Functional and neural mechanisms of human fear conditioning: studies in healthy and brain-damaged individuals

Fear conditioning represents the learning process by which a stimulus, after repeated pairing with an aversive event, comes to evoke fear and becomes intrinsically aversive. This learning is essential to organisms throughout the animal kingdom and represents one the most successful laboratory paradigm to reveal the psychological processes that govern the expression of emotional memory and explore its neurobiological underpinnings. Although a large amount of research has been conducted on the behavioural or neural correlates of fear conditioning, some key questions remain unanswered. Accordingly, this thesis aims to respond to some unsolved theoretic and methodological issues, thus furthering our understanding of the neurofunctional basis of human fear conditioning both in healthy and brain-damaged individuals. Specifically, in this thesis, behavioural, psychophysiological, lesion and non-invasive brain stimulation studies were reported. Study 1 examined the influence of normal aging on context-dependent recall of extinction of fear conditioned stimulus. Study 2 aimed to determine the causal role of the ventromedial PFC (vmPFC) in the acquisition of fear conditioning by systematically test the effect of bilateral vmPFC brain-lesion. Study 3 aimed to interfere with the reconsolidation process of fear memory by the means of non-invasive brain stimulation (i.e. TMS) disrupting PFC neural activity. Finally, Study 4 aimed to investigate whether the parasympathetic – vagal – modulation of heart rate might reflect the anticipation of fearful, as compared to neutral, events during classical fear conditioning paradigm. Evidence reported in this PhD thesis might therefore provide key insights and deeper understanding of critical issues concerning the neurofunctional mechanisms underlying the acquisition, the extinction and the reconsolidation of fear memories in humans

The Effect of Anticipatory Anxiety on Fear Extinction Learning

Adaptive regulation of fear is dependent on successful fear extinction learning; therefore, investigating factors that both enhance and diminish fear extinction learning is a critical line of research. In the present study, we induce mild anticipatory anxiety during fear extinction learning in an attempt to modulate how participants extinguish fear memory. In the experiment, we apply a classic three-day fear learning protocol to both control participants (N = 20) and an experimental group (N = 20) with fear acquisition, fear extinction, and fear recovery phases; each phase is separated by a period of 24 hours and we use a skin conductance response as an index of fear learning. Unlike control participants, experimental participants are verbally instructed that they may receive an additional, unrelated aversive stimulus on day two of the experiment, prior to the onset of the fear learning phase, thus inducing mild anticipatory anxiety. To investigate the effect of anticipatory anxiety on fear extinction learning, we compared mean skin conductance responses between condition groups for all three phases of the experiment. We also accounted for the effect of stimulus type (paired conditioned stimulus, unpaired conditioned stimulus) on mean skin conductance responses for each experimental phase. Ultimately, we found evidence that our novel induction of anticipatory anxiety enhanced fear extinction learning in the experimental group, relative to the control group. Likewise, we found preliminary evidence that our methodology diminished fear recovery 24 hours later in the experimental group, relative to controls. Our findings are partially supported by previous studies and justify the need for further research on how mild anticipatory anxiety, among other factors, might enhance fear extinction learning

A dimensional approach to modeling symptoms of neuropsychiatric disorders in the marmoset monkey.

Some patients suffering from the same neuropsychiatric disorder may have no overlapping symptoms whilst others may share symptoms common to other distinct disorders. Therefore, the Research Domain Criteria initiative recognises the need for better characterisation of the individual symptoms on which to focus symptom-based treatment strategies. Many of the disorders involve dysfunction within the prefrontal cortex (PFC) and so the marmoset, due to their highly developed PFC and small size, is an ideal species for studying the neurobiological basis of the behavioural dimensions that underlie these symptoms.Here we focus on a battery of tests that address dysfunction spanning the cognitive (cognitive inflexibility and working memory), negative valence (fear generalisation and negative bias) and positive valence (anhedonia) systems pertinent for understanding disorders such as ADHD, Schizophrenia, Anxiety, Depression and OCD. Parsing the separable prefrontal and striatal circuits and identifying the selective neurochemical modulation (serotonin vs dopamine) that underlie cognitive dysfunction have revealed counterparts in the clinical domain. Aspects of the negative valence system have been explored both at individual- (trait anxiety and genetic variation in serotonin transporter) and circuit-based levels enabling the understanding of generalisation processes, negative biases and differential responsiveness to SSRIs. Within the positive valence system, the combination of cardiovascular and behavioural measures provides a framework for understanding motivational, anticipatory and consummatory aspects of anhedonia and their neurobiological mechanisms. Together, the direct comparison of experimental findings in marmosets with clinical studies is proving an excellent translational model to address the behavioural dimensions and neurobiology of neuropsychiatric symptoms. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 328-353, 2017.This work was supported by long term funding from the MRC (ACR) and the Wellcome Trust (TWR) and was performed within the Behavioural and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. LO is supported by an MRC studentship.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/dneu.2244

