors implicated in synaptic plasticity, excitability and neuronal connectivity; and ionotropic (iGluR) which are ligand-dependent cation channels. Ionotropic receptors are membrane proteins composed of four subunits that constitute the ion channel which allows the influx of calcium cations following glutamate binding. The subunits are essential for synaptogenesis, the synaptic remodeling dependent on changes in synaptic potency. In depression, there is overstimulation of these receptors caused by high concentrations of glutamate leading to an excitotoxic condition. Phamacological therapies based on this theory target N-methyl-D-aspartate (NMDA) receptor inhibition. The main progenitor from the pharmacological point of view is ketamine, widespread as a local anesthetic, which has shown rapid and sustained antidepressant activity. However, ketamine cannot be regarded as a safe drug because its administration requires ambulatory treatment of the patient, due to the occurrence of dissociative side effects and the potential for abuse. For this reason, research has focused on the development of other active compounds. In addition to ketamine, other NMDA receptor antagonists include: memantine, a drug prescribed for Alzheimer's disease; norketamine, a ketamine derivative; MK-801, dextromethorphan, dextromethadone, and lanicemine. However, there are also other drugs having different mechanism of action such as rapastinel, an NMDA receptor partial agonist. In addition to the glutamatergic system, the involvement of other systems including the serotonergic system, the cholinergic system, and the hypothalamic-pituitary-adrenal axis has been demonstrated in recent years. Each of these systems has at least one drug candidate in clinical trials for the treatment of major depressive disorder. In conclusion, this thesis work proposes a comparison of currently prescribed therapies and new therapeutic approaches for depression by comparing their main characteristics