Seeing Fear: It's All in the Eyes?

Is an amygdala necessary to experience and perceive fear? Intriguing evidence comes from patient S.M. who lost her left and right amygdalae to disease. Initial testing suggested that S.M.'s most defining symptom was an inability to recognize fear in other people's facial expressions. A fascinating paper by Adolphs and colleagues in 2005 examined one potential mechanism for this impairment: a failure to spontaneously attend to widened eyes, the most distinctive physical feature portrayed in symbolic fear expressions. This study helped to invigorate debates about the brain basis of fear and paved the way for a more nuanced understanding of amygdalar function.

The Basolateral Amygdalae and Frontotemporal Network Functions for Threat Perception.

Although the amygdalae play a central role in threat perception and reactions, the direct contributions of the amygdalae to specific aspects of threat perception, from ambiguity resolution to reflexive or deliberate action, remain ill understood in humans. Animal studies show that a detailed understanding requires a focus on the different subnuclei, which is not yet achieved in human research. Given the limits of human imaging methods, the crucial contribution needs to come from individuals with exclusive and selective amygdalae lesions. The current study investigated the role of the basolateral amygdalae and their connection with associated frontal and temporal networks in the automatic perception of threat. Functional activation and connectivity of five individuals with Urbach-Wiethe disease with focal basolateral amygdalae damage and 12 matched controls were measured with functional MRI while they attended to the facial expression of a threatening face-body compound stimuli. Basolateral amygdalae damage was associated with decreased activation in the temporal pole but increased activity in the ventral and dorsal medial prefrontal and medial orbitofrontal cortex. This dissociation between the prefrontal and temporal networks was also present in the connectivity maps. Our results contribute to a dynamic, multirole, subnuclei-based perspective on the involvement of the amygdalae in fear perception. Damage to the basolateral amygdalae decreases activity in the temporal network while increasing activity in the frontal network, thereby potentially triggering a switch from resolving ambiguity to dysfunctional threat signaling and regulation, resulting in hypersensitivity to threat.

An Enhanced Default Approach Bias Following Amygdala Lesions in Humans.

Approach and avoidance constitute a basic dimension of all animal behavior. Although a large number of studies have investigated approach and avoidance elicited by specific sensory stimuli, comparatively little is known about default approach biases when stimulus information is absent or reduced. The amygdala is well known to contribute to approach and avoidance behaviors in response to specific sensory stimuli; we tested whether the amygdala's role might extend to situations in which stimulus information is reduced. In a novel task, 3 patients with rare bilateral amygdala lesions (and control subjects) made approach-related judgments about photos of intact faces and of the same faces with all internal facial features occluded. Direct comparisons of the judgments of these stimuli isolated a default bias. The patients showed a greater tendency than the control subjects to rate occluded faces as more approachable than whole faces. These findings suggest that the amygdala's role in approach behavior extends beyond responses to specific stimuli.

Impaired threat prioritisation after selective bilateral amygdala lesions.

The amygdala is proposed to process threat-related information in non-human animals. In humans, empirical evidence from lesion studies has provided the strongest evidence for a role in emotional face recognition and social judgement. Here we use a face-in-the-crowd (FITC) task which in healthy control individuals reveals prioritised threat processing, evident in faster serial search for angry compared to happy target faces. We investigate AM and BG, two individuals with bilateral amygdala lesions due to Urbach-Wiethe syndrome, and 16 control individuals. In lesion patients we show a reversal of a threat detection advantage indicating a profound impairment in prioritising threat information. This is the first direct demonstration that human amygdala lesions impair prioritisation of threatening faces, providing evidence that this structure has a causal role in responding to imminent danger.

Structural focal temporal lobe seizures in a child with lipoproteinosis.

BACKGROUND: Lipoproteinosis is a rare autosomal recessive disorder caused by a mutation in a gene (ECM1) on chromosome 1q21. Alterations of membrane and vessels in the dermal-epidermal junction represent the pathologic background of the disease. Calcification in the temporal lobes and hippocampi are common and may be associated with epileptic seizures. PATIENT DESCRIPTION: We describe a 7-year-old girl with lipoproteinosis who presented with hoarseness, typical skin lesions, and seizures. RESULTS: Video electroencephalography demonstrated focal temporal lobe seizures. Intelligence quotient was normal, but psychologic tests revealed depressed mood. Neuroimaging revealed bilateral mesial temporal lobe calcifications. CONCLUSIONS: The report reveals that the temporal lobe calcifications and the consequent epileptic seizures can appear even very early. The psychological signs may reflect limbic system dysfunction.

