Resting state connectivity correlates with drug and placebo response in fibromyalgia patients

AbstractFibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response.We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition.15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex.This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response

Brain circuitry of compulsivity.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.Dr. Soriano-Mas is funded by a ׳Miguel Servet׳ contract from the Carlos III Health Institute (CP10/00604). Dr. Goudriaan is supported by a VIDI Innovative Research Grant (Grant no. 91713354) funded by the Dutch Scientific Research Association (NWO-ZonMW). Dr. Alonso was funded by the Instituto de Salut Carlos III-FISPI14/00413. Dr. Nakamae received Grant support from MEXT KAKENHI (Nos. 24791223 and 26461753).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.12.00

Disconnectivity between Dorsal Raphe Nucleus and Posterior Cingulate Cortex in Later Life Depression

The dorsal raphe nucleus (DRN) has been repeatedly implicated as having a significant relationship with depression, along with its serotoninergic innervation. However, functional connectivity of the DRN in depression is not well understood. The current study aimed to isolate functional connectivity of the DRN distinct in later life depression (LLD) compared to a healthy age-matched population. Resting state functional magnetic resonance imaging (rsfMRI) data from 95 participants (33 LLD and 62 healthy) were collected to examine functional connectivity from the DRN to the whole brain in voxel-wise fashion. The posterior cingulate cortex (PCC) bilaterally showed significantly smaller connectivity in the LLD group than the control group. The DRN to PCC connectivity did not show any association with the depressive status. The findings implicate that the LLD involves disruption of serotoninergic input to the PCC, which has been suggested to be a part of the reduced default mode network in depression

Ovarian hormones shape brain structure, function, and chemistry: A neuropsychiatric framework for female brain health

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................19

Neuropsychopharmacology of appetite in healthy volunteers

This thesis aimed to develop an Experimental Medicine Model for the assessment of the potential efficacy and psychiatric safety of novel anti-obesity drugs. Chapter 1 provides a general introduction. In Chapter 2, a Universal Eating Monitor (UEM) detected the satiety enhancing effects of an appetite suppressant drug (meta-chlorophenylpiperazine – mCPP) and the P1vital® Oxford Emotional Test Battery (ETB) suggested an absence of psychiatric side-effects. In Chapter 3, UEM measures of eating behaviour were similar whether or not the participants were aware of the UEM. Chapter 4 presents two studies providing evidence that 1) repeated use of the ETB is feasible and 2) performance on the ETB is not affected by satiety. In Chapter 5, functional magnetic resonance imaging (fMRI) was used to identify a profile of natural satiety. In Chapter 6, mCPP reduced brain activity to high calorie food images. It also reduced consumption of a palatable cookie snack but not a pasta meal. Analysis of individual differences to the drug showed that brain activity predicted anorectic response. Chapter 7 concludes that the Experimental Medicine Model may be valuable for the development of efficacious and safe appetite suppressant drugs, providing data to inform go/no go decisions in early phase clinical trials

The Psychedelic State Induced by Ayahuasca Modulates the Activity and Connectivity of the Default Mode Network

The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.The Brazilian Federal Agencies: CNPq, CAPES; FINEP; The Sao Paulo State financial agency (FAPESP)

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

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