Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage.

Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach-Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes.

[1]  D. Amaral,et al.  The Nonhuman Primate Amygdala Is Necessary for the Acquisition but not the Retention of Fear-Potentiated Startle , 2009, Biological Psychiatry.

[2]  Stephen Maren,et al.  Nuclear disconnection within the amygdala reveals a direct pathway to fear. , 2009, Learning & memory.

[3]  Iole Indovina,et al.  Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans , 2011, Neuron.

[4]  M. Bradley,et al.  Emotion, attention, and the startle reflex. , 1990, Psychological review.

[5]  J. Price Comparative Aspects of Amygdala Connectivity , 2003, Annals of the New York Academy of Sciences.

[6]  Uwe Runge,et al.  Fear Conditioning following Unilateral Temporal Lobectomy: Dissociation of Conditioned Startle Potentiation and Autonomic Learning , 2005, The Journal of Neuroscience.

[7]  Andrew M. Poulos,et al.  Persistence of fear memory across time requires the basolateral amygdala complex , 2009, Proceedings of the National Academy of Sciences.

[8]  Simon B. Eickhoff,et al.  Assignment of functional activations to probabilistic cytoarchitectonic areas revisited , 2007, NeuroImage.

[9]  J. Kenemans,et al.  Genetic variation in serotonin transporter function affects human fear expression indexed by fear-potentiated startle , 2012, Biological Psychology.

[10]  Joseph E LeDoux,et al.  Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala , 1999, Neuron.

[11]  Justin S. Feinstein,et al.  Fear and panic in humans with bilateral amygdala damage , 2013, Nature Neuroscience.

[12]  C. Grillon,et al.  Classical fear conditioning in the anxiety disorders: a meta-analysis. , 2005, Behaviour research and therapy.

[13]  C. Grillon,et al.  The strong situation: A potential impediment to studying the psychobiology and pharmacology of anxiety disorders , 2006, Biological Psychology.

[14]  Dan J Stein,et al.  Paradoxical Facilitation of Working Memory after Basolateral Amygdala Damage , 2012, PloS one.

[15]  Alfons O. Hamm,et al.  Genetic Gating of Human Fear Learning and Extinction , 2009, Psychological science.

[16]  R. Martinez,et al.  Conditioned and unconditioned fear organized in the inferior colliculus are differentially sensitive to injections of muscimol into the basolateral nucleus of the amygdala. , 2006, Behavioral neuroscience.

[17]  Michael Davis,et al.  Fear-potentiated startle: A neural and pharmacological analysis , 1993, Behavioural Brain Research.

[18]  W. Paesschen,et al.  Classically conditioned fear responses are preserved following unilateral temporal lobectomy in humans when concurrent US-expectancy ratings are used , 2009, Neuropsychologia.

[19]  R. Martinez,et al.  Serotonergic mechanisms in the basolateral amygdala differentially regulate the conditioned and unconditioned fear organized in the periaqueductal gray , 2007, European Neuropsychopharmacology.

[20]  G. Quirk,et al.  Neuronal signalling of fear memory , 2004, Nature Reviews Neuroscience.

[21]  A. Bechara The role of emotion in decision-making: Evidence from neurological patients with orbitofrontal damage , 2004, Brain and Cognition.

[22]  C. Grillon,et al.  Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans , 2012, Journal of psychopharmacology.

[23]  S. Mineka,et al.  The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. , 2008, Acta Psychologica.

[24]  K. Amunts,et al.  Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps , 2005, Anatomy and Embryology.

[25]  N. Mackintosh A Theory of Attention: Variations in the Associability of Stimuli with Reinforcement , 1975 .

[26]  Michael Davis,et al.  The amygdala: vigilance and emotion , 2001, Molecular Psychiatry.

[27]  J. D. Nichols,et al.  Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. , 1997, Science.

[28]  M. Egan,et al.  Serotonin Transporter Genetic Variation and the Response of the Human Amygdala , 2002, Science.

[29]  Jean-Luc Anton,et al.  Region of interest analysis using an SPM toolbox , 2010 .

[30]  Dan J Stein,et al.  Generous economic investments after basolateral amygdala damage , 2013, Proceedings of the National Academy of Sciences.

[31]  Joseph E LeDoux The Emotional Brain, Fear, and the Amygdala , 2003, Cellular and Molecular Neurobiology.

[32]  B. Cuthbert,et al.  Committee report: Guidelines for human startle eyeblink electromyographic studies. , 2005, Psychophysiology.

[33]  S. Shelton,et al.  The Role of the Central Nucleus of the Amygdala in Mediating Fear and Anxiety in the Primate , 2004, The Journal of Neuroscience.

[34]  J. Kenemans,et al.  Failure to condition to a cue is associated with sustained contextual fear. , 2008, Acta psychologica.

[35]  R. Adolphs,et al.  Anteromedial temporal lobe damage blocks startle modulation by fear and disgust. , 2004, Behavioral neuroscience.

[36]  Ralph Adolphs,et al.  The Biology of Fear , 2013, Current Biology.

[37]  J. Kenemans,et al.  Prefrontal Mechanisms of Fear Reduction After Threat Offset , 2010, Biological Psychiatry.

[38]  Joseph E LeDoux,et al.  Molecular Mechanisms of Fear Learning and Memory , 2011, Cell.

[39]  Olga V. Demler,et al.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[40]  Joseph E LeDoux,et al.  Impaired fear conditioning following unilateral temporal lobectomy in humans , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  A. McDonald Cortical pathways to the mammalian amygdala , 1998, Progress in Neurobiology.

[42]  A. Hamm,et al.  Affective learning: awareness and aversion. , 1996, Psychophysiology.

[43]  Dan J Stein,et al.  Hypervigilance for fear after basolateral amygdala damage in humans , 2012, Translational Psychiatry.

[44]  Stephen Maren Neurotoxic Basolateral Amygdala Lesions Impair Learning and Memory But Not the Performance of Conditional Fear in Rats , 1999, The Journal of Neuroscience.

[45]  Christian Grillon,et al.  A review of the modulation of the startle reflex by affective states and its application in psychiatry , 2003, Clinical Neurophysiology.

[46]  Dan J Stein,et al.  The neuropsychiatry and neuropsychology of lipoid proteinosis. , 2008, The Journal of neuropsychiatry and clinical neurosciences.

[47]  Lief E. Fenno,et al.  Amygdala circuitry mediating reversible and bidirectional control of anxiety , 2011, Nature.

[48]  Johannes J. Letzkus,et al.  Amygdala interneuron subtypes control fear learning through disinhibition , 2014, Nature.

[49]  K. Tye,et al.  Amygdala Inputs to the Ventral Hippocampus Bidirectionally Modulate Social Behavior , 2014, The Journal of Neuroscience.

[50]  Arne Öhman,et al.  Phobias and preparedness: the selective, automatic, and encapsulated nature of fear , 2002, Biological Psychiatry.

[51]  R. Clark,et al.  Classical conditioning and brain systems: the role of awareness. , 1998, Science.

[52]  J. Kenemans,et al.  Attentional bias in high- and low-anxious individuals: Evidence for threat-induced effects on engagement and disengagement , 2011, Cognition & emotion.

[53]  D. Amaral,et al.  Role of the Primate Amygdala in Fear-Potentiated Startle: Effects of Chronic Lesions in the Rhesus Monkey , 2007, The Journal of Neuroscience.