Preferential attention to animals and people is independent of the amygdala.

The amygdala is thought to play a critical role in detecting salient stimuli. Several studies have taken ecological approaches to investigating such saliency, and argue for domain-specific effects for processing certain natural stimulus categories, in particular faces and animals. Linking this to the amygdala, neurons in the human amygdala have been found to respond strongly to faces and also to animals. However, the amygdala's necessary role for such category-specific effects at the behavioral level remains untested. Here we tested four rare patients with bilateral amygdala lesions on an established change-detection protocol. Consistent with prior published studies, healthy controls showed reliably faster and more accurate detection of people and animals, as compared with artifacts and plants. So did all four amygdala patients: there were no differences in phenomenal change blindness, in behavioral reaction time to detect changes or in eye-tracking measures. The findings provide decisive evidence against a critical participation of the amygdala in rapid initial processing of attention to animate stimuli, suggesting that the necessary neural substrates for this phenomenon arise either in other subcortical structures (such as the pulvinar) or within the cortex itself.

Temporal lobe epilepsy and emotion recognition without amygdala: a case study of Urbach-Wiethe disease and review of the literature.

We describe the epilepsy features and emotion recognition abilities (recognition of basic facial emotions and recognition of emotional prosody) in a patient with Urbach-Wiethe disease with bilateral amygdala calcifications. Our data, supported by ictal video-EEG recording, indicated that our patient suffered from mesial temporal lobe epilepsy. Emotion recognition abilities were compared to those of healthy controls and those of patients with bilateral mesial temporal lobe epilepsy. Our patient showed a selective impairment of the recognition of facial expression of fear, whereas recognition of emotional prosody was preserved, in contrast to bilateral mesial temporal lobe epilepsy patients that presented with deficits in both domains. We also reviewed the literature on epilepsy in Urbach-Wiethe disease (41 patients). Our findings suggest that in Urbach-Wiethe disease, the circumscribed damage of both amygdalae results in a selective dysfunction of fearful face processing, in contrast to bilateral mesial temporal lobe epilepsy patients who present with a widespread and multimodal impairment in the judgement of emotional stimuli.

Molecular and neurological characterizations of three Saudi families with lipoid proteinosis.

BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families. METHODS: Clinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene. RESULTS: All seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8. CONCLUSIONS: These individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.

Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.

Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

Reduced 5-HT(2A) receptor signaling following selective bilateral amygdala damage.

Neurobiological evidence implicates the amygdala as well as serotonergic (serotonin, 5-HT) signaling via postsynaptic 5-HT(2A) receptors as essential substrates of anxiety behaviors. Assuming a functional interdependence of these substrates, we hypothesized that a low-fear behavioral phenotype due to bilateral lesion of the amygdala would be associated with significant 5-HT(2A) receptor changes. Thus, we used [(18)F]altanserin positron emission tomography (PET) referenced to radioligand plasma levels and corrected for partial volume effects to quantify the spatial distribution of 5-HT(2A) receptor binding potential (BP(P)) in a rare patient with Urbach-Wiethe disease and selective bilateral amygdala calcification damage relative to 10 healthy control subjects. Consistent with our a priori hypothesis, we observed a 70% global decrease in 5-HT(2A) receptor BP(P) in the Urbach-Wiethe patient relative to controls. Thus, brain abnormalities in this patient are not restricted to the amygdala, but extend to overall 5-HT neurotransmission via 5-HT(2A) receptors. Our findings provide important insights into the molecular architecture of human anxiety behaviors and suggest the 5-HT(2A) receptor as a promising pharmacological target to control pathological anxiety.

The neuropsychiatry and neuropsychology of lipoid proteinosis.

