Affective and cognitive prefrontal cortex projections to the lateral habenula in humans

Anterior insula (AI) and dACC are known to process information about pain, loss, adversities, bad, harmful or suboptimal choices and consequences that threaten survival or well-being. Pain and loss activate also pregenual ACC (pgACC), linked to sad thoughts, hurt and regrets. The lateral habenula (LHb) is stimulated by predicted and received pain, discomfort, aversive outcome, loss. Its chronic stimulation makes us feel worse/low and gradually stops us choosing and moving for suboptimal, hurtful or punished choices, by direct and indirect (via RMTg) inhibition of DRN and VTA/SNc. Response selectivity of LHb neurons suggests their cortical input from affective and cognitive evaluative regions that make expectations about bad or suboptimal outcomes. Based on these facts I predicted direct corticohabenular projections from the dACC, pgACC and AI, as part of the adversity processing circuit that learns to avoid bad outcomes by suppressing dopamine and serotonin signal. Using DTI I found dACC, pgACC, AI, adjacent caudolateral and lateral OFC projections to LHb. I predicted no corticohabenular projections from the reward processing regions: medial OFC and vACC because both respond most strongly to good, high value stimuli and outcomes, inducing serotonin and dopamine release respectively. This lack of LHb projections was confirmed for vACC and likely for mOFC. The surprising findings were the corticohabenular projections from the cognitive prefrontal cortex regions, known for flexible reasoning, planning and combining whatever information are relevant for reaching current goals. I propose that prefrontohabenular projections provide a teaching signal for value-based choice behaviour, to learn to deselect, avoid or inhibit the potentially harmful, low valued or wrong choices, goals, strategies, predictions, models and ways of doing things, to prevent bad or suboptimal consequences.Comment: I renamed the medioventral part of the anterior thalamus via which the PFC to LHb fibre tracts from ventral anterior (AV) to medial anterior thalamic region. Apologies for that. My co-author decided to remove his nam

Functional magnetic resonance imaging shows oxytocin activates brain regions associated with mother-pup bonding during suckling

Oxytocin is released in the maternal brain during breastfeeding and may help strengthen the mother-infant relationship. Here, we used functional magnetic resonance imaging to determine whether oxytocin modulates brain activity in postpartum day 4-8 dams receiving suckling stimulation. During imaging sessions, dams were exposed to pup suckling before and after administration of an oxytocin receptor antagonist. Another group of dams received oxytocin alone. Changes in brain activation in response to suckling closely matched that elicited by oxytocin administration. The overlapping brain areas included the olfactory system, nucleus accumbens, insular cortex, prefrontal cortex, ventral tegmental area, cortical amygdala, and several cortical and hypothalamic nuclei. Blockade of oxytocin receptors largely attenuated activation in these regions. The data suggest that oxytocin may strengthen mother-infant bond formation partly by acting through brain areas involved in regulating olfactory discrimination, emotions, and reward

Investigation of Memory Related Cortical Thalamic Circuitry in the Human Brain

This dissertation examined the role of medial prefrontal cortex (mPFC) and the hippocampus (HC) in episodic memory, and provides a novel approach to identify the midline thalamus mediating mPFC-HC interactions in humans. The mPFC and HC are critical to the temporal organization of episodic memory, and these interactions are disrupted in several mental health and neurological disorders. In the first study, I provide evidence that the mPFC is involved in ordinal retrieval, and the HC is active in temporal context retrieval in remembering the order of when events happen. In the second study, I focus on the anatomical basis of the mPFC-HC interactions which is reliant on the midline thalamus. I review in detail the anatomy of the midline thalamus both in location, and connectivity profile with the rest of the brain comparing the extensive anatomical evidence in rodents with the available evidence in monkeys and humans. This section also elaborates on the role of the midline thalamus in memory, stress regulation, wakefulness, and feeding behavior, and how pathological markers along the midline thalamus are a vanguard of several neurological disorders including Alzheimer’s Disease, schizophrenia, depression, and drug addiction. Lastly, I devised a new approach to identify the midline thalamus in humans in vivo using diffusion weighted imaging, capitalizing on known fiber connections gleaned from non-human animals, focusing on connections between the midline thalamus and the mPFC, medial temporal lobe and the nucleus accumbens. The success of this approach is promising for translational imaging. Overall, this dissertation provides new evidence on 1) complementary functional roles of the mPFC and HC in sequence memory, 2) a cross-species anatomical framework for understanding the midline thalamus in humans and neurological disorders, and 3) a new method for non-invasive identification of the midline thalamus in humans in vivo. Thus, this dissertation provides a new fundamental understanding of mPFC-midline thalamic-HC circuit in humans and tools for its non-invasive study in human disease

Spectroscopic measurement of cortical nitric oxide release induced by ascending activation

[Abstract] The transition from sleep to the awake state is regulated by the activation of subcortical nuclei of the brainstem (BS) and basal forebrain (BF), releasing acetylcholine and glutamate throughout the cortex and inducing a tonic state of neural activity. It has been suggested that such activation is also mediated by the massive and diffuse cortical release of nitric oxide (NO). In this work we have combined the spectroscopic measurement of NO levels in the somatosensory cortex of the cat through its marker methemoglobin, as well as two other hemodynamic markers (oxyhemoglobin – oxyHb – and deoxyhemoglobin – deoxyHb), together with the electrical stimulation of BS and BF – to induce an experimental transition from a sleep-like state to an awake-like mode. The results show an increase of NO levels either after BS or BF activation. The response induced by BS stimulation was biphasic in the three studied markers, and lasted for up to 30 s. The changes induced by BF were monophasic lasting for up to 20 s. The systemic blockade of NO production abolished the observed responses to BS whereas responses to BF stimulation were much less affected. These results indicate a crucial role for NO in the neuronal activation induced by the ascending systems.Galicia. Consellería de Economía e Industria; INCITE09137272P

