Non-Pharmacological Treatments

In clinical psychiatry, we dispose of different non-pharmacological approaches, such as somatic treatments, chronobiological treatments, cognitive remediation, and psychotherapy. Somatic treatments include transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and electroconvulsive therapy (ECT). These techniques, which exert their function through the modulation of cortical excitability, find an application in many psychiatric disorders, but mainly in resistant depression. Chronotherapies, a group of non-pharmacological therapeutic approaches to mood disorder treatment, are rooted in the hypothesis of chronobiology aetiopathogenesis of psychiatric disorders (mainly mood disorders). Chrono-biological treatments include light therapy (LT), sleep deprivation (SD), and dark therapy (DT). While LT and SD are mainly used in depression, DT finds a clinical application in mania. Cognitive remediation (CR) is a set of interventions based on behavioural training whose goal is to enhance neurocognitive abilities. This technique finds its main application in schizophrenia. Psychotherapy approaches have a proved effectiveness for the treatment of various psychiatric conditions when combined to psychopharmacological treatment. The two main approaches are cognitive-behavioural therapy and psychodynamic therapy

Intervention to Extrasynaptic Gabaa Receptors for Symptom Relief in Mouse Models of Rett Syndrome

Rett Syndrome (RTT) is a neurodevelopmental disorder affecting 1 out of 10,000 females worldwide. Mutations of the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2) accounts for \u3e90% of RTT cases. People with RTT and mice with Mecp2 disruption show autonomic dysfunction, especially life-threatening breathing disorders, which involves defects in brainstem neurons for breathing controls, including neurons in the locus coeruleus (LC). Accumulating evidence obtained from Mecp2−/Y mice suggests that imbalanced excitation/inhibition or the impaired synaptic communications in central neurons plays a major role. LC neurons in Mecp2−/Ymice are hyperexcited, attributable to the deficiency in GABA synaptic inhibition. Several previous studies indicate that augmenting synaptic GABA receptors (GABARs) leads to a relief of RTT-like symptoms in mice. The extrasynaptic GABARs located outside synaptic cleft, which have the capability to produce sustained inhibition, and may be a potential therapeutic target for the rebalance of excitation/inhibition in RTT. In contrast to the rich information of the synaptic GABARs in RTT research, however, whether Mecp2 gene disruption affects the extrasynaptic GABARs remains unclear. In this study, we show evidence that the extrasynaptic GABAR mediated tonic inhibition of LC neurons was enhanced in Mecp2−/Ymice, which seems attributable to the augmented δ subunit expression. Low-dose THIP exposure, an agonist specific to δ subunit containing extrasynaptic GABARs, extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of Mecp2−/Ymice. Such beneficial effects were associated with stabilization of brainstem neuronal hyperexcitability, including neurons in the LC and the mesencephalic trigeminal V nucleus (Me5), and improvement of norepinephrine (NE) biosynthesis. Such phenomena were found in symptomatic Mecp2+/− (sMecp2+/−) female mice model as well, in which the THIP exposure alleviated the hyperexcitability of both LC and Me5 neurons to a similar level as their counterparts in Mecp2−/Y mice, and improved breathing function. In identified LC neurons of sMecp2+/− mice, the hyperexcitability appeared to be determined by both MeCP2 expression and their environmental cues. In conclusion, intervention to extrasynaptic GABAAR by chronic treatment with THIP might be a therapeutic approach to RTT-like symptoms in both Mecp2−/Y and Mecp2+/− mice models and perhaps in people with RTT as well

The role of central catecholamines in performance during prolonged exercise in warm conditions

Performance during prolonged exercise capacity diminishes with increasing temperatures. The onset of fatigue under these conditions is not adequately explained by peripheral mechanisms. Recently, drugs which inhibit the reuptake of dopamine and noradrenaline in the brain have been found to improve exercise performance in warm conditions. The aim of this thesis was to further explore and characterise the role of these neurotransmitters during prolonged exercise in warm conditions by manipulating their reuptake or synthesis. The first series of experiments were designed to further investigate the effects of bupropion, a dopamine and noradrenaline reuptake inhibitor, which has been found to improve performance in warm conditions. To explore gender differences in response to acute bupropion administration, the effects of bupropion on prolonged exercise performance in warm conditions in women was investigated in Chapter 3. The results of this study suggest that during the follicular phase of the menstrual cycle, acute administration of bupropion improves exercise performance. To determine whether there are any dose-dependent effects of bupropion, the experiment in Chapter 4 was designed to test three different doses of bupropion. Exercise performance was only improved for the maximal dose, suggesting a threshold for the performance effects of bupropion. Catecholamine precursors do not appear to improve exercise performance as consistently as reuptake inhibitors. In agreement with previous studies, the dopamine precursor L-DOPA did not affect exercise performance in warm conditions in Chapter 5. In Chapter 6 the effect of the atypical antidepressant nutritional supplement S-adenosylmethionine was investigated for its role in the synthesis of dopamine and noradrenaline. S-adenosylmethionine appeared to negatively influence cognitive function, increased skin temperature and circulating prolactin concentrations, but no effects on exercise performance were observed

