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Over the last decades, important advances in neuroimaging have prompted remarkable progress in mapping the human brain; from characterizing the structural scaffolds underlying brain communication to revealing the signatures of spatiotemporal dynamics underlying different brain states. In particular, statistical descriptions of brain states have started to show promise as robust biomarkers of brain functioning. Increasing evidence of the strong link between specific patterns of brain network disruption and the symptoms of different brain disorders combined with causal whole-brain modeling have raised great expectations of bringing about rational, novel ways to predict optimal rebalancing of affected brain circuitry.

Anatomic tracing is recognized as a critical source of knowledge on brain circuitry that can be used to assess the accuracy of diffusion MRI (dMRI) tractography. However, most prior studies that have performed such assessments have used dMRI and tracer data from different brains and/or have been limited in the scope of dMRI analysis methods allowed by the data. In this work, we perform a quantitative, voxel-wise comparison of dMRI tractography and anatomic tracing data in the same macaque brain. An ex vivo dMRI acquisition with high angular resolution and high maximum b-value allows us to compare a range of q-space sampling, orientation reconstruction, and tractography strategies. The availability of tracing in the same brain allows us to localize the sources of tractography errors and to identify axonal configurations that lead to such errors consistently, across dMRI acquisition and analysis strategies. We find that these common failure modes involve geometries such as branching or turning, which cannot be modeled well by crossing fibers. We also find that the default thresholds that are commonly used in tractography correspond to rather conservative, low-sensitivity operating points. While deterministic tractography tends to have higher sensitivity than probabilistic tractography in that very conservative threshold regime, the latter outperforms the former as the threshold is relaxed to avoid missing true anatomical connections. On the other hand, the q-space sampling scheme and maximum b-value have less of an impact on accuracy. Finally, using scans from a set of additional macaque brains, we show that there is enough inter-individual variability to warrant caution when dMRI and tracer data come from different animals, as is often the case in the tractography validation literature. Taken together, our results provide insights on the limitations of current tractography methods and on the critical role that anatomic tracing can play in identifying potential avenues for improvement.

The dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) as two major amygdalar nuclei, are recognized to play distinct roles in affective functions and internal states, via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with K-means clustering approach in a total of 79 young healthy individuals (cohort 1: 42; cohort 2: 37), we identified two distinct states of BLA- and CMA-based intrinsic connectivity patterns, with one state (integration) showing generally stronger BLA- and CMA-based intrinsic connectivity with multiple brain networks, while the other (segregation) exhibiting weaker yet dissociable connectivity patterns. In an independent cohort 2 of fMRI data with concurrent recording of skin conductance, we replicated two similar dynamic states and further found higher skin conductance level in the integration than segregation state. Moreover, machine learning-based Elastic-net regression analyses revealed that time-varying BLA and CMA intrinsic connectivity with distinct network configurations yield higher predictive values for spontaneous fluctuations of skin conductance level in the integration than segregation state. Our findings highlight dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans.

Highlights • Lower family income was related to lower prefrontal activity during decision-making. • Associations were found in subgenual anterior cingulate (sACC) for expected value. • Greater adolescent depressive symptoms were related to lower sACC activation., Lower family income during childhood is related to increased rates of adolescent depression, though the underlying mechanisms are poorly understood. Evidence suggests that individuals with depression demonstrate hypoactivation in brain regions involved in reward learning and decision-making processes (e.g., portions of the prefrontal cortex). Separately, lower family income has been associated with neural alterations in similar regions. Motivated by this research, we examined associations between family income, depression, and brain activity during a reward learning and decision-making fMRI task in a sample of adolescents (full n = 94; usable n = 78; mean age = 15.2 years). We focused on brain activity for: 1) expected value (EV), the learned subjective value of an object, and 2) prediction error, the difference between EV and the actual outcome received. Regions of interest related to reward learning were examined in connection to childhood family income and parent-reported adolescent depressive symptoms. As hypothesized, lower activity in the subgenual anterior cingulate (sACC) for EV in response to approach stimuli was associated with lower childhood family income, as well as greater symptoms of depression measured one-year after the neuroimaging session. These results are consistent with the hypothesis that lower early family income leads to disruptions in reward and decision-making brain circuitry, contributing to adolescent depression.

