Faraneh Vargha-Khadem

University College London | UCL · UCL Great Ormond Street Institute of Child Health

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 de...

Episodic memory refers to the ability to recall unique events from the past, including what happened, when it happened and who was there. This ability is thought to develop over early childhood. However, the development of episodic memory is difficult to assess because young children are unable to complete rigorous laboratory studies of memory or v...

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 stud...

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 stud...

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 regio...

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 m...

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 fe...

The hippocampus is critical for cognitive memory and spatial processing but what are the specific functions of the different hippocampal subregions in humans? Can we provide evidence of functional correlations between cognitive performance and volumes of residual hippocampal subregions in patients with hippocampal damage? Here, we studied a large...

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....

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-t...

Mutations in the thyroid hormone receptor α 1 gene ( THRA ) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pl...

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the ‘KE family’, who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene’s early and prominent expression in the cereb...

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 bra...

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 para...

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to foreb...

Additional supporting information can be found in the online version of this article. Supplemental table 1: Summary of neurocognitive assessments and interpretation Supplemental table 2: Outcome categories in each domain according to patient; the grey boxes indicate poor outcome. Where blank the domain could not be assessed.

Objective describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation (VGM) identified before 28 days of life. Methods Neonates with angiographically confirmed vein of Galen malformation presenting to one of the two UK treatment centres (2006‐2016) were included; those surviving were invited to participate...

BACKGROUND Craniopharyngiomas are the commonest suprasellar tumour in childhood. Despite high overall survival, children with craniopharyngiomas are at risk of multiple relapses and long-term tumour- and treatment-related morbidity. We sought to provide, for the first time, a national evidence-based standard for best practice for the assessment, tr...

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 cha...

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 sem...

The discovery and description of the affected members of the KE family (aKE) initiated research on how genes enable the unique human trait of speech and language. Many aspects of this genetic influence on speech-related cognitive mechanisms are still elusive, e.g. if and how cognitive processes not directly involved in speech production are affecte...

Cognitive Neuroscience and Neuropsychiatry Section, Institute of Child Health, 30 Guildford Street, London, UK Background Transposition of the great arteries (TGA) is congenital heart defect which is associated with a risk of systemic hypoxia/ischaemic (HI) brain injury in the neonatal period. Children and adolescents with corrected TGA have been...

Reading and spelling performance was analysed for a sample of 45 children with unilateral brain damage. Boys showed impairments only when the lesion was on the left, while girls showed no significant impairments when either hemisphere was affected. The results support the hypothesis that specialised substrates, which underlie literacy acquisition,...

Resistance to Thyroid Hormone beta (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five cases reported worldwide; cardiac dysfunction, which can be life-threatening, is recognised in the disorder. Here we describe the clinical, metabolic, ophthalmic and cardiac findings in a nine-year old boy harbouring a biallelic THRB mutat...

Resistance to Thyroid Hormone beta (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five cases reported worldwide; cardiac dysfunction, which can be life-threatening, is recognised in the disorder. Here we describe the clinical, metabolic, ophthalmic and cardiac findings in a nine-year old boy harbouring a biallelic THRB mutat...

Purpose: To investigate visual function in adults post hemispherectomy in childhood. Design: Non-comparative case series. Methods: All participants underwent visual acuity, binocular function, visual field, optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL), and monocular pattern reversal visually evoked potentials (prV...

Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalisability 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 w...

Developmental amnesia is a selective episodic memory disorder associated with hypoxia-induced bilateral hippocampal atrophy of early onset. Despite the systemic impact of hypoxia-ischaemia, the resulting brain damage was previously reported to be largely limited to the hippocampus. However, the thalamus and the mammillary bodies are parts of the hi...

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...

Abstract: It is well-established that following cardiac arrest some adult patients suffer impairments in various cognitive domains, with memory and executive functions most commonly affected. It is also commonly found that verbal long term memory is more affected than visual long term memory, suggesting that subtle language impairment might also be...

One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocamp...

Unlabelled: 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....

