Biomedical subjects

Faraneh Vargha-Khadem

Publications and source records attributed to Faraneh Vargha-Khadem.

At least 19 recordsLinked to original sources

PubMed2007

The hippocampus is required for short-term topographical memory in humans.

The hippocampus plays a crucial role within the neural systems for long-term memory, but little if any role in the short-term retention of some types of stimuli. Nonetheless, the hippocampus may be specialized for allocentric topographical processing, which impacts on short-term memory or even perception. To investigate this we developed performance-matched tests of perception (match-to-sample) and short-term memory (2 s delayed-match-to-sample) for the topography and for the nonspatial aspects of visual scenes. Four patients with focal hippocampal damage and one with more extensive damage, including right parahippocampal gyrus, were tested. All five patients showed impaired topographical memory and spared nonspatial processing in both memory and perception. Topographical perception was profoundly impaired in the patient with parahippocampal damage, mildly impaired in two of the hippocampal cases, and clearly preserved in the other two hippocampal cases (including one with dense amnesia). Our results suggest that the hippocampus supports allocentric topographical processing that is indispensable when appropriately tested after even very short delays, while the presence of the sample scene can allow successful topographical perception without it, possibly via a less flexible parahippocampal representation.

Adult↗

PubMed2007

Modified constraint-induced movement therapy after childhood stroke.

The aim of this pilot study was to investigate feasibility, tolerability, and effect of modified constraint-induced movement therapy (mCIT) in children with hemiparesis after arterial ischaemic stroke (AIS). Children with chronic hemiparesis and impaired hand function after AIS had mCIT for 2 hours a day, 5 days a week for 4 weeks. Pre- and post-therapy assessments included indices of sensorimotor function, quality of upper limb movement, functional therapy goals, and child and parent interviews. Of eight participants initially recruited, six (one male, five females) completed mCIT (median age 12y 3mo; range 6y 10mo-15y 2mo). Hemiparesis was predominantly spastic in three participants and dystonic in the others; all had severely impaired hand function. After mCIT there were no significant improvements in sensorimotor function or quality of upper limb movement. However, all children improved in individual therapy goals related to functional performance. Children and parents were positive about mCIT. The use of mCIT is a promising intervention for children with chronic acquired hemiparesis. In this severely impaired group functional improvements were seen after therapy despite unchanged sensorimotor measures.

Adolescent↗

PubMed2006

Using semantic memory to boost 'episodic' recall in a case of developmental amnesia.

We report two experiments that investigated factors that might boost 'episodic' recall for Jon, a developmental amnesic whose episodic memory is gravely impaired but whose semantic memory seems relatively normal. Experiment 1 showed that Jon's recall improved following a semantic study task compared with a non-semantic study task, as well as following four repeated study trials compared with only one. Experiment 2 additionally revealed that Jon's recall improved after acting compared with reading action phrases at study, but only if the phrases were well integrated semantically. The results provide some support for the hypothesis that Jon's 'episodic' recall depends on the extent to which he is able to retrieve events using semantic memory.

Adult↗

PubMed2006

Impact of frontal white matter lesions on performance monitoring: ERP evidence for cortical disconnection.

We examined the impact of discrete white matter lesions in the frontal lobes on event-related potential (ERP) correlates of performance monitoring. We tested the hypothesis that abnormal performance monitoring may result from injury to white matter without evidence of injury to grey matter in the frontal lobes. It was predicted that such lesions may result in disconnection of the lateral and medial frontal cortices. The close interaction of these two areas has been implicated in performance monitoring. Two fast-choice response tasks were administered to patients with MRI-confirmed frontal white matter lesions due to sickle cell disease (SCD) vasculopathy (n = 11; age = 11-23 years; 6 unilateral left lesions and 5 bilateral lesions) and two control groups: SCD patients without brain lesions and non-sickle cell sibling controls (n = 11 each). Stimulus-locked ERP components N2 and P3 were not significantly affected by presence of lesions. The difference between response-locked components to correct trials (correct-response negativity--CRN) and erroneous trials (error-related negativity--ERN) was diminished in patients with unilateral and bilateral frontal white matter lesions. This finding was due to a significantly attenuated ERN amplitude in lesion patients compared with both sibling and non-lesion control groups. These ERP findings were not due to performance differences between groups and hence reflect a compromised neural substrate underlying performance monitoring. The latter may also contribute to the deficits in executive function tasks observed in these patients. As disruption to ERP markers of error processing was found in the absence of lesions to the lateral or medial frontal cortex, we conclude that a functional connection between these areas facilitates performance monitoring, possibly implemented via tracts traversing the deep frontal white matter.

Adolescent↗

PubMed2006

Human memory development and its dysfunction after early hippocampal injury.

Cognitive memory involves long-term memories for facts (semantic memory) and personal experiences (episodic memory) that can be brought to mind. There is consensus that the hippocampus and related medial temporal lobe (MTL) structures are crucial for adult cognitive memory, but much less is known about their contribution to memory during infancy and childhood. We argue that the MTL is involved in memory from early in life, supporting recognition memory within the first postnatal months and recall memory within the first year. We propose that normal development involves a sequence in which a form of semantic-like memory emerges first, whereas the characteristics of episodic memory develop only later with progressive development of the hippocampus. Early bilateral injury to the hippocampus disrupts this normal pattern such that memory skills cannot develop beyond the stage of semantic memories. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Brain Injuries↗

PubMed2006

Detecting white matter injury in sickle cell disease using voxel-based morphometry.

OBJECTIVE: Sickle cell disease (SCD) is associated with cerebrovascular disease, cerebral infarction, and cognitive dysfunction. This study aimed to detect the presence and extent of white matter abnormalities in individuals with SCD using voxel-based morphometry (VBM). METHODS: Thirty-six children and adolescents with SCD (age range, 9-24 years) and 31 controls (8-25 years) underwent magnetic resonance investigations using T1- and T2-weighted protocols. White and gray matter density maps were obtained from three-dimensional magnetic resonance imaging (MRI) data sets. Using VBM, we compared the maps between controls and SCD individuals with silent white matter infarct lesions (SCD+L; n = 16), and those without visible abnormality (SCD-L; n = 20). RESULTS: In comparison with controls, intelligence quotients (IQs) were lower in both SCD groups irrespective of presence of visible lesions. VBM showed widespread bilateral white matter abnormalities in the SCD+L group, extending beyond the regions of focal infarction in the deep anterior and posterior white matter borderzones. Bilateral white matter abnormalities were also observed in the SCD-L group, in locations similar to those in the SCD+L group. INTERPRETATION: VBM is sensitive to detection of widespread white matter injury in SCD patients in borderzones between arterial territories even in the absence of evidence of infarction. Those changes may contribute to cognitive deficits in this population.

Adolescent↗

PubMed2006

An exploratory study of physiological correlates of neurodevelopmental delay in infants with sickle cell anaemia.

This study aimed to investigate whether infants with sickle cell anaemia (SCA) are at risk of neurodevelopmental delay, and whether any delay is associated with SCA pathology. Twenty-eight infants (14 SCA; 14 age- and ethnic-similar controls) were assessed longitudinally with the Bayley Infant Neurodevelopmental Screener (BINS) at 3, 9 and 12 months. Transcranial Doppler (TCD) and pulse oximetry (SpO2) measures were recorded longitudinally in SCA infants, and a subgroup of controls. Haemoglobin values were obtained from SCA infants. At each age, SCA infants obtained BINS scores indicative of greater risk of neurodevelopmental delay compared with controls. The number of moderate-high BINS risk scores increased significantly between 3 and 9 months. At 9 months BINS raw scores correlated negatively with TCD velocity and positively with haemoglobin. This exploratory study suggests that SCA infants may be at greater risk of neurodevelopmental delay than previously considered, and may provide the impetus for further research into the very early precursors of cognitive impairment.