Major Depressive Disorder (MDD) is a mood disorder characterized by a large number and variety of symptoms, including affective/emotional (persistent sadness, anhedonia, anxiety, agitation, guilt feelings, hopelessness, etc.), somatic (tiredness, loss of energy, sleep disturbances, reduced/increased appetite, weight gain/loss etc.) and cognitive symptoms (slowness of thinking, concentration difficulties, etc.). Overall, this suggests the presence of derangements of nerve transmission in different areas/circuits involved in the control of these disturbed brain functions., Supported by the Spanish Ministry of Economy and Competitiveness, SAF2015–68346-P MINECO/FEDER, co-financed by the European Regional Development Fund “A way to build Europe”. Supported also by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and by CERCA Programme from the Generalitat de Catalunya. I also would like to thank the support of the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya (2017SGR717).

Early-life experience can modulate risk versus resilience to emotional and cognitive disorders in adulthood. This suggests that there is a particularly sensitive period early in life, during which beneficial or adverse events can cause a later propensity toward stress resilience or vulnerability, respectively. Most early-life experiences are generated from signals received from the primary caregiver, and perturbations in these signals can program stress-related behaviors throughout life. These maternal signals cause lasting changes in brain circuitry and function, including networks associated with learning and memory, and with emotional and stress responses. Underlying these changes in brain circuits are transcriptional and epigenetic mechanisms. These molecular changes are instigated by early-life experiences and set in motion a signaling cascade that can determine resilience or vulnerabilities in adulthood.

Animals, including humans, require a highly coordinated and flexible system of social behavior and threat evaluation. However, trauma can disrupt this system, with the amygdala implicated as a mediator of these impairments in behavior. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences, with trauma experienced from an attachment figure, such as occurs in cases of caregiver-child maltreatment, as particularly detrimental. This review focuses on the unique role of caregiver presence during early-life trauma in programming deficits in social behavior and threat processing. Using data primarily from rodent models, we describe the interaction between trauma and attachment during a sensitive period in early life, which highlights the role of the caregiver’s presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. These data suggest that trauma experienced directly from an abusive caregiver and trauma experienced in the presence of caregiver cues produce similar neurobehavioral deficits, which are unique from those resulting from trauma alone. We go on to integrate this information into social experience throughout the lifespan, including consequences for complex scenarios, such as dominance hierarchy formation and maintenance. Keywords: Development, Threat, Amygdala, Social behavior, Dominance hierarchy

Substance abuse disorder is a chronically relapsing disease that is characterized in part by compulsion to seek and take drug in the presence of adverse consequences and in inappropriate situations. Compulsivity develops progressively, and is hypothesized to derive from dysfunction in motivational and reward processing. Preclinical models have been developed that recapitulate endophenotypes of compulsive drug behaviors to study the pathophysiology and etiology of compulsivity. These models have been used to identify adaptations in brain circuitry, neurotransmission, and epigenetics that underlie compulsive drug use, and have provided a framework for theories that describe the development and expression of compulsivity.

This chapter reviews in vivo characterization of brain structural and functional changes associated with chronic, excessive alcohol consumption. The whole-brain and whole-systems approaches afforded by in vivo magnetic resonance imaging to quantify brain structure and function have yielded two principles of alcohol’s effect on the brain: 1) Alcoholism affects selective brain systems, leaving others relatively intact; and 2) alcoholism modifies brain structure without necessarily killing neurons, thereby providing a basis for the “incomplete lesion” as the underlying neuropathology of alcoholism and potential for recovery. A unifying biological substrate of the alcoholism syndrome is identification of selective neural circuits commonly compromised in alcoholism. Target networks relevant to alcoholism’s loci of neuropathology and neuropsychological compromise involve frontocerebellar circuitry, frontolimbic circuitry, and frontostriatal circuitry. With their multiple, segregated loops, these widely distributed, frontally based networks link organized systems of brain anatomy and underlie selective constellations of brain functions.

Disorders of cognition are a major societal burden. As the population grows and ages, these conditions demand urgent attention, as healthcare resources stretch to accommodate the growing number of patients. Although much is known about the neurobiology of dementia and Alzheimer's disease (AD), few treatments are available to arrest or slow down the illness. By targeting specific structures within known circuits, deep brain stimulation (DBS) can have effects across memory and cognitive networks, and is therefore a potentially promising avenue for novel dementia treatments. This chapter reviews the literature on DBS for AD and dementia associated with Parkinson's disease, and highlight some of the neuroanatomical targets that offer the most promise in modulating the underlying pathological activity in brain circuitry.

The hypothalamus is an integrative center essential for survival of an organism and reproduction of its species. The diversity in regulatory function of the hypothalamus is reflected in its structure, neurochemistry, and connections. Almost every major subdivision of the central nervous system communicates with the hypothalamus and is subject to its influence. In addition, the hypothalamus communicates with peripheral organ systems by converting synaptic information to blood-borne hormonal signals and, in turn, responds to feedback signaling from those peripheral systems. The purpose of this chapter is to provide an introductory context for the more detailed chapters in the “Regulatory Systems” portion of the text. We provide a short historical perspective on research that defined the hypothalamus as an important regulatory center, continue with an overview of its structural and functional organization, and conclude with a discussion of how it functions within brain circuitry devoted to the control of motivated behaviors.

Trichotillomania is characterized by repetitive hair pulling leading to noticeable hair loss and functional impairment. This article considers the phenomenology, neurobiology, and treatment of trichotillomania. Animal models and human studies suggest underlying dysregulation of the brain circuitry involved in habit regulation, impulse control, and reward processing. Treatment studies are considered. These include behavioral (e.g., habit-reversal therapy) and pharmacological (e.g., selective serotonin-reuptake inhibitors) therapies.

The findings on dopamine in mood disorders suggest that decreased dopamine activity is involved in depression, while increased dopamine function contributes to mania. This report reviews the considerable preclinical and clinical evidence supporting this hypothesis, with particular emphasis on specific subtypes of depression. We also discuss the importance of integrating these dopamine findings with dopamine brain circuitry and with other neurotransmitter theories of affective disorders.

Absence (petit mal) seizures are a type of generalized seizure disorder. They occur during childhood and are diagnosed on the EEG by the characteristic spike and wave pattern. They have a characteristic set of clinical symptoms. Brain circuitry between the thalamus and the cortex is involved. Treatment is aimed at controlling channel activity including the ‘T’ type calcium channel.

Publisher Summary This chapter discusses recent studies of the noradrenergic locus coeruleus (LC) system to consider its possible roles in emotion. It describes the recent studies of the effects of manipulating LC neurons on electroencephalographic (EEG) activity and attentional behavior. Emotional responses are typically measured by EEG or autonomic arousal. Emotionally arousing stimuli produce activation of the cortical EEG, and parallel activation of autonomic measures such as blood pressure, heart rate, or galvanic skin response (as commonly used in lie detector tests). Recent results link the LC both to the EEG and autonomic responses that accompany emotionally arousing events LC neuronal projections, effects of NE on LC target cells, and discharge characteristics of LC neurons in unanesthetized, unconditioned animals are reviewed. More recent studies on the effects of stress on LC neurons, and on activity of LC neurons in behaving monkeys during a conditioned attentional task are also examined. The chapter reviews new findings on afferents to the LC that indicate the status of this key noradrenergic system in brain circuitry. Although the LC is not typically considered in the context of emotion, the analysis suggests that the LC system could play an important role in the process of emotional activation.