Neuroexcitability control by adenosine and BDNF at the adult hippocampus

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2017The traditional view of neuronal communication involves a network of neurons communicating through neurotransmitters, which either lead to neuronal depolarization or hyperpolarization. However, the overall output is also determined by the presence of neuromodulators. These are molecules able to alter the function of a circuitry by modifying the properties of synaptic conductance and the intrinsic membrane properties of individual neurons. Neuromodulators are thus critical in the regulation of synaptic transmission and plasticity. Adenosine and Bain-Derived Neurotrophic Factor (BDNF) are two well-known modulators of the central nervous system. BDNF induces pre- and post-synaptic changes that lead to a facilitation of glutamatergic transmission through its high affinity receptor, TrkB receptor. However, BDNF influence upon GABAergic transmission in the adult brain is poorly understood. I now evaluated whether BDNF modulates GABAergic transmission in the adult hippocampus. Evoked and spontaneous synaptic currents were recorded from CA1 pyramidal cells in acute hippocampal slices from young adult rat brains (6 to 10 weeks-old). BDNF (10-100 ng/mL) increased miniature inhibitory post-synaptic currents (mIPSCs) frequency, but not amplitude, as well as increased the amplitude of inhibitory post-synaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75NTR blockade (Anti-p75NTR IgG, 50 μg/mL). Since adenosine A2A receptor is an upstream regulator of TrkB activity, a putative influence of this receptor was also investigated. The facilitatory action of BDNF onto GABAergic transmission was also prevented upon adenosine A2A receptor antagonism (SCH 58261, 50 nM). I thus concluded that BDNF facilitates GABAergic signaling at the adult hippocampus via a pre-synaptic mechanism that depends on TrkB and adenosine A2A receptor activation. Adenosine net effect is to inhibit synaptic activity through the binding to the adenosine A1 receptor (A1R). Despite the low expression of the adenosine A2A receptor (A2AR), through its activation, adenosine may also enhance synaptic strength. Astrocytic Adenosine kinase (ADK) accounts as the major contributor for adenosine metabolic clearance from synaptic cleft, determining the intra- and extracellular concentrations of adenosine. Accordingly, ADK up-regulation correlates with decreased adenosine levels, with consequent impaired A1R-mediated signaling and increased susceptibility to epileptic seizures. Surprisingly, mice lacking ADK expression in the entire brain develop progressive epilepsy with stress-induced seizures in an age-dependent way. They present spontaneous convulsive seizures by the age of 5 months old, until their first year old, when they become asymptomatic. Functional and biochemical studies were performed in order to characterize adenosine and BDNF receptors in pre-symptomatic (2 months old), symptomatic (5 to 8 months old) and post-symptomatic (over 1 year old) mice. ADK knockout mice at all ages demonstrated enhanced adenosine levels around synapses, but impaired A1R receptor function of synaptic transmission with concomitant lower expression protein levels of the receptor. Lack of A1R inhibitory signaling is observed independently of animal age, so it cannot account for the epileptic phenotype, despite it may account for a higher neuronal excitability. However, adenosine A2AR and BDNF signaling undergo a shift from the pre- to the symptomatic stage. In mice lacking ADK, A2AR activation and BDNF signaling is augmented leading to enhanced synaptic plasticity, which may play a role in the triggering of the seizure phenotype. Accordingly, A2AR and BDNF are overexpressed in epileptic mice lacking Adk in the brain. This work besides suggesting that A2AR and BDNF exacerbated signaling have pro-epileptic affects, provide evidence that ADK may present a genetic risk for the development of epilepsy since it has intrinsic effects onto brain activity, but also offers new opportunities for the development of pharmacologic tools for seizure disorders

In vivo functional role of the 5-HT2A/mGlu2 receptor heterocomplex in rodents

275 p.La esquizofrenia es una enfermedad prototípica humana de etiología aún desconocida. La investigación con modelos animales permite estudiar las causas y mecanismos afectados en dicha enfermedad. Así, fármacos como el DOI, actuando como agonista del receptor de serotonina 5-HT2A, induce sintomatología similar a la esquizofrenia de tipo paranoide.Existe un heterocomplejo formado entre los receptores 5-HT2A/mGlu2 en la corteza prefrontal de cerebros humanos y roedores, necesario para desencadenar dicha sintomatología positiva de esquizofrenia. Un número sustancial de artículos habían demostrado la interacción entre ambos receptores, incluyendo estudios celulares, genéticos, biofísicos y bioquímicos in vitro, pero la funcionalidad de este complejo in vivo permanecía aún poco conocida.La presente Tesis Doctoral evalúa la funcionalidad de este heterocomplejo in vivo, mediante elestudio de la liberación de catecolaminas en la corteza frontal de roedor tras la administración del alucinógeno DOI. Asimismo, se ha realizado un estudio de algunos circuitos noradrenérgicos modulados por la administración de este alucinógeno y se ha estudiado brevemente la señalización celular desencadenada por la activación del receptor 5-HT2A.Cibersam:Centro de Investigación Biomédica en Red Salud Menta

Cortical mechanisms for tinnitus in humans /

PhD ThesisThis work sought to characterise neurochemical and neurophysiological processes underlying tinnitus in humans. The first study involved invasive brain recordings from a neurosurgical patient, along with experimental manipulation of his tinnitus, to map the cortical system underlying his tinnitus. Widespread tinnitus-linked changes in low- and high-frequency oscillations were observed, along with inter-regional and cross-frequency patterns of communication. The second and third studies compared tinnitus patients to controls matched for age, sex and hearing loss, measuring auditory cortex spontaneous oscillations (with magnetoencephalography) and neurochemical concentrations (with magnetic resonance spectroscopy) respectively. Unlike in previous studies not controlled for hearing loss, there were no group differences in oscillatory activity attributable to tinnitus. However, there was a significant correlation between gamma oscillations (>30Hz) and hearing loss in the tinnitus group, and between delta oscillations (1-4Hz) and perceived tinnitus loudness. In the neurochemical study, tinnitus patients had significantly reduced GABA concentrations compared to matched controls, and within this group there was a positive correlation between choline concentration (potentially linked to acetylcholine and/or neuronal plasticity) and both hearing loss, and subjective tinnitus intensity and distress. In light of present and previous findings, tinnitus may be best explained by a predictive coding model of perception, which was tested in the final experiment. This directly controlled the three main quantities comprising predictive coding models, and found that delta/theta/alpha oscillations (1-12Hz) encoded the precision of predictions, beta oscillations (12-30Hz) encoded changes to predictions, and gamma oscillations represented surprise (unexpectedness of stimuli based on predictions). The work concludes with a predictive coding model of tinnitus that builds upon the present findings and settles unresolved paradoxes in the literature. In this, precursor processes (in varying combinations) synergise to increase the precision associated with spontaneous activity in the auditory pathway to the point where it overrides higher predictions of ‘silence’.Medical Research Council Wellcome Trust and the National Institutes of Healt

In vivo functional role of the 5-HT2A/mGlu2 receptor heterocomplex in rodents

275 p.La esquizofrenia es una enfermedad prototípica humana de etiología aún desconocida. La investigación con modelos animales permite estudiar las causas y mecanismos afectados en dicha enfermedad. Así, fármacos como el DOI, actuando como agonista del receptor de serotonina 5-HT2A, induce sintomatología similar a la esquizofrenia de tipo paranoide.Existe un heterocomplejo formado entre los receptores 5-HT2A/mGlu2 en la corteza prefrontal de cerebros humanos y roedores, necesario para desencadenar dicha sintomatología positiva de esquizofrenia. Un número sustancial de artículos habían demostrado la interacción entre ambos receptores, incluyendo estudios celulares, genéticos, biofísicos y bioquímicos in vitro, pero la funcionalidad de este complejo in vivo permanecía aún poco conocida.La presente Tesis Doctoral evalúa la funcionalidad de este heterocomplejo in vivo, mediante elestudio de la liberación de catecolaminas en la corteza frontal de roedor tras la administración del alucinógeno DOI. Asimismo, se ha realizado un estudio de algunos circuitos noradrenérgicos modulados por la administración de este alucinógeno y se ha estudiado brevemente la señalización celular desencadenada por la activación del receptor 5-HT2A.Cibersam:Centro de Investigación Biomédica en Red Salud Menta