Aging↗

PubMed2006

Brain and cognitive-behavioural development after asphyxia at term birth.

Perinatal asphyxia occurs in approximately 1-6 per 1000 live full-term births. Different patterns of brain damage can result, though the relation of these patterns to long-term cognitive-behavioural outcome remains under investigation. The hippocampus is one brain region that can be damaged (typically not in isolation), and this site of damage has been implicated in two different long-term outcomes, cognitive memory impairment and the psychiatric disorder schizophrenia. Factors in addition to the acute episode of asphyxia likely contribute to these specific outcomes, making prediction difficult. Future studies that better document long-term cognitive-behavioural outcome, quantitatively identify patterns of brain injury over development and consider additional variables that may modulate the impact of asphyxia on cognitive and behavioural function will forward the goals of predicting long-term outcome and understanding the mechanisms by which it unfolds.

Asphyxia Neonatorum↗

PubMed2006

Physiological correlates of intellectual function in children with sickle cell disease: hypoxaemia, hyperaemia and brain infarction.

Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain. We investigated the relationship between daytime oxyhaemoglobin saturation (SpO2), cerebral blood flow velocity (CBFV) and intellectual function (IQ) using path-analysis in 30 adolescents with sickle cell disease (mean age 17.4 years, SD 4.2). Initial analyses revealed that the association between SpO2 and Full Scale IQ (FSIQ) was fully mediated by increased CBFV, whereby SpO2 was negatively correlated with CBFV and CBFV was negatively correlated with FSIQ, i.e. decreases in oxygen saturation are associated with increases in velocity, and increased velocity is associated with lowered IQ scores. The mediated relationship suggests that lowered IQ may be a function of abnormal oxygen delivery to the brain. Further analyses showed that the association between CBFV and IQ was significant for verbal but not for performance IQ. The pathophysiology characteristic of SCD can interfere with brain function and constrain intellectual development, even in the absence of an infarct. This supports the hypothesis that lowered intellectual function is partly explained by chronic hypoxia, and has wider implications for our understanding of SCD pathophysiology.

Adolescent↗

PubMed2005

Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.

Alternative Splicing↗

PubMed2005

The primate hippocampus: ontogeny, early insult and memory.

Recent evidence suggests that in primates, as in rodents, the hippocampus shows a developmental continuum that affects memory abilities from infancy to adulthood. In primates relatively few hippocampal-dependent abilities (e.g. some aspects of recognition memory) are present in early infancy, whereas others (e.g. relational memory) begin to show adult-like characteristics around 2 years of age in monkeys and 5-7 years in humans. Profound and persistent memory loss resulting from insult to the hippocampus in infancy becomes evident in everyday behavior only later in childhood. This pattern of results suggests a maturational gradient within the medial temporal lobe memory system, with most abilities crucially dependent upon the hippocampus emerging in later stages of development, supporting a model of hierarchical organization of memory within the medial temporal lobe.

Animals↗

PubMed2005

Extra-hippocampal grey matter density abnormalities in paediatric mesial temporal sclerosis.

The aim of this study was to identify grey matter density abnormalities in children with temporal lobe epilepsy and mesial temporal sclerosis. Magnetic resonance T1 weighted 3D datasets were obtained in children with temporal lobe epilepsy (20 left and 10 right sided, mean age 11.9 years, range 6.6-17.5) and compared to scans obtained from age-matched controls (n = 22, mean age 12.8 years, range 7.1-17.5) using voxel-based morphometry. This method detected reduced grey matter ipsilateral to the seizure focus not only in the hippocampus, but also in the lateral temporal lobe and in extra-temporal regions including the thalamus, posterior cingulate cortex and cerebellum. Bilateral differences were present in the frontal and parietal opercular cortices and lateral temporal regions. These grey matter density reductions broadly reflect the pattern of hippocampal connections and may be caused by the disruption of cortical development by the recurrent seizures, as well as by loss of functional input from the sclerotic hippocampus.

Adolescent↗

PubMed2005

FOXP2 and the neuroanatomy of speech and language.

That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

Animals↗

PubMed2005

Maturation of action monitoring from adolescence to adulthood: an ERP study.

This study investigated the development of the frontal lobe action-monitoring system from late childhood and adolescence to early adulthood using ERP markers of error processing. Error negativity (ERN) and correct response negativity (CRN) potentials were recorded while adolescents and adults (aged 12-22 years, n = 23) performed two forced-choice visual reaction time tasks of differing complexity. Significant age differences were seen for behavioural and ERP responses to complex (infrequent, incompatible) trials: adolescents elicited an error negativity of reduced magnitude compared with adults. Furthermore, in contrast to adults, adolescents showed a non-significant differentiation between response-locked ERP components elicited by correct (CRN) and error responses (ERN). Behaviourally, adolescents corrected fewer errors in incompatible trials, and with increasing age there was greater post-error slowing. In conclusion, the neural systems underlying action-monitoring continue to mature throughout the second decade of life, and are associated with increased efficiency for fast error detection and correction during complex tasks.

Adolescent↗

PubMed2005

Deferred imitation of action sequences in developmental amnesia.

The aims of this study were to investigate whether patients with developmental amnesia (DA) associated with bilateral hippocampal volume reduction show an impairment in incidental nonverbal recall of action sequences, and whether the severity of this memory impairment is influenced by the sequence structure (causal vs. arbitrary). Like adult-onset cases of amnesia (McDonough, Mandler, McKee, & Squire, 1995), patients with DA did not differ significantly from their age-, sex-, and IQ-matched controls in spontaneous production of the sequences prior to modeling but recalled fewer target actions and action pairs than the control group after a 24-hour delay, independent of sequence structure. Unlike the patients with adult-onset amnesia, however, the patients with DA showed some memory for both types of sequences after a 24-hour delay. This difference in severity of memory impairment might reflect differences in extent of pathology and/or age at injury.

Adolescent↗

PubMed2004

Cortical lateralization during verb generation: a combined ERP and fMRI study.

Lateralization of scalp-recorded event-related potentials (ERPs) and functional MRI (fMRI) activation was investigated using a verb generation task in 10 healthy right-handed adults. ERPs showed an early transient positivity in the left inferior temporal region (500-1250 ms) following auditory presentation of the stimulus noun. A sustained slow cortical negativity of later onset (1250-3000 ms) was then recorded, most pronounced over left inferior frontal regions. fMRI data were in agreement with both ERP effects, showing left lateralized activation in inferior and superior temporal as well as inferior frontal cortices. Lateralized ERP effects occurred during the verb generation task but not during passive word listening or during word- and nonword repetition. Thus, ERPs and fMRI provided convergent evidence regarding language lateralization, with ERPs revealing the temporal sequence of posterior to anterior cortical activation during semantic retrieval.

Acoustic Stimulation↗

PubMed2004

The hippocampal role in spatial memory and the familiarity--recollection distinction: a case study.

Memory for object locations and for events (comprising the receipt of an object) was tested in a case of developmental amnesia with focal hippocampal damage. Tests used virtual reality environments and forced-choice recognition with foils chosen to equalize the performance of control participants across conditions. Memory for the objects received was unimpaired, but the context of their receipt was forgotten. Memory for short lists of object locations was unimpaired when tested from the same viewpoint as presentation but impaired when tested from a shifted viewpoint. Same-view performance was disrupted by changing the background scene. These results are consistent with Jon having preserved matching to fixed sensory-bound representations but impaired reconstructed or manipulable representations underlying shifted-viewpoint recognition and episodic recollection.

Adult↗

PubMed2003

Language fMRI abnormalities associated with FOXP2 gene mutation.

Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.

Brain Mapping↗