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.

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.

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.

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.

National UK guidelines for the management of paediatric craniopharyngioma.

Although rare, craniopharyngiomas constitute up to 80% of tumours in the hypothalamic-pituitary region in childhood. Despite being benign, the close proximity of these tumours to the visual pathways, hypothalamus, and pituitary gland means that both treatment of the tumour and the tumour itself can cause pronounced long-term neuroendocrine morbidity against a background of high overall survival. To date, the optimal management strategy for these tumours remains undefined, with practice varying between centres. In light of these discrepancies, as part of a national endeavour to create evidence-based and consensus-based guidance for the management of rare paediatric endocrine tumours in the UK, we aimed to develop guidelines, which are presented in this Review. These guidelines were developed under the auspices of the UK Children's Cancer and Leukaemia Group and the British Society for Paediatric Endocrinology and Diabetes, with the oversight and endorsement of the Royal College of Paediatrics and Child Health using Appraisal of Guidelines for Research & Evaluation II methodology to standardise care for children and young people with craniopharyngiomas.

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.

Mapping degeneration of the visual system in long-term follow-up after childhood hemispherectomy - A series of four cases.

OBJECTIVE: Although hemidisconnection surgery may eliminate or reduce seizure activity in patients with epilepsy, there are visual, cognitive and motor deficits which affect patients' function post-operatively, with varying severity and according to pathology. Consequently, there is a need to map microstructural changes over long time periods and develop/apply methods that work with legacy data. METHODS: In this study, we applied the novel single shell 3-Tissue method to data from a cohort of 4 patients who were scanned 20-years following childhood hemidisconnection surgery and presented with variable clinical outcomes. We have successfully reconstructed tractography of the whole visual pathway from single shell diffusion data with reduced number of gradient directions. RESULTS: All patients presented with degeneration of the visual system characterised by low fractional anisotropy and high mean diffusivity. There were no apparent microstructural differences between both optic nerves that could explain the different level of visual function across patients. However, we provide evidence suggesting an association between the level of visual function and DTI metrics within the remaining components of the visual system, particularly the optic tract, of the contralateral hemisphere post-surgery. SIGNIFICANCE: We believe this study suggests that diffusion MRI can be used to monitor the integrity of the visual system following hemispherectomy and if extended to larger cohorts and a greater number of time-points, including pre-surgically, can provide a clearer picture of the natural history of visual system degeneration. This knowledge may in turn help to identify patients at greatest risk of poor visual outcomes that might benefit from rehabilitation therapies.

When the brain, but not the person, remembers: Cortical reinstatement is modulated by retrieval goal in developmental amnesia.

Developmental amnesia (DA) is associated with early hippocampal damage and subsequent episodic amnesia emerging in childhood alongside age-appropriate development of semantic knowledge. We employed fMRI to assess whether patients with DA show evidence of 'cortical reinstatement', a neural correlate of episodic memory, despite their amnesia. At study, 23 participants (5 patients) were presented with words overlaid on a scene or a scrambled image for later recognition. Scene reinstatement was indexed by scene memory effects (greater activity for previously presented words paired with a scene rather than scrambled images) that overlapped with scene perception effects. Patients with DA demonstrated scene reinstatement effects in the parahippocampal and retrosplenial cortex that were equivalent to those shown by healthy controls. Behaviourally, however, patients with DA showed markedly impaired scene memory. The data indicate that reinstatement can occur despite hippocampal damage, but that cortical reinstatement is insufficient to support accurate memory performance. Furthermore, scene reinstatement effects were diminished during a retrieval task in which scene information was not relevant for accurate responding, indicating that strategic mnemonic processes operate normally in DA. The data suggest that cortical reinstatement of trial-specific contextual information is decoupled from the experience of recollection in the presence of severe hippocampal atrophy.

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.

Volume reduction of caudate nucleus is associated with movement coordination deficits in patients with hippocampal atrophy due to perinatal hypoxia-ischaemia.

