Language difficulties in children adopted internationally: neuropsychological and functional neural correlates.

Children who have experienced deprivation as a result of orphanage care during early development are at increased risk for a number of cognitive, emotional, and social difficulties (MacLean, 2003). This study examined the neuropsychological and behavioral profile of internationally adopted children with language difficulties, one of the most common cognitive challenges (Behen et al., 2008). In addition to neuropsychological testing, fMRI was utilized to examine activation patterns during expressive fluency and receptive language tasks. In comparison to internationally adopted children without language difficulties and nonadopted controls, participants with language difficulty had worse performance on tasks of verbal memory and reasoning, academic skills, and working memory. Behaviorally, all internationally adopted participants, regardless of language ability, had more parent-reported hyperactivity and impulsivity compared with controls. The fMRI tasks revealed reduced activation in traditional language areas in participants with language difficulty. The impact of early adverse experience on later development is discussed.

Thalamocortical connectivity in healthy children: asymmetries and robust developmental changes between ages 8 and 17 years.

BACKGROUND AND PURPOSE: Thalamocortical connections play a crucial role in complex cognitive functioning, and several neuropsychiatric disorders may involve aberrant thalamocortical circuitry. Here, we quantified the cortical pattern and age-related changes of thalamocortical connections by using probabilistic tractography in children and adolescents. We hypothesized that detectable asymmetry (left>right) exists in thalamocortical fiber connections and the connectivity increases with age during maturation. MATERIALS AND METHODS: Diffusion tensor imaging was acquired in 15 normally developing children (age range, 8.3-17.3 years; 11 males), and fiber tracking was initiated from the thalami. The cortical distribution of ipsilateral thalamocortical fibers was quantified by using a landmark-constrained conformal mapping technique. Furthermore, hemispheric asymmetries and potential age-related changes in regional thalamocortical connections were assessed. RESULTS: The left thalamus had significantly higher overall cortical connectivity than the right thalamus (P < .001). Left prefrontal cortical areas showed significantly higher thalamic connectivity compared with homotopic regions of the right hemisphere (P < .001), regardless of the applied parameters. There was an increase of overall thalamocortical connectivity with age, with the most pronounced age-related increases in bilateral prefrontal areas (P < .002). However, thalamic connectivity of some other cortical regions (right sensorimotor, left inferior temporal) showed a decrease with age. CONCLUSIONS: Our results indicate a region-specific left>right asymmetry and robust developmental changes in thalamocortical (particularly thalamo-prefrontal) connectivity during late childhood and adolescence. These data further add to our knowledge about structural lateralizations and their development in the maturing brain.

Increased visual cortex glucose metabolism contralateral to angioma in children with Sturge-Weber syndrome.

Functional reorganization after focal brain injury can lead to altered cerebral metabolism of glucose. Sturge-Weber syndrome (SWS) with unilateral involvement is a clinical model for evaluating the effects of early focal brain injury on brain metabolism and function. In this study, 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) was used to measure glucose metabolism in cortex and basal ganglia, both ipsilateral and contralateral to the angioma, in 17 children (eight males, nine females; age range 1y 8mo-10y 4mo; mean 5y 7mo [SD 2y 11mo]) with unilateral SWS and epilepsy. The PET findings were compared with those of a control group of 11 age-matched children (four males, seven females; age range 3y-10y 8mo; mean 6y [SD 2y 10mo]) with partial epilepsy but normal magnetic resonance imaging and PET scans. In the SWS group, visual and parietal cortex showed decreased glucose metabolism on the side of the angioma (p=0.001) but increased metabolism on the contralateral side (p=0.002). In particular, glucose metabolism was very high in contralateral visual cortex of childrenwith SWS, showing severe occipital hypometabolism on the side of the angioma. Eight children with visual field defect showed increased metabolism in the contralateral visual cortex (p=0.012). These findings indicate that early, severe unilateral cortical damage in SWS may induce increased glucose metabolism in the contralateral visual cortex, probably reflecting reorganization.