Disruption of Bradycardia During Vigilance: Autonomic Cardiac Dysregulation is Prelude to Disinhibition, Hyperarousal, and Attention Bias in Combat Veterans with PTSD

We propose a model to account for the post‐traumatic stress disorder (PTSD) symptoms of disinhibition, hyperarousal, and attention bias. We review the background literature which is the foundation on which our model rests, present key results of our ongoing research, and suggest testable hypotheses for further research. Our laboratory is in a Veterans Affairs (VA) Medical Center, where we began our work with a search for the significant causes and predictors of hyperarousal in combat veterans with PTSD using eyeblink and autonomic conditioning protocols. We believe our studies will lead to integration of a treatment intervention for war veterans (and equally as well for treatment of the traumatically stressed in the general population). Our research has begun to show strong associations between lowered heart rate variability (HRV) and PTSD. Loss of bradycardia during normal vigilance is the cause of lowered HRV, which impairs appraisal of threat value of environmental stimulation, thereby leading to disinhibition, hyperarousal, and attention bias toward and away from threat. The next steps of research we plan are outlined and designed to elucidate how HRV biofeedback is a promising intervention to increase HRV during vigilance of stimuli and restore cognitive appraisal and response selection, thereby reducing PTSD symptoms and normalizing behavior

Local and regional heterogeneity underlying hippocampal modulation of cognition and mood.

While the hippocampus has been classically studied for its role in learning and memory, there is significant support for a role of the HPC in regulating emotional behavior. Emerging research suggests these functions may be segregated along the dorsoventral axis of the HPC. In addition to this regional heterogeneity, within the HPC, the dentate gyrus is one of two areas in the adult brain where stem cells continuously give rise to new neurons. This process can influence and be modulated by the emotional state of the animal, suggesting that adult neurogenesis within the DG may contribute to psychiatric disorders and cognitive abilities. Yet, the exact mechanism by which these newborn neurons influence behavior remains unknown. Here, we will examine the contribution of hippocampal neurogenesis to the output of the HPC, and suggest that the role of neurogenesis may vary along the DV axis. Next, we will review literature indicating that anatomical connectivity varies along the DV axis of the HPC, and that this underlies the functional segregation along this axis. This analysis will allow us to synthesize novel hypotheses for the differential contribution of the HPC to cognition and mood

帯状疱疹後神経痛患者における右背外側前頭前野の血行動態の障害は、プラシーボ効果の障害および臨床症状に関与する

富山大学・富医薬博甲第323号・日比 大亮・2020/03/24公表論文IBRO Reports, Volume 8, June 2020, Pages 56-64, https://doi.org/10.1016/j.ibror.2020.01.003富山大

An insula hierarchical network architecture for active interoceptive inference

In the brain, the insular cortex receives a vast amount of interoceptive information, ascending through deep brain structures, from multiple visceral organs. The unique hierarchical and modular architecture of the insula suggests specialization for processing interoceptive afferents. Yet, the biological significance of the insula's neuroanatomical architecture, in relation to deep brain structures, remains obscure. In this opinion piece, we propose the Insula Hierarchical Modular Adaptive Interoception Control (IMAC) model to suggest that insula modules (granular, dysgranular and agranular), forming parallel networks with the prefrontal cortex and striatum, are specialized to form higher order interoceptive representations. These interoceptive representations are recruited in a context-dependent manner to support habitual, model-based and exploratory control of visceral organs and physiological processes. We discuss how insula interoceptive representations may give rise to conscious feelings that best explain lower order deep brain interoceptive representations, and how the insula may serve to defend the body and mind against pathological depression