Hippocampus in autism: a Golgi analysis

Autism is a behaviorally defined syndrome in which neuropathological abnormalities have been identified in the limbic system and cerebellum. The morphology of hippocampal neurons in two cases of infantile autism was studied and compared to age-matched controls. CA4 neurons in autistic children were smaller in perikaryon area and dendritic branching of both CA4 and CA1 neurons was less than in controls. These findings are consistent with previous studies and suggest a curtailment in maturation in the pathogenesis of autism. Received: 23 January 1995 / Revised, accepted: 6 September 1995     

Does bilateral damage to the human amygdala produce autistic symptoms?

A leading neurological hypothesis for autism postulates amygdala dysfunction. This hypothesis has considerable support from anatomical and neuroimaging studies. Individuals with bilateral amygdala lesions show impairments in some aspects of social cognition. These impairments bear intriguing similarity to those reported in people with autism, such as impaired recognition of emotion in faces, impaired theory of mind abilities, failure to fixate eyes in faces, and difficulties in regulating personal space distance to others. Yet such neurological cases have never before been assessed directly to see if they meet criteria for autism spectrum disorders (ASD). Here we undertook such an investigation in two rare participants with developmental-onset bilateral amygdala lesions. We administered a comprehensive clinical examination, as well as the Autism Diagnostic Observation Schedule (ADOS), the Social Responsiveness Scale (SRS), together with several other standardized questionnaires. Results from the two individuals with amygdala lesions were compared with published norms from both healthy populations as well as from people with ASD. Neither participant with amygdala lesions showed any evidence of autism across the array of different measures. The findings demonstrate that amygdala lesions in isolation are not sufficient for producing autistic symptoms. We suggest instead that it may be abnormal connectivity between the amygdala and other structures that contributes to autistic symptoms at a network level.     

Medial temporal-lobe damage and memory for emotionally arousing odors

Recently, we found that healthy young adults remember odors leading to large emotional reactions better than odors provoking smaller emotional reactions. Because the amygdala is believed to be critically implicated in memory for emotionally arousing information and because it is part of the primary olfactory area, we hypothesized that patients with a unilateral medial temporal-lobe resection including the amygdala would not show enhanced memory for arousing compared to nonarousing odors. We tested odor memory in 19 patients (10 left, 9 right) who had undergone a unilateral medial temporal-lobe resection including the amygdala (MTLR) for treatment of intractable epilepsy and 19 healthy control subjects. Healthy individuals and patients with left or right MTLR showed comparable subjective emotional reactions to odors. Similarly, healthy individuals and patients with MTLR remembered unpleasant odors better than pleasant ones. However, unlike healthy individuals, patients with MTLR did not show better memory for emotionally arousing odors compared to nonarousing ones. Patients undergoing a MTLR, whether in the left or right hemisphere, lose the specific memory advantage that odors causing strong emotional reactions normally have.     

Association Between the Density of Mossy Fiber Sprouting and Seizure Frequency in Experimental and Human Temporal Lobe Epilepsy

Summary: Purpose : If the sprouting of granule cell axons or mossy fibers in the dentate gyrus is critical for the generation of spontaneous seizures in temporal lobe epilepsy (TLE), one could hypothesize that epileptic animals or humans with increased sprouting would have more frequent seizures. This hypothesis was tested by analyzing the data gathered from experimental and human epilepsy.
Methods : In experiment I (rats with "newly diagnosed" TLE), self-sustained status epilepticus was induced in rats by electrically stimulating the amygdala. Thereafter, the appearance of spontaneous seizures was monitored by continuous video-electroencephalography (EEG) until the animal developed two spontaneous seizures and for 11 d thereafter. Rats were perfused for histology, and mossy fibers were stained using the Timm method. In experiment II (rats with "recently diagnosed" TLE), status epilepticus was induced in rats and the development of seizures was monitored by video-EEG for 24 h/d every other day for 60 days. All animals were then perfused for histology. In experiment III (rats with "chronic" TLE), animals were monitored by video-EEG for 24 h/d every other day for 6 months before histologic analysis. To assess mossy fiber sprouting in human TLE, hippocampal sections from 31 patients who had undergone surgery for drug-refractory TLE were stained with an antibody raised against dynorphin.
Results and Conclusions : Our data indicate that the density of mossy fiber sprouting is not associated with the total number of lifetime seizures or the seizure frequency in experimental or human TLE.     

Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area

Autism is a severe developmental disorder marked by a triad of deficits, including impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. In this review, it is argued that the search for the neurobiological bases of the autism spectrum disorders should focus on the social deficits, as they alone are specific to autism and they are likely to be most informative with respect to modeling the pathophysiology of the disorder. Many recent studies have documented the difficulties persons with an autism spectrum disorder have accurately perceiving facial identity and facial expressions. This behavioral literature on face perception abnormalities in autism is reviewed and integrated with the functional magnetic resonance imaging (fMRI) literature in this area, and a heuristic model of the pathophysiology of autism is presented. This model posits an early developmental failure in autism involving the amygdala, with a cascading influence on the development of cortical areas that mediate social perception in the visual domain, specifically the fusiform "face area" of the ventral temporal lobe. Moreover, there are now some provocative data to suggest that visual perceptual areas of the ventral temporal pathway are also involved in important ways in representations of the semantic attributes of people, social knowledge and social cognition. Social perception and social cognition are postulated as normally linked during development such that growth in social perceptual skills during childhood provides important scaffolding for social skill development. It is argued that the development of face perception and social cognitive skills are supported by the amygdala-fusiform system, and that deficits in this network are instrumental in causing autism.     

Glucose administration enhances fMRI brain activation and connectivity related to episodic memory encoding for neutral and emotional stimuli

Glucose enhances memory in a variety of species. In humans, glucose administration enhances episodic memory encoding, although little is known regarding the neural mechanisms underlying these effects. Here we examined whether elevating blood glucose would enhance functional MRI (fMRI) activation and connectivity in brain regions associated with episodic memory encoding and whether these effects would differ depending on the emotional valence of the material. We used a double-blind, within-participants, crossover design in which either glucose (50 g) or a saccharin placebo were administered before scanning, on days approximately 1 week apart. We scanned healthy young male participants with fMRI as they viewed emotionally arousing negative pictures and emotionally neutral pictures, intermixed with baseline fixation. Free recall was tested at 5 min after scanning and again after 1 day. Glucose administration increased activation in brain regions associated with successful episodic memory encoding. Glucose also enhanced activation in regions whose activity was correlated with subsequent successful recall, including the hippocampus, prefrontal cortex, and other regions, and these effects differed for negative vs. neutral stimuli. Finally, glucose substantially increased functional connectivity between the hippocampus and amygdala and a network of regions previously implicated in successful episodic memory encoding. These findings fit with evidence from nonhuman animals indicating glucose modulates memory by selectively enhancing neural activity in brain regions engaged during memory tasks. Our results highlight the modulatory effects of glucose and the importance of examining both regional changes in activity and functional connectivity to fully characterize the effects of glucose on brain function and memory.     

Neural long-term effects of emotion regulation on episodic memory processes

Emotions can enhance memory which is on the one hand advantageous, but on the other hand may be detrimental in the long term, for example in the case of traumatic events. Although cognitive emotion regulation may reduce emotion experience and corresponding neural activation, at present little is known about its influence on long-term memory. We investigated memory for emotional pictures in healthy female subjects 1 year after voluntary emotion regulation using fMRI. Whereas memory performance was not affected by regulation, our data revealed a dissociation of brain regions involved in memory encoding and recognition depending on whether emotional engagement during encoding had been downregulated. Emotional engagement during encoding resulted in a long-term subsequent memory effect in mesolimbic brain regions and hippocampus, and in recognition-related activation in the amygdala. In contrast, when negative emotions had been downregulated during encoding memory performance was predicted by prefrontal activation. Our data suggest that memory for emotionally encoded stimuli is supported by emotional re-activation, whereas memory for successfully encoded items during emotion regulation is rather supported by recognition of features and cognitive contents. These results contribute to research on long-term effects of emotion regulation in everyday life and open new avenues to understand and possibly influence traumatic memory traces.     

Recognition of Immaturity and Emotional Expressions in Blended Faces by Children with Autism and Other Developmental Disabilities

The recognition of facial immaturity and emotional expression by children with autism, language disorders, mental retardation, and non-disabled controls was studied in two experiments. Children identified immaturity and expression in upright and inverted faces. The autism group identified fewer immature faces and expressions than control (Exp. 1 & 2), language disordered (Exp. 1), and mental retardation (Exp. 2) groups. Facial inversion interfered with all groups’ recognition of facial immaturity and with control and language disordered groups’ recognition of expression. Error analyses (Exp. 1 & 2) showed similarities between autism and other groups’ perception of immaturity but differences in perception of expressions. Reasons for similarities and differences between children with and without autism when perceiving facial immaturity and expression are discussed.     

Hippocampal and amygdalar volume changes in elderly patients with Alzheimer's disease and schizophrenia

Patients with Alzheimer's disease (AD) and schizophrenia display cognitive, behavioural disturbances and morphological abnormalities. Although these latter reflect progressive neurodegeneration in AD, their significance in schizophrenia is still unclear. We explored the patterns of hippocampal and amygdalar atrophy in those patients and their associations with clinical parameters. Structural magnetic resonance imaging was performed in 20 elderly schizophrenia patients, 20 AD and 19 healthy older controls. Hippocampal and amygdalar volumes were obtained by manual segmentation with a standardized protocol and compared among groups. In both schizophrenia and AD patients, left hippocampal and amygdalar volumes were significantly smaller. The hippocampus/amygdala ratio was significantly lower in schizophrenia compared to both AD cases [2.4 bilaterally, 95% C.I. 2.2 to 2.7] and healthy controls bilaterally [2.5, 95% C.I. 2.3 to 2.9 in left and 2.7, 95% C.I. 2.4 to 3.1 in right hemisphere]. In schizophrenia patients, a significant positive correlation was found between age at disease onset and the right hippocampus/amygdala volume ratio (Spearman rho = 0.56). Negative symptoms correlated with higher right/left amygdala volume ratio (Spearman's rho = 0.43). Our data show that unlike AD, the hippocampus/amygdala ratio is abnormally low and correlates with the age at onset in schizophrenia, being a neurodevelopmental signature of the disease.     

Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation

The role of the basolateral complex of the amygdala (BLA) in recognition memory remains poorly understood. The mammalian target of rapamycin (mTOR) in the BLA and other brain areas has been implicated in synaptic plasticity and memory. We have recently shown that mTOR signaling in both the BLA and the dorsal hippocampus (DH) is required for formation and reconsolidation of inhibitory avoidance, a fear-motivated memory task. Here we examined the effects of infusions of the mTOR inhibitor rapamycin into the BLA before or after either training or reactivation on retention of novel object recognition (NOR) memory in rats, and compared the effects with those obtained using intra-DH infusions. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after NOR training or reactivation. Rapamycin impaired NOR retention tested 24 h after training when given either before or immediately after training into the BLA or DH. Rapamycin also impaired retention measured 24 h after reactivation when infused before reactivation into the BLA or DH, or immediately after reactivation into the BLA, but not when given 6 h after reactivation into either the BLA or DH. The results suggest that mTOR signaling in the BLA and DH is involved in NOR memory formation and stabilization.     

Amygdala and hippocampal volumes in Turner syndrome: a high-resolution MRI study of X-monosomy

Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits in visuospatial functioning as well as social cognition and memory. Neuroimaging studies have demonstrated volumetric differences in the parietal region of females with TS compared to controls. The present study examined amygdala and hippocampus morphology in an attempt to further understand the neural correlates of psychosocial and memory functioning in TS. Thirty females with TS age 7.6–33.3 years (mean = 14.7 ± 6.4) and 29 age-matched controls (mean AGE = 14.8 ± 5.9; RANGE = 6.4–32.7) were scanned using high resolution MRI. Volumetric analyses of the MRI scans included whole brain segmentation and manual delineation of the amygdala and hippocampus. Compared to controls, participants with TS demonstrated significantly larger left amygdala gray matter volumes, irrespective of total cerebral tissue and age. Participants with TS also showed disproportionately reduced right hippocampal volumes, involving both gray and white matter. Amygdala and hippocampal volumes appear to be impacted by X-monosomy. Aberrant morphology in these regions may be related to the social cognition and memory deficits often experienced by individuals with TS. Further investigations of changes in medial temporal morphology associated with TS are warranted.     

The effect of experimental epilepsy induced by injection of tetanus toxin into the amygdala of the rat on eating behaviour and response to novelty

A minute dose of tetanus toxin injected into the amygdala of rats produced an apparently reversible epileptiform syndrome similar to that previously described after injection of the toxin into the hippocampus. During the active epilepsy the toxin-injected rats occasionally exhibited ‘paroxysmal eating’ and also sometimes ran round in circles attempting to bite their own tails. When presented with a novel but palatable food (chocolate buttons or harvest crunch) the toxin-injected rats showed less neophobia than their controls—they ate sooner and ate more. This was found both during the active epilepsy and several weeks later when they had recovered. A similar effect of amygdala injections was found in a second experiment, in which the effect was compared with that of toxin injection in the hippocampus. These rats were tested also on the playground maze on their approach response to a neutral novel object (in a familiar environment in the context of seven familiar objects). The amygdala rats did not show any increase in their novelty response; thus their reduction in neophobia was specific to an appetitive behaviour. In contrast, the hippocampally-injected rats did not exhibit a novelty response in the playground maze, but showed normal neophobia to a new food.