Multimodality imaging of cortical and white matter abnormalities in Sturge-Weber syndrome.

BACKGROUND AND PURPOSE: Impaired cortical venous outflow and abnormal deep venous collaterals are common in Sturge-Weber syndrome (SWS), but their relation to brain metabolism and function is poorly understood. In this study, advanced MR imaging techniques, such as susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI), were applied in conjunction with positron-emission tomography (PET), to assess cortical and white matter structural abnormalities and their relation to cortical glucose metabolism and cognitive functions in children with unilateral SWS. MATERIALS AND METHODS: Thirteen children (age, 1.5-10.3 years) with unilateral SWS underwent MR imaging with SWI and DTI, glucose metabolism PET, and comprehensive neuropsychologic assessment prospectively. The MR imaging and PET images were coregistered and cortical regions showing decreased glucose metabolism were compared with locations of SWI signal intensity abnormalities, changes in white matter water diffusion, and cognitive functions. RESULTS: SWI detected both cortical abnormalities (n=8) and deep transmedullary veins (n=9), including those in young children with no cortical SWI signal intensity changes. These veins were often located under cortex adjacent to hypometabolic regions. DTI showed abnormal water diffusion both under hypometabolic cortex and in adjacent white matter with collateral veins. Cognitive dysfunction was associated with abnormal water diffusion in the posterior white matter. CONCLUSIONS: Transmedullary venous collaterals can be detected early by SWI and persist in white matter adjacent to damaged cortex in children with SWS. Microstructural white matter damage extends beyond cortical abnormalities and may contribute to cognitive impairment. SWI and DTI can be incorporated into clinical MR imaging acquisitions to objectively assess microstructural abnormalities at different stages of SWS.

Evolution of cortical metabolic abnormalities and their clinical correlates in Sturge-Weber syndrome.

BACKGROUND: The natural course of Sturge-Weber syndrome (SWS) is poorly understood, although neurological symptoms are often progressive. AIMS: To track longitudinal changes in brain glucose metabolism measured with positron emission tomography (PET) and their relation to clinical changes during the early course of SWS. METHODS: Fourteen children (age 3 months to 3.9 years at enrollment) with SWS and unilateral leptomeningeal angioma underwent two consecutive glucose metabolism PET scans with a mean follow-up time of 1.2 years. Longitudinal changes of the extent of cortical glucose hypometabolism on the angioma side were measured and correlated with age, clinical seizure frequency and hemiparesis. RESULTS: An increase in the size of the hypometabolic cortex was seen in 6 children, coinciding with an age-related increase in cortical glucose metabolism measured in unaffected contralateral cortex. These 6 patients were younger both at the initial (mean age 0.75 vs. 2.8 years; p<0.001) and the second scan (mean age 1.8 vs. 4.2 years; p=0.001) than those with no change in the extent of hypometabolic cortex (n=6). The area of cortical hypometabolism decreased in the two remaining children, and this was associated with resolution of an initial hemiparesis in one of them. Seizure frequency between the two scans was higher in children who showed progressive enlargement of cortical hypometabolism, as compared to those with no progression (p=0.008). CONCLUSIONS: In SWS, detrimental metabolic changes occur before 3 years of age coinciding with a sharp increase of developmentally regulated cerebral metabolic demand. Progressive hypometabolism is associated with high seizure frequency in these children. However, metabolic abnormalities may remain limited or even partially recover later in some children with well-controlled seizures. Metabolic recovery accompanied by neurological improvement suggests a window for therapeutic intervention in children with unilateral SWS.

Myocardial blood flow and flow reserve in response to hormone therapy in postmenopausal women with risk factors for coronary disease.