Increasing evidence is emerging for sexual dimorphism in the trajectory of white matter development in children assessed using volumetric MRI and more recently diffusion MRI. Recent studies using diffusion MRI have examined cohorts with a wide age range (typically between 5 and 30 years) showing focal regions of differential diffusivity and fractio...

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 t...

1- BIHE (Baha’i Institute for Higher Education), Tehran, Iran 2- UCL Institute of Child Health, London, United Kingdom 3- Department of Neuropsychology, The Wellington Hospital, London, UK 4- UCL Section on Cognitive Neuroscience & Neuropsychiatry, Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom 5- Ki...

The optic radiation (OR) is a component of the visual system known to be myelin mature very early in life. Diffusion tensor imaging (DTI) and its unique ability to reconstruct the OR in vivo were used to study structural maturation through analysis of DTI metrics in a cohort of 90 children aged 5-18 years. As the OR is at risk of damage during epil...

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, espe...

Background: Patients with developmental amnesia (DA) experi-ence a profound yet selective episodic memory loss. We previ-ously showed that this impairment is related to severe bilateral hippocampal atrophy (of ~30% and above) sustained during an early episode of hypoxia-ischaemia (Isaacs et al., PNAS, 2003). Milder deficits in memory function and/o...

Background: The severe neurodevelopmental phenotype of untreated congenital hypothyroidism exemplifies the critical role of thyroid hormones (TH) in CNS development, acting via thyroid hormone receptor α1 (TRα1) on cortical neurogenesis, cerebellar development and oligodendrocyte differentiation. We have identified the first humans with defective T...

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 i...

Amnesic patients with bilateral hippocampal damage sustained in adulthood are generally unable to construct scenes in their imagination. By contrast, patients with developmental amnesia (DA), where hippocampal damage was acquired early in life, have preserved performance on this task, although the reason for this sparing is unclear. One possibility...

Abstract: Hypoxia-ischemia in full-term neonates targets two brain regions: the hippocampus which underpins cognitive memory, and the basal ganglia which supports motor learning (De Vries and Cowan 2009). Studies examining motor function in children aged 1 to 7, exposed to neonatal hypoxia-ischemia, suggest a reduction in the occurrence of motor im...

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 epileptogen...

We systematically compared fMRI results for covert (silent) and overt (spoken) versions of a language task in a representative sample of children with lesional focal epilepsy being considered for neurosurgical treatment (N=38, aged 6-17 years). The overt task was advantageous for presurgical fMRI assessments of language; it produced higher quality...

The hippocampus, a structure located in the temporal lobes of the brain, is critical for the ability to recollect contextual details of past episodes. It is still debated whether the hippocampus also enables recognition memory for previously encountered context-free items. Brain imaging [1, 2] and neuropsychological patient studies [3, 4] have both...

One of the features of amnesia resulting from bilateral medial temporal lobe damage, or even selective damage to the hippocampus, is the sparing of working memory (Milner, 1966; Baddeley et al., 2011). In recent years, however, some studies have reported memory deficits at very short delays in patients with restricted damage to the hippocampus (Ols...

Purpose: The early diagnosis of Rasmussen’s syndrome (RS) is often difficult, with differentiation between RS and focal cortical dysplasia (FCD) at epilepsy onset problematic. This study reviewed electroencephalography (EEG) in the two conditions for early indicators of either pathology. Methods: All children with either suspected RS or with unilat...

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 speec...

This study investigated the role of underlying pathology on memory function of children with temporal lobe epilepsy (TLE). Memory was assessed in 44 children with TLE resulting from hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNT), and 22 control children. Delayed story and paired associate recall performance was signifi...

Few reports exist on motor speech profiles of children with congenital or acquired brain damage, relating the speech disorder to its compromised neural substrate. This chapter examines motor speech characteristics in representative cases with: speech and orofacial dyspraxia resulting from mutation of the FOXP2 gene; dysarthria resulting from the re...

Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) 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...

To re-examine whether or not selective hippocampal damage reduces novelty preference in visual paired comparison (VPC), we presented two different versions of the task to a group of patients with developmental amnesia (DA), each of whom sustained this form of pathology early in life. Compared with normal control participants, the DA group showed a...