Lipoid proteinosis is a rare hereditary disease which often results in bilateral calcifications in the medial temporal region. Thirty-four adults living with lipoid proteinosis (>10% of the world population) were extensively assessed with standardized neuropsychiatric and neuropsychological measures. Of these, 27 patients representing a homogenous group living in the Northern Cape were matched with 47 controls. Subjects with lipoid proteinosis had a high incidence of neuropsychiatric disorders and performed poorly on facial recognition of positive and negative emotions and on many neuropsychological measures. These findings are consistent with involvement of the medial temporal areas in cognitive and emotive processing.

Amygdala control of emotion-induced forgetting and remembering: evidence from Urbach-Wiethe disease.

When presented in a neutral context, emotional items interfere with episodic encoding of temporally contiguous non-emotional items, resulting in dissociable valence-dependent retrograde and arousal-dependent anterograde modulatory effects. By studying two rare patients with congenital lipoid proteinosis (Urbach-Wiethe) and a focal disease emphasis on the basolateral amygdala (BLA), we demonstrate that this bidirectional modification of episodic encoding by emotion depends on the integrity of the amygdala, as both retrograde and anterograde modulatory effects are absent. Our findings implicate the amygdala in a neural circuitry that orchestrates rapid retrograde and anterograde regulation of episodic memory access upon criteria of behavioral significance.

Role of the amygdala in decisions under ambiguity and decisions under risk: evidence from patients with Urbach-Wiethe disease.

Various neuropsychological studies have shown that decision-making deficits can occur in a wide range of patients with brain damage or dysfunctions. Decisions under ambiguity, as measured with the Iowa Gambling Task, primarily depend on the integrity of the ventromedial prefrontal cortex and the amygdala, as well as on further brain regions such as the somatosensory cortex. However, little is known about the specific role of these structures in decisions under risk measured with tasks that offer explicit rules for gains and losses and winning probabilities, for example, the Game of Dice Task. We aimed to investigate the potential role of the amygdala for decisions under risk. For this purpose, we examined three patients with Urbach-Wiethe disease--a rare syndrome associated with selective bilateral mineralisation of the amygdalae. Neuropsychological performance was assessed with the Iowa Gambling Task (decisions under ambiguity), the Game of Dice Task (decisions under risk), and an extensive neuropsychological test battery focussing on executive functions. Furthermore, previous studies found relationships between generating skin conductance responses and deciding advantageously in the Iowa Gambling Task. Accordingly, we recorded skin conductance responses during both decision tasks as a measure of emotional reactivity. Results indicate that patients with selective amygdala damage have lower scores in both decisions under ambiguity and decisions under risk. Decisions under risk are especially compromised in patients who also demonstrate deficits in executive functioning. In both gambling tasks, patients showed reduced skin conductance responses compared to healthy comparison subjects. The results suggest that deciding advantageously under risk conditions involves both the use of feedback from previous trials, as required by decisions under ambiguity, and in addition, executive functions.

Lipoid proteinosis: A case with ophthalmological and psychiatric findings.

Lipoid proteinosis (LP) is an uncommon, recessively inherited disorder. The disease usually has its onset in the newborn period and is manifested by hoarseness. The skin and mucous membrane involvement arises between the first and second year of age. A 14-year-old male presented with the complaint of blistering on various sites of his skin, from the age of 12 months, resulting in scarring. Ophthalmological and psychiatric findings also appeared during the clinical course. The histological findings of skin biopsy included extensive deposits of amorphous eosinophilic material in the papillary dermis. No known therapy exists for LP.

Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease.

Patients with Urbach-Wiethe disease constitute a unique nature experiment as more than half have bilaterally symmetrical damage in the amygdaloid region. Ten such patients were studied neuropsychologically and, nine of them, neuroradiologically with static (CT) and functional imaging techniques [single-photon emission computed tomography (SPECT) and PET]. Their principal bilateral amygdala damage was confirmed. Neuropsychologically, the patients showed cognitively little deviation from normal subjects, while they differed emotionally. This was evident in their judgement of all emotions in facial expressions, in an odour-figure association test as well as in remembering negative and positive pictures. This suggests that the human amygdala influences both negative and positive emotional processing.

Lipoid proteinosis presenting with neuropsychiatric manifestations.

Two patients with lipoid proteinosis are reported in whom paranoid symptoms were the presenting feature. Both had a long standing impairment of memory and bilateral medial temporal lobe calcification demonstrated by CT scan. Possible associations between the anatomical site of these lesions and the neuropsychiatric manifestations are discussed.