Acute sentinel hypoxia-ischaemia in neonates can target the hippocampus, mammillary bodies, thalamus, and the basal ganglia. Our previous work with paediatric patients with a history of hypoxia-ischaemia has revealed hippocampal and diencephalic damage that impacts cognitive memory. However, the structural and functional status of other brain regions vulnerable to hypoxia-ischaemia, such as the basal ganglia, has not been investigated in these patients. Furthermore, it is not known whether there are any behavioural sequelae of such damage, especially in patients with no diagnosis of neurological disorder. Based on the established role of the basal ganglia and the thalamus in movement coordination, we studied manual motor function in 20 participants exposed to neonatal hypoxia-ischaemia, and a group of 17 healthy controls of comparable age. The patients' handwriting speed and accuracy was within the normal range (Detailed Assessment of Speed of Handwriting), and their movement adaptation learning (Rotary Pursuit task) was comparable to the control group's performance. However, as a group, patients showed an impairment in the Grooved Pegboard task and a trend for impairment in speed of movement while performing the Rotary Pursuit task, suggesting that some patients have subtle deficits in fine, complex hand movements. Voxel-based morphometry and volumetry showed bilateral reduction in grey matter volume of the thalamus and caudate nucleus. Reduced volumes in the caudate nucleus correlated across patients with performance on the Grooved Pegboard task. In summary, the fine movement coordination deficit affecting the hand and the wrist in patients exposed to early hypoxic-ischaemic brain injury may be related to reduced volumes of the caudate nucleus, and consistent with anecdotal parental reports of clumsiness and coordination difficulties in this cohort.

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.

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.

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.

Little evidence for fast mapping in adults with developmental amnesia.

Cooper, Greve, and Henson (this issue) conclude that hippocampal-independent learning, as operationalised by 'fast mapping' (FM), is unlikely to facilitate learning in adults. We provide evidence from patients with Developmental Amnesia (DA), who acquire language and semantic knowledge despite early hippocampal pathology. We administered an FM paradigm to three patients with DA and controls. Patients showed no benefit of FM compared to explicit encoding. These data support the conclusion that FM is unlikely to facilitate learning in amnesia, regardless of age at onset. Hippocampal-independent learning may be possible in adults with DA, but such learning requires a prolonged consolidation period.

A Functional MRI Paradigm Suitable for Language and Memory Mapping in Pediatric Temporal Lobe Epilepsy.

Functional Magnetic Resonance Imaging (fMRI) is a technique frequently used to determine the territories of eloquent tissue that serve critical functions, such as language. This can be particularly useful as part of the pre-surgical assessment for temporal lobe epilepsy (TLE) in order to predict cognitive outcome and guide surgical decision-making. Whereas language fMRI is widely used, memory fMRI is less frequently employed in adult TLE, and lacking in childhood TLE. We have developed a combined language/memory fMRI paradigm that is suitable for children, to provide clinically useful information for surgical planning in pediatric TLE. We evaluated this paradigm in 28 healthy children, aged 8 to 18 years. The advantages of this paradigm are: (a) it examines the functional mapping of language and memory networks within one scanning session, (b) provides assessment of both memory encoding- and retrieval-related neural networks, (c) examines recall-based retrieval to engage hippocampal involvement compared to recognition-based retrieval, and (d) provides overt verbal responses to monitor in-scanner memory performance. This novel fMRI paradigm was designed for language and memory mapping in pediatric TLE and could provide clinically useful information for surgical planning. Finally, parallel versions of the paradigm allow the comparison of brain activations pre- and post-surgical intervention.

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.

Semantic memory in developmental amnesia.

Patients with developmental amnesia resulting from bilateral hippocampal atrophy associated with neonatal hypoxia-ischaemia typically show relatively preserved semantic memory and factual knowledge about the natural world despite severe impairments in episodic memory. Understanding the neural and mnemonic processes that enable this context-free semantic knowledge to be acquired throughout development without the support of the contextualised episodic memory system is a serious challenge. This review describes the clinical presentation of patients with developmental amnesia, contrasts its features with those reported for adult-onset hippocampal amnesia, and analyses the effects of variables that influence the learning of new semantic information.

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.

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.