Structural connectivity of autonomic, pain, limbic, and sensory brainstem nuclei in living humans based on 7 Tesla and 3 Tesla MRI

Autonomic, pain, limbic, and sensory processes are mainly governed by the central nervous system, with brainstem nuclei as relay centers for these crucial functions. Yet, the structural connectivity of brainstem nuclei in living humans remains understudied. These tiny structures are difficult to locate using conventional in vivo MRI, and ex vivo brainstem nuclei atlases lack precise and automatic transformability to in vivo images. To fill this gap, we mapped our recently developed probabilistic brainstem nuclei atlas developed in living humans to high-spatial resolution (1.7 mm isotropic) and diffusion weighted imaging (DWI) at 7 Tesla in 20 healthy participants. To demonstrate clinical translatability, we also acquired 3 Tesla DWI with conventional resolution (2.5 mm isotropic) in the same participants. Results showed the structural connectome of 15 autonomic, pain, limbic, and sensory (including vestibular) brainstem nuclei/nuclei complex (superior/inferior colliculi, ventral tegmental area-parabrachial pigmented, microcellular tegmental-parabigeminal, lateral/medial parabrachial, vestibular, superior olivary, superior/inferior medullary reticular formation, viscerosensory motor, raphe magnus/pallidus/obscurus, parvicellular reticular nucleus-alpha part), derived from probabilistic tractography computation. Through graph measure analysis, we identified network hubs and demonstrated high intercommunity communication in these nuclei. We found good (r = .5) translational capability of the 7 Tesla connectome to clinical (i.e., 3 Tesla) datasets. Furthermore, we validated the structural connectome by building diagrams of autonomic/pain/limbic connectivity, vestibular connectivity, and their interactions, and by inspecting the presence of specific links based on human and animal literature. These findings offer a baseline for studies of these brainstem nuclei and their functions in health and disease, including autonomic dysfunction, chronic pain, psychiatric, and vestibular disorders

The influence of diet and metabolism on hippocampus and hypothalamus connectivity across the lifespan

The high prevalence of unhealthy dietary patterns, obesity, and related brain disorders such as dementia emphasise the importance of research that examines the effect of dietary and metabolic factors on brain health. Using magnetic resonance imaging (MRI) to assess brain grey matter functional connectivity (FC) and volumes, this thesis aimed to examine the relationship between measures of diet and metabolism and the brain over the adult lifespan. First, a systematic review was conducted, to examine the relationship between dietary and metabolic health in relation to a wide range of brain MRI markers. The reviewed evidence suggested that lower dietary and metabolic health quality was related to reduced brain volume and connectivity, especially in the default mode network and the frontal and temporal lobes, although there were contrasting trends for each of these associations. To address the gaps identified by the review, we examined the association between dietary and metabolic health in relation to the hippocampus and hypothalamus FC and volumes in the cross-sectional Human Connectome Project cohort of 400 younger adults and in the longitudinal Whitehall II cohort of 775 midlife-older aged adults. The Whitehall cohort had longitudinal measures of diet/metabolic markers collected every 5 years throughout their midlife (40-70 years old). First, we note that different dietary and metabolic markers have unique patterns of longitudinal trajectories from mid-to-old-age. Our findings supported the hypothesis that better dietary and metabolic health is associated with volumetric and FC differences of the hippocampus and the hypothalamus both in younger and older cohorts. Specifically, dietary and metabolic health was linked to (1) hippocampal FC with the frontal lobe, precentral gyrus, and occipital lobe and (2) hypothalamic FC with the brainstem and the basal forebrain. These findings contribute to a growing understanding of the brain networks associated with dietary and metabolic health. The thesis provides insights into when in life dietary and metabolic health measures are related to brain health. Our findings indicated that in order to promote brain health in older age, some metabolic factors may be better targeted in midlife (e.g., cholesterol, diet, abdominal fat), while other factors should be targeted as early as possible (blood pressure, body composition/BMI). This may have implications for preventative lifestyle interventions to reduce the risk of developing dementia and to maintain overall brain health

The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species

Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders

The bed nucleus of the stria terminalis (BNST) is a center of integration for limbic information and valence monitoring. The BNST, sometimes referred to as the extended amygdala, is located in the basal forebrain and is a sexually dimorphic structure made up of between 12 and 18 sub-nuclei. These sub-nuclei are rich with distinct neuronal subpopulations of receptors, neurotransmitters, transporters and proteins. The BNST is important in a range of behaviors such as: the stress response, extended duration fear states and social behavior, all crucial determinants of dysfunction in human psychiatric diseases. Most research on stress and psychiatric diseases has focused on the amygdala, which regulates immediate responses to fear. However, the BNST, and not the amygdala, is the center of the psychogenic circuit from the hippocampus to the paraventricular nucleus. This circuit is important in the stimulation of the hypothalamic-pituitary-adrenal axis. Thus, the BNST has been largely overlooked with respect to its possible dysregulation in mood and anxiety disorders, social dysfunction and psychological trauma, all of which have clear gender disparities. In this review, we will look in-depth at the anatomy and projections of the BNST, and provide an overview of the current literature on the relevance of BNST dysregulation in psychiatric diseases

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin