Resting state connectivity of the human habenula at ultra-high field

The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network

Towards dynamical network biomarkers in neuromodulation of episodic migraine

Computational methods have complemented experimental and clinical neursciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. In this paper, we firstly explore the relevant state of the art in fusion of both developments towards translational computational neuroscience. Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.Comment: 13 pages, 5 figure

The role of the cingulate cortex in depression in dementia with Lewy bodies

PhD ThesisDementia with Lewy bodies (DLB) is a significant cause of dementia in the older population with a core set of clinical symptoms that help to distinguish DLB from other forms of dementia such as Alzheimer’s disease (AD). The core symptoms of DLB include fluctuating cognition, recurrent complex visual hallucinations and parkinsonism. Additionally, depression is experienced in around half of DLB patients and is associated with faster rate of cognitive decline, higher mortality rates and a poor response to treatment. The subgenual anterior cingulate cortex (sgACC) is integral in mood regulation, displaying structural, functional and metabolic abnormalities in depression, and shows early and extensive pathological changes in DLB. However, little is known about how any pathological or neurochemical changes in sgACC contribute to the aetiology of depression in DLB. Post-mortem tissue from cingulate cortex subregions was used to quantify neuropathological lesions in DLB cases with and without depression, and cognitively normal controls. Neurochemical analysis was performed to assess disease and depression specific changes in the sgACC in GABAergic, glutamatergic and monoaminergic transmission. Synaptic changes were assessed using confocal and stimulated emission depletion (STED) microscopy. Neuropathological burden in cingulate subregions showed disease, but not depression specific changes in DLB. Abnormalities in GABAergic and glutamatergic neurotransmission were observed in DLB cases with depression, showing greater dysregulation compared to DLB cases without depression. Dopaminergic deficits were observed in sgACC in DLB cases, with a greater reduction in DLB cases with depression, whereas no major changes in serotonergic or noradrenergic neurotransmission were observed in DLB. The results demonstrate that neurodegenerative neuropathological changes within the cingulate cortex do not appear to influence the development of depression in DLB. An imbalance in GABAergic/glutamatergic transmission within the sgACC was greater in DLB cases with depression, which may suggest greater dysregulation in excitation and inhibition, possibly contributing to the development of depression in DLB. This work also demonstrates the major role of dopaminergic neurotransmission in the aetiology of depression in DLB. Overall, this work indicates that treatment of depressive symptoms in DLB could benefit from modulation of dopaminergic, glutamatergic, or GABAergic transmission.The Alzheimer’s Societ

Sex, aggression and pair-bond : a study on the serotonergic regulation of female sexual function in the marmoset monkey

Women diagnosed with a sexual dysfunction often suffer from marked distress and interpersonal difficulty that arise from unwanted, persistent or recurrent low sexual desire (hypoactive sexual desire disorder, HSDD). An imbalance of excitatory and inhibitory neurotransmitters has been proposed to underlie certain forms of HSDD. Serotonin (5-HT) is a key neurotransmitter involved in female sexual inhibition. Animal studies that apply 5-HT receptor subtype specific ligands permit mechanistic examination of 5-HT mediated effects on sexual behavior. The aim of this thesis was to investigate the serotonergic regulation of female sexual behavior in the common marmoset (Callithrix jacchus), a nonhuman primate that is characterized by a pairmate social setting comparable to humans. The experimental agents employed in the study were (1) flibanserin, a 5-HT1A agonist, 5-HT2A antagonist and putative pharmacotherapeutic treatment for HSDD in women, and (2) 8-OH-DPAT, a prototype 5-HT1A agonist. Neuroendocrine, PET imaging and genetic experiments were conducted to explore hormonal, brain activity and gene expression patterns that underlie female sexual behavior. While flibanserin, administered daily to the female for several weeks, enhanced the male pairmate’s sexual interest and increased pro-social interactions between pairmates, 8-OH-DPAT reduced female sexual receptivity and increased aggressive interactions between pairmates. HPA responses to restraint stress were enhanced after both flibanserin and 8-OH-DPAT. Furthermore, 8-OH-DPAT treated females showed reduced glucose uptake to the medial occipital cortex that correlated with sexual rejection behavior, while gene transcription of the serotonin transporter in the dorsal raphé nucleus, and of oxytocin in the medial preoptic area of the hypothalamus, was increased. Gene cluster analysis of microarray data indicated brain region-specific alterations in neural development, neurotransmission and energy production after 8-OH-DPAT. The results presented in this thesis demonstrate that pair-bond quality between partners and sexual behavior are closely linked and suggest that oxytocin may be the pivot of serotonergic regulation of female sexual behavior, pair-bond and pharmacotherapy of HSDD.Boehringer Ingelheim; Reseach Facilities Improvement Program, National Institutes of Health, U.S.A.; Netherlands Organization for Scientific Research (NWO); Royal Netherlands Academy of Arts and Sciences (KNAW

Neuromodulation in Experimetal Animal Models of Epilepsy

Epilepsy is the most common serious brain disorder affecting 0.5-1% of the general population. This neurological disorder consists of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Despite the pharmacological development of new treatments, still one third of the epilepsy patients does not respond sufficiently to anti-epileptic drugs (AED) and are called refractory patients. Hence, there is a constant impetus to search for other treatment strategies like epilepsy surgery, vagus nerve stimulation and deep brain stimulation. Besides the ongoing research on the efficacy of anti-epileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic changes in the epileptic network and in this way have a modulating effect. The impact of such therapies cannot be overlooked, because they may slow down processes underlying epilepsy, might prevent or even cure epilepsy. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. Acute application of both treatment options can be very effective. LEV can act rapidly on seizures in both animals and humans. In addition, preclinical studies suggest that LEV may have anti-epileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in animals and patients with in addition a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations (age, course of the epilepsy, type of epilepsy, AED regime and genetic background) and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two models mimicking epilepsy in humans. They are both chronic models with seizures evolving from true, genetically-driven epileptogenesis. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that these treatments can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals

Advanced MRI techniques in the study of cerebellar cortex

The cerebellum (from the Latin "little brain") is the dorsal portion of the metencephalon and is located in the posterior cranial fossa. Although representing only 10% of the total brain volume, it contains more than 50% of the total number of neurons of the central nervous system (CNS). Its organization resembles the one found in the telencephalon, with the presence of a superficial mantle of gray matter (GM) known as the cerebellar cortex, covering the cerebellar white matter (WM) in which three pairs of deep cerebellar GM nuclei are embedded. The number of studies dedicated to the study of the cerebellum and its function has significantly increased during the last years. Nevertheless, although many theories on the cerebellar function have been proposed, to date we still are not able to answer the question about the exact function of this structure. Indeed, the classical theories focused on the role of the cerebellum in fine-tuning for muscle control has been widely reconsidered during the last years, with new hypotheses that have been advanced. These include its role as sensory acquisition device, extending beyond a pure role in motor control and learning, as well as a pivotal role in cognition, with a recognized cerebellar participation in a variety of cognitive functions, ranging from mood control to language, memory, attention and spatial data management. A huge contribution to our understanding of how the cerebellum participates in all these different aspects of motor and non-motor behavior comes from the application of advanced imaging techniques. In particular, Magnetic Resonance Imaging (MRI) can provide a non-invasive evaluation of anatomical integrity, as well as information about functional connections with other brain regions. This thesis is organized as follows: - In Chapter 1 is presented a general introduction to the cerebellar anatomy and functions, with particular reference to the anatomical organization of cerebellar cortex and its connections with the telencephalon - Chapter 2 will contain a general overview about some of the major advanced MRI methods that can be applied to investigate the anatomical integrity and functional status of the cerebellar cortex - In Chapter 3 will be presented a new method to evaluate the anatomy and integrity of cerebellar cortex using ultra-high field MRI scanners - Chapters 4, 5 and 6 will contain data obtained from the application of some of the previously described advanced imaging techniques to the study of cerebellar cortex in neurodegenerative and neuroinflammatory disorders affecting the CNS

Neuro-behavioural impact of changes in hippocampal neural activity

Hippocampal metabolic hyperactivity and neural disinhibition, i.e. reduced GABAergic inhibition, have been associated with schizophrenia, although a causal link between disinhibition and metabolic hyperactivity remains to be demonstrated. Regional neural disinhibition might also disrupt neural activation in projection sites, such as the prefrontal cortex and striatum, which may contribute to cognitive impairments and positive symptoms characteristic of schizophrenia. To further examine the brain-wide impact of hippocampal disinhibition and the associated behavioural and cognitive changes, we combined ventral hippocampal infusion of the GABA-A antagonist picrotoxin with translational neural imaging and behavioural methods in rats. First, we used a conditioned emotional response paradigm to assess the impact of hippocampal disinhibition on aversive conditioning and salience modulation in the form of latent inhibition (chapter 2), both of which have been reported to be disrupted in schizophrenia. These experiments demonstrated hippocampal disinhibition caused disrupted cue and contextual fear conditioning, whilst we found no evidence that hippocampal disinhibition affects salience modulation as reflected by latent inhibition of fear conditioning. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing at hippocampal projection sites. Second, we used SPECT imaging to map changes in brain-wide activation patterns caused by hippocampal GABA dysfunction (chapter 3). SPECT experiments revealed increased neural activation around the infusion site in the ventral hippocampus, resembling metabolic hippocampal hyperactivity consistently reported in schizophrenia. In contrast, activation in the dorsal hippocampus was significantly reduced. This resembles the finding of anterior hippocampal hyperactivity coupled with reduced posterior hippocampal activation in patients with schizophrenia. Hippocampal disinhibition also caused marked extra-hippocampal activation changes in neocortical and subcortical sites, including sites implicated in fear learning and anxiety such as the medial prefrontal cortex (mPFC), septum, lateral hypothalamus and extended amygdala which may contribute to the disruption of fear conditioning demonstrated in chapter 2. Importantly, increased activation in the mPFC corresponds with previously reported prefrontal-dependent attentional deficits caused by hippocampal disinhibition. Third, to complement these findings we used magnetic resonance spectroscopy (MRS) to determine the effects of hippocampal disinhibition on neuro-metabolites within the mPFC (chapter 4). Using MRS, we demonstrated that hippocampal disinhibition causes metabolic changes in the mPFC, reflected by increased myo-inositol and reduced GABA concentrations. Overall, our results demonstrate ventral hippocampal disinhibition causes regional metabolic hyperactivity, supporting a causal role between GABA dysfunction and increased anterior hippocampal activity. In addition, hippocampal disinhibition causes activation and metabolic changes at distal sites, which may contribute to clinically relevant behavioural deficits, including impaired aversive conditioning, as demonstrated in our behavioural studies

Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors

A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years, and this has lead to the development of novel therapeutic strategies for these patients. In this book a review of the options available for the clinical management of patients with these tumors are outlined. In addition advances in radiology both for pre-operative diagnostic purposes along with surgical planning are described. Furthermore a review of newer developments in chemotherapy along with the evolving field of photodynamic therapy both for intra-operative management and subsequent therapy is provided. A discussion of certain surgical management issues along with tumor induced epilepsy is included. Finally a discussion of the management of certain unique problems including brain metastases, brainstem glioma, central nervous system lymphoma along with issues involving patients with a brain tumor and pregnancy is provided

Psychiatric Disorders

A psychiatric disorder is defined as any complex condition that involves the impairment of cognitive, emotional, or behavioral functioning. Aside from knowing the physical organic factors, its causal pathology has remained a mystery. Regarding recent advances in psychiatry and neurosciences, psychiatric disorders have been closely associated with socio-cultural, psychological, biochemical, epigenetic or neural-networking factors. A need for diverse approaches or support strategies is present, which should serve as common knowledge, empathetic views or useful skills for specialists in the filed. This book contains multifarious and powerful papers from all over the world, addressing themes such as the neurosciences, psychosocial interventions, medical factors, possible vulnerability and traumatic events. Doubtlessly, this book will be fruitful for future development and collaboration in "world psychiatry"

Neuro-behavioural impact of changes in hippocampal neural activity

Hippocampal metabolic hyperactivity and neural disinhibition, i.e. reduced GABAergic inhibition, have been associated with schizophrenia, although a causal link between disinhibition and metabolic hyperactivity remains to be demonstrated. Regional neural disinhibition might also disrupt neural activation in projection sites, such as the prefrontal cortex and striatum, which may contribute to cognitive impairments and positive symptoms characteristic of schizophrenia. To further examine the brain-wide impact of hippocampal disinhibition and the associated behavioural and cognitive changes, we combined ventral hippocampal infusion of the GABA-A antagonist picrotoxin with translational neural imaging and behavioural methods in rats. First, we used a conditioned emotional response paradigm to assess the impact of hippocampal disinhibition on aversive conditioning and salience modulation in the form of latent inhibition (chapter 2), both of which have been reported to be disrupted in schizophrenia. These experiments demonstrated hippocampal disinhibition caused disrupted cue and contextual fear conditioning, whilst we found no evidence that hippocampal disinhibition affects salience modulation as reflected by latent inhibition of fear conditioning. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing at hippocampal projection sites. Second, we used SPECT imaging to map changes in brain-wide activation patterns caused by hippocampal GABA dysfunction (chapter 3). SPECT experiments revealed increased neural activation around the infusion site in the ventral hippocampus, resembling metabolic hippocampal hyperactivity consistently reported in schizophrenia. In contrast, activation in the dorsal hippocampus was significantly reduced. This resembles the finding of anterior hippocampal hyperactivity coupled with reduced posterior hippocampal activation in patients with schizophrenia. Hippocampal disinhibition also caused marked extra-hippocampal activation changes in neocortical and subcortical sites, including sites implicated in fear learning and anxiety such as the medial prefrontal cortex (mPFC), septum, lateral hypothalamus and extended amygdala which may contribute to the disruption of fear conditioning demonstrated in chapter 2. Importantly, increased activation in the mPFC corresponds with previously reported prefrontal-dependent attentional deficits caused by hippocampal disinhibition. Third, to complement these findings we used magnetic resonance spectroscopy (MRS) to determine the effects of hippocampal disinhibition on neuro-metabolites within the mPFC (chapter 4). Using MRS, we demonstrated that hippocampal disinhibition causes metabolic changes in the mPFC, reflected by increased myo-inositol and reduced GABA concentrations. Overall, our results demonstrate ventral hippocampal disinhibition causes regional metabolic hyperactivity, supporting a causal role between GABA dysfunction and increased anterior hippocampal activity. In addition, hippocampal disinhibition causes activation and metabolic changes at distal sites, which may contribute to clinically relevant behavioural deficits, including impaired aversive conditioning, as demonstrated in our behavioural studies