Cognitive outcome and its neural correlates after cardiorespiratory arrest in childhood.

Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long-term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. RESEARCH HIGHLIGHTS: Our data shed light on the long-term outcome and associated neural mechanisms after paediatric hypoxia-ischaemia as a result of cardiorespiratory arrest. Patients had impaired scores on memory, language and academic attainment. Memory impairments were associated with smaller hippocampi, thalami, and striatum. Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle.

Using recognition testing to support semantic learning in developmental amnesia.

ABSTRACTPatients with developmental amnesia (DA) have suffered hippocampal damage in infancy and subsequently shown poor episodic memory, but good semantic memory. It is not clear how patients with DA learn semantic information in the presence of episodic amnesia. However, patients with DA show good recognition memory and it is possible that semantic learning may be supported by recognition. Building on previous work, we compared two methods for supporting semantic learning in DA; recognition-learning and recall-learning. In each condition, a patient with DA (aged 8 years) was presented with semantic information in animated videos. After each presentation of a video, learning was supported by an immediate memory test. Two videos were paired with a cued recall test. Another two videos were paired with a multiple-choice test to enable recognition-based learning. The outcome measure was semantic recall performance after a short delay of 30 min and a long delay of one week. Results showed a benefit of recognition-learning compared to recall-learning on cued recall in the patient with DA (76% vs. 35%). This finding indicates that young people with severe hippocampal damage can utilize recognition to support semantic learning. This has implications for the support of school-aged children with episodic memory difficulties.

Intact high-resolution working memory binding in a patient with developmental amnesia and selective hippocampal damage.

Debate continues regarding the possible role of the hippocampus across short-term and working memory tasks. The current study examined the possibility of a hippocampal contribution to precise, high-resolution cognition and conjunctive memory. We administered visual working memory tasks featuring a continuous response component to a well-established developmental amnesic patient with relatively selective bilateral hippocampal damage (Jon) and healthy controls. The patient was able to produce highly accurate response judgments regarding conjunctions of color and orientation or color and location, using simultaneous or sequential presentation of stimuli, with no evidence of any impairment in working memory binding, categorical accuracy, or continuous precision. These findings indicate that hippocampal damage does not necessarily lead to deficits in high-resolution cognitive performance, even when the damage is severe and bilateral.

Contributions of nonhuman primate research to understanding the consequences of human brain injury during development.

In this introductory review we first present a theoretical framework as well as a clinical perspective regarding the effects of early brain injury on the development of cognitive and behavioral functions in humans. Next, we highlight the contributions that nonhuman primate research make toward identifying some of the variables that influence long-term cognitive outcome after developmental disease, or damage. We start our review by arguing that in contrast to adult-onset injury, developmental brain insults alter the ontogenetic pattern of brain organization and circuit specialization depending on the variables of age at injury, the focality of the lesion, and the potential for reorganization. We then introduce the 2 nonhuman primate studies in this section (Kiorpes on vision; Bachevalier on cognitive memory), and highlight the relevance of their findings to our understanding of developmental conditions or injuries in humans, with the ultimate goal of improving the health and development of the young.

The Pair Test: A computerised measure of learning and memory.

There is increasing interest in the assessment of learning and memory in typically developing children as well as in children with neurodevelopmental disorders. However, neuropsychological assessments have been hampered by the dearth of standardised tests that enable direct comparison between distinct memory processes or between types of stimulus materials. We developed a tablet-based paired-associate learning paradigm, the Pair Test, based on neurocognitive models of learning and memory. The aims are to (i) establish the utility of this novel memory tool for use with children across a wide age range, and (ii) examine test validity, reliability and reproducibility of the construct. The convergent validity of the test was found to be adequate, and higher test reliability was shown for the Pair Test compared to standardised measures. Moderate test-retest reproducibility was shown, despite a long time interval between sessions (14 months). Moreover, the Pair Test is able to capture developmental changes in memory, and can therefore chart the developmental trajectory of memory and learning functions across childhood and adolescence. Finally, we used this novel instrument to acquire normative data from 130 typically developing children, aged 8-18 years. Age-stratified normative data are provided for learning, delayed recall and delayed recognition, for measures of verbal and non-verbal memory. The Pair Test thus provides measures of learning and memory accounting for encoding, consolidation and retrieval processes. As such, the standardised test results can be used to determine the status of learning and memory in healthy children, and also to identify deficits in paediatric patients at risk of damage to the neural network underlying mnemonic functions.

Clinical use of the Insight Inventory in cerebral visual impairment and the effectiveness of tailored habilitational strategies.

AIM: To investigate the utility of the Insight Inventory (a structured clinical inventory completed by caregivers) for assessment of children with cerebral visual impairment; and to investigate effectiveness of tailored habilitational strategies derived from the responses to the Insight Inventory. METHOD: Fifty-one eligible children (26 males, 25 females; mean age 9y 5mo, SD 3y, range 5-16y) were recruited from Great Ormond Street Hospital, London. They underwent baseline assessment including neuro-ophthalmological and neuropsychological evaluations, and parent- and child-reported ratings on a questionnaire-based measure of quality of life. Parents also completed the Insight Inventory. On the basis of responses to the Inventory, families received individualized habilitational strategies. Follow-up assessments 6 months later included repeating the Insight Inventory and quality of life questionnaires. RESULTS: Correlations were found between the Insight Inventory and the Wechsler Intelligence Scale for Children, Fourth Edition, the Beery-Buktenica Test of Visual-Motor Integration, and the Benton Facial Recognition Test, suggesting that the Insight Inventory is an effective tool to estimate visual-perceptual difficulties. At 6 months follow-up, caregiver reports indicated significant improvements in the quality of life of children below the age of 12 years. INTERPRETATION: The Insight Inventory is a simple questionnaire which covers practical aspects of cognitive visual function in everyday life. It provides in-depth information about the aspects that children struggle with. It can also guide programmes of individualized habilitation strategies, which may enhance the quality of life of younger children. WHAT THIS PAPER ADDS: Questionnaire scores demonstrate biologically plausible correlations with formal neuropsychological tests of visual function. After administration of matched practical habilitational strategies, younger children showed improvement in quality of life and functional vision scores.

Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation.

OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.

Determinants of IQ outcome after focal epilepsy surgery in childhood: A longitudinal case-control neuroimaging study.

OBJECTIVE: Intelligence quotient (IQ) outcomes after pediatric epilepsy surgery show significant individual variation. Clinical factors such as seizure cessation or antiepileptic medication discontinuation have been implicated, but do not fully account for the heterogeneity seen. Less is known about the impact of neurobiological factors, such as brain development and resection location. This study examines clinical and neuroimaging factors associated with cognitive outcome after epilepsy surgery in childhood. METHODS: Fifty-two children (28 boys, 24 girls) were evaluated for epilepsy surgery and reassessed on average 7.7 years later. In the intervening time, 13 were treated pharmacologically and 39 underwent focal surgery (17 temporal, 16 extratemporal, six multilobar; mean age at surgery = 14.0 years). Pre- and postsurgical assessments included IQ tests and T1-weighted brain images. Predictors of IQ change were investigated, including voxel-based analyses of resection location, and gray and white matter volume change. RESULTS: Overall modest IQ improvement was seen in children treated surgically, but not in those treated pharmacologically only. Applying a ≥10-point change threshold, 39% of the surgically treated children improved, whereas 10% declined. Clinical factors associated with IQ increases were lower preoperative IQ and longer follow-up duration, whereas seizure and antiepileptic medication cessation were not predictive. Among neuroimaging factors, we observed that left anterior temporal resections impacted negatively on verbal reasoning, linked to full-scale IQ decline. In contrast, gray matter volume change in ipsi- and contralesional hemispheres was positively correlated with IQ change. Voxel-based morphometry identified the gray matter volume change in the contralesional dorsolateral frontal cortex as most strongly associated with IQ improvement. SIGNIFICANCE: We show that a variety of factors are likely to contribute to patterns of postsurgical change in IQ. Neuroimaging results indicate that left anterior temporal resections constrain development of verbal cognition, whereas simultaneously cortical growth after surgical treatment can support improvements in IQ.

Pre- and postsurgical cognitive trajectories and quantitative MRI changes in Rasmussen syndrome.

OBJECTIVE: To quantify the longitudinal cognitive trajectory, before and after surgery, of Rasmussen syndrome (RS), a rare disease characterized by focal epilepsy and progressive atrophy of one cerebral hemisphere. METHOD: Thirty-two patients (mean age = 6.7 years; 17 male, 16 left hemispheres affected) were identified from hospital records. The changes in intelligence scores during 2 important phases in the patients' journey to treatment were investigated: (1) during the preoperative period (n = 28, mean follow-up 3.4 years) and (2) from before to after surgery (n = 21 patients, mean time to follow-up 1.5 years). A volumetric magnetic resonance imaging (MRI) analysis of longitudinal changes in gray matter volume was conducted in a subsample of 18 patients. RESULTS: (1) IQ during the preoperative period: At baseline assessment (on average 2.4 years after seizure onset), the left RS group had lower verbal than nonverbal intellectual abilities, whereas the right group exhibited more difficulties in nonverbal than verbal intellect. Verbal and nonverbal scores declined during the follow-up in both groups, irrespective of the affected side. Hemispheric gray matter volumes declined over time in both groups in affected as well as unaffected hemispheres. (2) Postoperative IQ change: The left surgery group declined further in verbal and nonverbal intellect. The right group's nonverbal intellect declined after surgery, whereas verbal abilities did not. Patients with higher abilities preoperatively experienced large declines, whereas those with poorer abilities showed little change. Postoperative seizures negatively impacted on cognitive abilities. SIGNIFICANCE: During the chronic phase of the disease, parallel decline of verbal and nonverbal abilities suggest progressive bilateral hemispheric involvement, supported by evidence from MRI morphometry. Postsurgical cognitive losses are predicted by greater presurgical ability and continuing seizures. A shorter duration from seizure onset to surgery could reduce the postoperative cognitive burden by minimizing the decline in functions supported by the unaffected hemisphere.

Extent of hippocampal atrophy predicts degree of deficit in recall.

Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition.

Alexander's disease and the story of Louise.

We describe the rare condition known as Alexander's disease or Alexander's leukodystrophy, which is essentially a childhood dementia. We then present the case of Louise Davies (we are using Louise's real name with the permission and special request of her mother), a woman who was diagnosed with this disease at the age of 5 years and is still alive at the age of 38, making her the longest known survivor of this condition. Although now severely impaired, both physically and mentally, and able to do very little, she has lived far longer than expected. We present some neuropsychological results from her childhood before measuring her decline over the past four years. We conclude by considering whether or not the diagnosis was correct and why she has lived so long.

Hippocampal damage and memory impairment in congenital cyanotic heart disease.

Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalizability of this causal sequence, we examined a cohort of 41 children aged 8-16, who, having received the arterial switch operation to correct for transposition of the great arteries, had sustained significant neonatal cyanosis but were otherwise neurodevelopmentally normal. As predicted, the cohort had significant bilateral reduction of hippocampal volumes relative to the volumes of 64 normal controls. They also had significant, yet selective, impairment of episodic memory as measured by standard tests of memory, despite relatively normal levels of intelligence, academic attainment, and verbal fluency. Across the cohort, degree of memory impairment was correlated with degree of hippocampal atrophy suggesting that even as early as neonatal life no other structure can fully compensate for hippocampal injury and its special role in serving episodic long term memory. © 2017 Wiley Periodicals, Inc.

Hippocampal Volume Reduction in Humans Predicts Impaired Allocentric Spatial Memory in Virtual-Reality Navigation.

The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with "moderate" hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes. SIGNIFICANCE STATEMENT: In humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated spatial recall using a virtual environment in two groups of patients with hippocampal damage (moderate/severe) and a normal control group. The results showed that patients with severe hippocampal damage are impaired in learning and recalling allocentric spatial information. Furthermore, hippocampal volume reduction impaired allocentric navigation beyond what can be predicted by memory quotient as a widely used measure of general memory function.

Temporal lobe surgery in childhood and neuroanatomical predictors of long-term declarative memory outcome.

The temporal lobes play a prominent role in declarative memory function, including episodic memory (memory for events) and semantic memory (memory for facts and concepts). Surgical resection for medication-resistant and well-localized temporal lobe epilepsy has good prognosis for seizure freedom, but is linked to memory difficulties in adults, especially when the removal is on the left side. Children may benefit most from surgery, because brain plasticity may facilitate post-surgical reorganization, and seizure cessation may promote cognitive development. However, the long-term impact of this intervention in children is not known. We examined memory function in 53 children (25 males, 28 females) who were evaluated for epilepsy surgery: 42 underwent unilateral temporal lobe resections (25 left, 17 right, mean age at surgery 13.8 years), 11 were treated only pharmacologically. Average follow-up was 9 years (range 5-15). Post-surgical change in visual and verbal episodic memory, and semantic memory at follow-up were examined. Pre- and post-surgical T1-weighted MRI brain scans were analysed to extract hippocampal and resection volumes, and evaluate post-surgical temporal lobe integrity. Language lateralization indices were derived from functional magnetic resonance imaging. There were no significant pre- to postoperative decrements in memory associated with surgery. In contrast, gains in verbal episodic memory were seen after right temporal lobe surgery, and visual episodic memory improved after left temporal lobe surgery, indicating a functional release in the unoperated temporal lobe after seizure reduction or cessation. Pre- to post-surgical change in memory function was not associated with any indices of brain structure derived from MRI. However, better verbal memory at follow-up was linked to greater post-surgical residual hippocampal volumes, most robustly in left surgical participants. Better semantic memory at follow-up was associated with smaller resection volumes and greater temporal pole integrity after left temporal surgery. Results were independent of post-surgical intellectual function and language lateralization. Our findings indicate post-surgical, hemisphere-dependent material-specific improvement in memory functions in the intact temporal lobe. However, outcome was linked to the anatomical integrity of the temporal lobe memory system, indicating that compensatory mechanisms are constrained by the amount of tissue which remains in the operated temporal lobe. Careful tailoring of resections for children undergoing epilepsy surgery may enhance long-term memory outcome.

Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence.

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life.

A mutation in the thyroid hormone receptor alpha gene.

Thyroid hormones exert their effects through alpha (TRα1) and beta (TRß1 and TRß2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.

Test of a motor theory of long-term auditory memory.

Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e.g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory-suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve.

Asymmetry of planum temporale constrains interhemispheric language plasticity in children with focal epilepsy.

Reorganization of eloquent cortex enables rescue of language functions in patients who sustain brain injury. Individuals with left-sided, early-onset focal epilepsy often show atypical (i.e. bilateral or right-sided) language dominance. Surprisingly, many patients fail to show such interhemispheric shift of language despite having major epileptogenic lesions in close proximity to eloquent cortex. Although a number of epilepsy-related factors may promote interhemispheric plasticity, it has remained unexplored if neuroanatomical asymmetries linked to human language dominance modify the likelihood of atypical lateralization. Here we examined the asymmetry of the planum temporale, one of the most striking asymmetries in the human brain, in relation to language lateralization in children with left-sided focal epilepsy. Language functional magnetic resonance imaging was performed in 51 children with focal epilepsy and left-sided lesions and 36 healthy control subjects. We examined the association of language laterality with a range of potential clinical predictors and the asymmetry of the length of the planum temporale. Using voxel-based methods, we sought to determine the effect of lesion location (in the affected left hemisphere) and grey matter density (in the unaffected right hemisphere) on language laterality. Atypical language lateralization was observed in 19 patients (38%) and in four controls (11%). Language laterality was increasingly right-sided in patients who showed atypical handedness, a left perisylvian ictal electroencephalographic focus, and a lesion in left anterior superior temporal or inferior frontal regions. Most striking was the relationship between rightward asymmetry of the planum temporale and atypical language (R = 0.70, P < 0.0001); patients with a longer planum temporale in the right (unaffected) hemisphere were more likely to have atypical language dominance. Voxel-based regression analysis confirmed that increased grey matter density in the right temporo-parietal junction was correlated with right hemisphere lateralization of language. The length of the planum temporale in the right hemisphere was the main predictor of language lateralization in the epilepsy group, accounting for 48% of variance, with handedness accounting for only a further 5%. There was no correlation between language lateralization and planum temporale asymmetry in the control group. We conclude that asymmetry of the planum temporale may be unrelated to language lateralization in healthy individuals, but the size of the right, contra-lesional planum temporale region may reflect a 'reserve capacity' for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions.

Anatomo-functional changes in neural substrates of cognitive memory in developmental amnesia: Insights from automated and manual MRI examinations.

Despite bilateral hippocampal damage dating to perinatal or early-childhood period, and severely-impaired episodic memory that unfolds in later childhood, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganise to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40% while the atrophy of the uncus was moderate (-23%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions, such that the greater the damage, the more likely it is that surrounding cortical areas will be recruited to rescue the putative functions of the damaged subregions. Our findings document for the first time not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.

Episodic memory development: Bridging animal and human research.

Human episodic memory is not functionally evident until about 2 years of age and continues to develop into the school years. Behavioral studies have elucidated this developmental timeline and its constituent processes. In tandem, lesion and neurophysiological studies in non-human primates and rodents have identified key neural substrates and circuit mechanisms that may underlie episodic memory development. Despite this progress, collaborative efforts between psychologists and neuroscientists remain limited, hindering progress. Here, we seek to bridge human and non-human episodic memory development research by offering a comparative review of studies using humans, non-human primates, and rodents. We highlight critical theoretical and methodological issues that limit cross-fertilization and propose a common research framework, adaptable to different species, that may facilitate cross-species research endeavors.