Estrogen has beneficial effects on markers of coronary heart disease (CHD) risk, but may increase overall CHD events. The effects of hormone therapy on vascular endothelial function have been mixed, and require further assessment. We studied the myocardial blood flow (MBF) response to postmenopausal combination hormone therapy (CHT) in postmenopausal women with risk factors for CHD. We performed dynamic [13N]ammonia positron emission tomography in 15 postmenopausal women in a 7-month placebo-controlled crossover trial of continuous conjugated equine estrogen/cyclical micronized progesterone. MBF was measured at rest, after sympathetic stimulation with the cold pressor test (CPT), and after i.v. adenosine infusion, to determine baseline, endothelium-dependent, and maximal flows, respectively. Response to CPT was neutral in all women at baseline (-0.51 +/- 27%). Adenosine induced a marked increase in MBF (161 +/- 111%). Treatment with 3 months of combined estrogen/progestin CHT did not change CPT or adenosine MBF responses. Myocardial flow reserve was unchanged as well. In this group of postmenopausal women at higher cardiovascular risk, no association was found between CHT assignment and change in MBF. Further study is needed to clarify the effects of CHT on the endothelium of women with presumably diseased vasculature.

Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy.

BACKGROUND: In children with tuberous sclerosis, the PET tracer alpha[11C]methyl-L-tryptophan (AMT) has been shown to be selectively taken up by epileptogenic tubers, thus allowing differentiation from nonepileptogenic tubers in the interictal state. OBJECTIVE: To determine whether cortical areas showing increased AMT uptake in children without tuberous sclerosis complex with intractable neocortical epilepsy indicate the epileptogenic zone, and to assess the relative contributions of AMT and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET abnormalities to the localization of epileptogenic cortical regions. METHODS: Areas of increased AMT and decreased FDG uptake were marked objectively as regions with abnormal asymmetry using an in-house written software in 27 children who underwent comprehensive evaluation for resective epilepsy surgery. The marked PET abnormalities were compared to the locations of scalp and subdural EEG epileptiform abnormalities, as well as histology and surgical outcome. RESULTS: Focal cortical increases of AMT uptake were found in 15 patients. The lobar sensitivity (39.0%) of AMT PET for seizure onset was lower, but its specificity (100%) was higher (p < 0.0001) than that of hypometabolism on FDG PET (sensitivity 73.2%, specificity 62.7%). AMT PET abnormalities were smaller than corresponding FDG PET hypometabolic regions (p = 0.002), and increased AMT uptake occurred in two patients with nonlocalizing FDG PET. Histologically verified cortical developmental malformations were associated with increased AMT uptake (p = 0.044). Subdural electrodes adjacent to the area of increased AMT uptake were most often involved in seizure onset. CONCLUSIONS: Focal increase of cortical AMT uptake in children is less sensitive but more specific for the lobe of seizure onset than corresponding FDG PET hypometabolism, and it is often associated with epileptogenic cortical developmental malformations. AMT PET can assist placement of subdural electrodes even when MRI and FDG PET fail to provide adequate localizing information. Cortical areas adjacent to increased AMT uptake should be carefully addressed by intracranial EEG because these regions often show a high degree of epileptogenicity.

Positron emission tomography myocardial perfusion imaging in children with suspected coronary abnormalities.

Positron emission tomography (PET) myocardial perfusion imaging has higher spatial resolution than conventional single photon emission computed tomography (SPECT) imaging and allows accurate and reproducible quantification of myocardial blood flow (MBF). In this article, we describe the role of PET myocardial perfusion imaging in clinical decision making in children with suspected coronary abnormalities. We performed a PET myocardial perfusion study using N-13 ammonia in 10 children (median age, 14 years; range, 1-17 years). The indications included exercise-induced chest pain and ST segment changes during exercise testing, coronary artery ectasia, hypertrophic cardiomyopathy with myocardial bridging of the left anterior descending coronary artery, and suspected left coronary stenosis in an infant with William's syndrome. MBF was assessed at baseline and during adenosine hyperemia in all 10 patients and postexercise in 8 patients. Myocardial perfusion was homogeneous at baseline in all 10 patients, during adenosine perfusion in 9 of 10 patients, and postexercise in all 8 patients. Three patients with homogeneous rest and stress perfusion had impaired myocardial flow reserve. The infant with William's syndrome developed a large, reversible perfusion defect in the left coronary territory during adenosine stress and underwent surgical repair. Myocardial flow reserve findings were valuable for clinical decision making in individual patients. We conclude that MBF quantification with N-13 ammonia and PET provides supplemental perfusion information and is helpful in clinical decision making in children with suspected coronary abnormalities.

Prolonged vigabatrin treatment modifies developmental changes of GABA(A)-receptor binding in young children with epilepsy.

PURPOSE: To determine whether prolonged treatment with vigabatrin (VGB), an antiepileptic drug (AED) that acts by elevating brain gamma-aminobutyric acid (GABA) levels, interferes with age-related changes of in vivo GABA(A)-receptor binding in children with epilepsy. METHODS: Using [11C]flumazenil (FMZ)-positron emission tomography (PET) imaging, 15 children (aged 1-8 years) with medically intractable epilepsy were studied. Seven of these children were treated with VGB (1,000-2,500 mg/day) for > or =3 months before the FMZ-PET study. The remaining eight patients were medicated with other drugs that are known not to act directly on the GABAergic system. Absolute quantification of PET data was performed by using the volume of distribution (VD) of FMZ in brain tissue representing FMZ ligand binding. RESULTS: After controlling for age, hemispheric FMZ VD values were significantly lower in children treated with VGB as compared with the non-VGB group (p = 0.012). Regional FMZ VD values of the VGB-treated patients were significantly lower in all cortical regions and the cerebellum, whereas the difference was not significant in the thalamus and basal ganglia. No significant drug effect or drug-by-region interaction could be determined when the patients were separated according to treatment with carbamazepine (p = 0.97) or valproate (p = 0.55). CONCLUSIONS: VGB induces a decrease in GABA(A)-receptor binding in the cortex and cerebellum of the developing epileptic brain. A similar effect of other drugs and substances of abuse targeting the GABAergic system may be hypothesized. Because of the important role of the GABAergic system in developmental plasticity, the reversibility and functional consequences of this age-specific drug effect should be further studied.

Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans.

Early global deprivation of institutionalized children may result in persistent specific cognitive and behavioral deficits. In order to examine brain dysfunction underlying these deficits, we have applied positron emission tomography using 2-deoxy-2-[(18)F]fluoro-D-glucose in 10 children (6 males, 4 females, mean age 8.8 years) adopted from Romanian orphanages. Using statistical parametric mapping (SPM), the pattern of brain glucose metabolism in the orphans was compared to the patterns obtained from two control groups: (i) a group of 17 normal adults (9 males, 8 females, mean age 27.6 years) and (ii) a group of 7 children (5 males and 2 females, mean age 10.7 years) with medically refractory focal epilepsy, but normal glucose metabolism pattern in the contralateral hemisphere. Consistent with previous studies of children adopted from Romanian orphanages, neuropsychological assessment of Romanian orphans in the present study showed mild neurocognitive impairment, impulsivity, and attention and social deficits. Comparing the normalized glucose metabolic rates to those of normal adults, the Romanian orphans showed significantly decreased metabolism bilaterally in the orbital frontal gyrus, the infralimbic prefrontal cortex, the medial temporal structures (amygdala and head of hippocampus), the lateral temporal cortex, and the brain stem. These findings were confirmed using a region-of-interest approach. SPM analysis showed significantly decreased glucose metabolism in the same brain regions comparing the orphans to the nonepileptic hemisphere of the childhood epilepsy controls. Dysfunction of these brain regions may result from the stress of early global deprivation and may be involved in the long-term cognitive and behavioral deficits displayed by some Romanian orphans.

Neuroradiological assessment of brain structure and function and its implication in the pathogenesis of West syndrome.

Neuroimaging studies with magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning have contributed significantly to our understanding of West syndrome. Cortical dysplastic lesions are the most common abnormalities seen with MRI in infants with spasms, but other structural lesions are also detected occasionally. An underlying cortical dysplasia may not be apparent until myelination has advanced in the brain and poor gray-white matter differentiation becomes observable. Many cortical dysplastic lesions can only be detected using PET scanning of glucose metabolism or gamma-aminobutyric acid(A) (GABA(A)) receptor binding. The MRI and PET findings, together with neurophysiological observations, strongly suggest that infantile spasms are initiated as cortical epileptic discharges that, during a 'critical' developmental period, may undergo secondary generalization in an age-dependent mechanism to emerge as spasms. The onset of spasms often coincides with the functional maturation of cerebral cortex. Based on data from glucose metabolism PET scanning as well as electrophysiological and neurochemical findings on infants with spasms, we have postulated that the offending lesion is a focal or diffuse cortical abnormality which, at a critical stage of maturation, causes abnormal functional interactions with brainstem raphe nuclei which project widely throughout the brain. Raphe-cortical projections could mediate the hypsarrhythmic changes seen on EEG. The prominent serotonergic raphe-striatal pathway and descending spinal pathways may be responsible for secondary generalization of the cortical discharges to result in the relatively symmetric spasms. It is likely that additional factors (e.g. genetic) play a role in the manifestation of the age-specific electroclinical features of West syndrome. Recently developed PET tracers can be used to detect epileptogenic brain regions and also to investigate developmental abnormalities of serotonergic (using the tracer alpha[(11)C]methyl-L-tryptophan) and GABAergic (using [(11)C]flumazenil) neurotransmitter systems. These systems are implicated in epileptogenesis, and their involvement in the pathophysiology of West syndrome can be further addressed by future functional neuroimaging studies.

Surgical treatment of West syndrome.

The discovery of focal or multifocal cortical lesions using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning in the majority of infants with West syndrome has led to a surgical approach in the treatment of some patients with intractable infantile spasms. The locations of these lesions should be concordant with localization of focal ictal and/or interictal electroencephalographic (EEG) abnormalities prior to proceeding with cortical resection. When a single lesion is present on the MRI or PET, and there is good correlation with EEG localization, surgical treatment is generally quite favorable in terms of both seizure control and cognitive development. Interictal glucose metabolism PET scans in children with intractable cryptogenic infantile spasms show unifocal cortical hypometabolism in about 20% of cases. In the majority, however, multifocal asymmetric hypometabolism is suggestive of multifocal underlying lesions, possibly multifocal cortical dysplasia. When the pattern of glucose hypometabolism is symmetric, a lesional etiology is less likely, thus neurometabolic or neurogenetic disorders should be considered. Therefore, the pattern of glucose hypometabolism on PET in infants with intractable cryptogenic spasms is a useful guide to decide whether a medical or surgical approach should be undertaken. In order to achieve the best cognitive outcome with surgery, it is important to resect the entire 'nociferous' area rather than just the seizure focus. Our research with new PET imaging probes has attempted to provide a comprehensive evaluation of the epileptogenic zone including the 'nociferous' cortex. We have used [(11)C]flumazenil (FMZ), which labels gamma aminobutyric acid(A) (GABA(A)) receptors, and have found this to be particularly useful in showing: (i) decreased receptor binding with medial temporal involvement thus indicating resection of medial temporal structures, (ii) the peri-lesional epileptogenic zone surrounding MRI lesions, (iii) the seizure onset zone in MRI-negative cases, and (iv) potential secondary epileptic foci. Another recently developed PET probe, alpha[(11)C]methyl-L-tryptophan (AMT) which is a precursor for the serotonin and the kynurenine metabolism pathways, is capable of differentiating between epileptogenic and non-epileptogenic tubers in patients with tuberous sclerosis complex and intractable epilepsy (including infantile spasms). Subsequently, we have applied AMT PET in patients with multifocal cortical dysplasia to determine the predominant seizure focus, and the results have been promising with regard to seizure control but not cognitive development. Thus, the introduction of newer more specific PET probes for epilepsy has led to improved and more accurate localization of seizure foci that should ultimately improve outcome of epilepsy surgery in West syndrome.

Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction.

OBJECTIVE: To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). METHODS: Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). RESULTS: PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. CONCLUSIONS: These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

Bilateral medial prefrontal and temporal neocortical hypometabolism in children with epilepsy and aggression.

PURPOSE: To identify brain regions with abnormal function in children with intractable partial epilepsy and aggressive behavior by using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET). METHODS: Six children (mean age, 9.9 years) with intractable partial epilepsy and aggressive behavior underwent detailed psychodevelopmental assessment and FDG-PET scanning. The objective technique of statistical parametric mapping (SPM) was applied to define focal abnormalities of glucose metabolism, and compared those with those of a group of normal adult subjects (n = 17) as well as age-matched children with epilepsy with similar seizure characteristics but without aggression (n = 7). The findings were analyzed further by using a region-of-interest (ROI) approach. RESULTS: The aggressive children all showed developmental delay, and four of them also manifested autistic symptoms. SPM analysis demonstrated extensive glucose hypometabolism in the aggressive group bilaterally in the temporal and prefrontal cortex compared with that in normal adult controls. A focal area of medial prefrontal glucose hypometabolism was defined in the aggressive children as compared with the nonaggressive pediatric group with SPM, whereas ROI comparison of these groups confirmed prefrontal hypometabolism and also showed glucose hypometabolism of the temporal neocortex in the aggressive children. Severity of aggression correlated inversely with glucose metabolism of the left temporal as well as bilateral medial prefrontal cortex. CONCLUSIONS: Bilateral prefrontal and temporal neocortical brain glucose hypometabolism in children with epilepsy and aggressive behavior may indicate a widespread dysfunction of cortical regions, which normally exert an inhibitory effect on subcortical aggressive impulses. PET studies may be used to elucidate the neurobiologic basis of aggressive behavior in children.

Sturge-Weber syndrome: correlation between clinical course and FDG PET findings.

OBJECTIVE: To determine whether the extent and degree of glucose hypometabolism defined by PET correlate with seizure characteristics, cognitive function, and interictal EEG abnormalities in children with unilateral cerebral involvement of Sturge-Weber syndrome (SWS). METHODS: 2-Deoxy-2[18F]fluoro-D-glucose (FDG) PET was performed in 13 children (age range 0.7 to 15.1 years; five boys, eight girls) with unilateral SWS. Based on asymmetries between homologous cortical areas in FDG PET images, cortical areas of mildly (10% to 20% decrease), and severely (>20% decrease) asymmetric cortical metabolism were defined. These areas were normalized to the size of the ipsilateral hemisphere and correlated with clinical seizure characteristics, full-scale IQ, and interictal EEG abnormalities. RESULTS: Both seizure frequency (p = 0.027) and lifetime number of seizures (p = 0.017) showed a positive correlation with the area (expressed as the percentage of cortical area of ipsilateral hemisphere) of mildly asymmetric cortical metabolism. Patients with higher IQ had a shorter duration of epilepsy (p = 0.044) and a larger area of severely asymmetric cortical metabolism (p = 0.044). Patients with bilateral interictal EEG abnormalities had larger lifetime number of seizures (p = 0.042), lower IQ (p = 0.024), and smaller area of severely asymmetric cortical metabolism (p = 0.019) than those with only ipsilateral EEG abnormalities. CONCLUSIONS: Association of severely asymmetric cortical metabolism with relatively preserved cognitive function in SWS suggests that functional reorganization occurs more readily when cortex is severely rather than mildly damaged. Therefore, the area of mildly asymmetric cortical metabolism may exert a nociferous effect on the remaining of the brain. Thus, the extent and degree of glucose asymmetry detected by PET are sensitive markers of seizure severity and cognitive decline in SWS.

Myocardial flow reserve in patients with a systemic right ventricle after atrial switch repair.

OBJECTIVES: The purpose of this study was to assess myocardial blood flow (MBF) and flow reserve in systemic right ventricles (RV) in long-term survivors of the Mustard operation. BACKGROUND: There is a high prevalence of systemic RV dysfunction and impaired exercise performance in long-term survivors of the Mustard operation. A mismatch between myocardial blood supply and systemic ventricular work demand has been proposed as a potential mechanism. METHODS: We assessed MBF at rest and during intravenous adenosine hyperemia in 11 long-term survivors of a Mustard repair (age 18+/-5 years, median age at repair 0.7 years, follow-up after repair 17+/-5 years) and 13 healthy control subjects (age 23+/-7 years), using N-13 ammonia and positron emission tomography imaging. RESULTS: There was no difference in basal MBF between the systemic RV of survivors of the Mustard operation and the systemic left ventricle (LV) of healthy control subjects (0.80+/-0.19 vs. 0.74+/-0.15 ml/g/min, respectively, p = NS). However, the hyperemic flows were significantly lower in systemic RVs than they were in systemic LVs (2.34+/-0.0.69 vs. 3.44+/-0.62 ml/g/min respectively, p < 0.01). As a result, myocardial flow reserve was lower in systemic RVs than it was in systemic LVs (2.93+/-0.63 vs. 4.74+/-1.09, respectively, p < 0.01). CONCLUSIONS: Myocardial flow reserve is impaired in systemic RVs in survivors of the Mustard operation. This may contribute to systemic ventricular dysfunction in these patients.

Relationship of flumazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome.

BACKGROUND: Cortical areas showing abnormal glucose metabolism and [(11)C]flumazenil (FMZ) binding are commonly seen on PET scans of patients with intractable partial epilepsy, but it is unclear whether these must be totally resected to achieve seizure control. OBJECTIVE: To analyze whether the extent of cortex showing 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) or FMZ PET abnormalities correlates with the outcome of resective epilepsy surgery. METHODS: Cortical FDG and FMZ PET abnormalities in 15 young patients (mean age, 12.2 +/- 7.0 years) with intractable partial epilepsy of neocortical origin were marked as regions with abnormal asymmetry using an objective semiautomated software package. These marked regions were then projected and measured on the brain surface reconstructed from the coregistered high-resolution MRI. Following cortical resection, the size of nonresected cortex with preoperative PET abnormalities was also measured (calculated separately for marked areas in the lobe of seizure onset as defined by long-term video EEG monitoring, and in remote cortical areas). Extent of preoperative PET abnormalities and postoperative nonresected cortex abnormalities on PET were correlated with outcome scores. RESULTS: Large preoperative FMZ PET abnormalities were associated with poor outcome (r = 0.57; p = 0.025). Larger areas of nonresected cortex with preoperative FMZ PET abnormalities in the lobe of seizure onset were also associated with worse outcome in the whole group (r = 0.66; p = 0.007) as well as in patients with extratemporal resection (r = 0.73; p = 0.007), and in those with no lesion on MRI (r = 0.60; p = 0.049). Patients with seizure-free outcome had significantly smaller nonresected cortex with preoperative FMZ PET abnormalities than those who continued to have seizures (p = 0.022). No significant correlations between nonresected FDG PET abnormalities and surgical outcome were found. CONCLUSIONS: Extensive cortical abnormalities on FMZ PET predict poor outcome in neocortical epilepsy surgery. Resection of FMZ abnormalities in the lobe of seizure onset is associated with excellent outcome even in the absence of a structural lesion. In contrast, although FDG PET abnormalities regionalized the epileptogenic area, their size was not related to the extent of epileptogenic tissue to be removed.

Postnatal maturation of human GABAA receptors measured with positron emission tomography.

During brain development in nonhuman primates, there are large changes in GABAA receptor binding and subunit expression. An understanding of human GABAA receptor ontogeny is highly relevant in elucidating the pathophysiology of neurodevelopmental disorders in which GABAergic mechanisms play a role as well as in understanding differences that occur during development in the pharmacology of drugs acting on this system. We have measured age-related changes in the brain distribution of the GABAA receptor complex in vivo using positron emission tomography (PET) in epileptic children under evaluation for surgical treatment. PET imaging was performed using the tracer [11C]flumazenil (FMZ), a ligand that binds to alpha subunits of the GABAA receptor. FMZ binding was quantified using a two-compartment model yielding values for the volume of distribution (VD) of the tracer in tissue. All brain regions studied showed the highest value for FMZ VD at the youngest age measured (2 years), and the values then decreased exponentially with age. Medial temporal lobe structures, primary visual cortex, and thalamus showed larger differences between values for age 2 years and adults (approximately 50% decrease) than did basal ganglia, cerebellum, and other cortical regions (25-40% decreases). Furthermore, subcortical regions reached adult values earlier (14-17.5 years) than did cortical regions (18-22 years). The ontogeny data of FMZ VD from children may contribute to understanding regional differences in synaptic plasticity as well as improve rational therapeutic use of drugs acting at the GABAA receptor in the pediatric population.

Assessment of skeletal muscle ventricle tissue blood flow using positron emission tomography.

In this pilot study, we assessed the feasibility of using positron emission tomography (PET) imaging for in vivo measurement of skeletal muscle ventricle (SMV) tissue blood flow. In 4 dogs, with SMVs prepared from their latissimus dorsi muscle, we quantified SMV tissue blood flow by PET and related it to the tissue flow measured by radiolabeled microspheres under similar physiologic conditions. The tissue blood flow was estimated in SMVs wrapped around a mandrel (not in circulation) at rest and during SMV stimulation (30 and 90 contraction-cycles/min). SMV tissue perfusion was heterogeneous, especially during SMV contraction. Furthermore, there was a linear relationship between SMV tissue flows estimated by PET and those measured by microspheres. We conclude that in vivo imaging of SMV is feasible by PET. Quantification of SMV tissue blood flow by PET has promise as a means of assessing changes in blood flow, but further technical progress needs to be made before absolute flows can be reliably measured.

Lissencephaly: fetal pattern of glucose metabolism on positron emission tomography?

BACKGROUND: In classical lissencephaly, the cerebral cortex is four-layered, containing neurons that have failed to complete their migration between 12 and 16 weeks of gestation. METHODS: The authors studied the functional activity of lissencephalic cortex using 2-deoxy-2[(18)F]fluoro-D-glucose PET (FDG PET) in eight patients (six girls and two boys, mean age 7.5 years) with isolated lissencephaly sequence. RESULTS: The PET scans revealed a remarkably similar and bilaterally symmetric pattern of glucose metabolism in all eight patients. The cerebral cortex of lissencephaly showed two layers that could be differentiated based on metabolic activity. The inner layer, which probably corresponds to the inner cellular layer of lissencephalic cortex, showed 8 to 63% higher glucose utilization rate than the outer layer, which probably represents a composite of the molecular, outer cellular, and cell-sparse layers. Patients with a higher metabolic ratio between the cortical layers (inner/outer) showed greater delay in communication (p = 0.007) and socialization (p = 0.03). CONCLUSIONS: These findings are consistent with [(14)C]-2-deoxyglucose autoradiography studies in fetal sheep that have shown that before the development of significant numbers of axons, dendrites, and synapses, glucose metabolism appears to be highest in regions with the highest density of cell bodies, compared to the more mature state when glucose metabolism is highest in areas of greatest dendritic arborization. FDG PET studies of classical lissencephaly provide a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques.