Reduced glutamate in white matter of male neonates exposed to alcohol in utero: a (1)H-magnetic resonance spectroscopy study.

In utero exposure to alcohol leads to a spectrum of fetal alcohol related disorders (FASD). However, few studies used have used proton magnetic resonance spectroscopy ((1)H-MRS) to understand how neurochemical disturbances relate to the pathophysiology of FASD. Further, no studies to date have assessed brain metabolites in infants exposed to alcohol in utero. We hypothesize that neonates exposed to alcohol in utero will show decreased glutamatergic activity, pre-emptive of their clinical diagnosis or behavioural phenotype. Single voxel (1)H-MRS data, sampled in parietal white and gray matter, were acquired from 36 neonates exposed to alcohol in utero, and 31 control unexposed healthy neonates, in their 2nd-4th week of life. Metabolites relative to creatine with phosophocreatine and metabolites absolute concentrations using a water reference are reported. Male infants exposed to alcohol in utero were found to have reduced concentration of glutamate with glutamine (Glx) in their parietal white matter (PWM), compared to healthy male infants (p = 0.02). Further, male infants exposed to alcohol in utero had reduced concentration and ratio for glutamate (Glu) in their PWM (p = 0.02), compared to healthy male infants and female infants exposed to alcohol in utero. Female infants showed higher relative Glx and Glu ratios for parietal gray matter (PGM, p < 0.01), compared to male infants. We speculate that the decreased Glx and Glu concentrations in PWM are a result of delayed oligodendrocyte maturation, which may be a result of dysfunctional thyroid hormone activity in males exposed to alcohol in utero. Further study is required to elucidate the relationship between Glx and Glu, thyroid hormone activity, and oligodendrocyte maturation in infants exposure to alcohol in utero.

Prenatal alcohol exposure and white matter microstructural changes across the first 6-7 years of life: A longitudinal diffusion tensor imaging study of a South African birth cohort.

Prenatal alcohol exposure (PAE) can affect brain development in early life, but few studies have investigated the effects of PAE on trajectories of white matter tract maturation in young children. Here we used diffusion weighted imaging (DWI) repeated over three time points, to measure the effects of PAE on patterns of white matter microstructural development during the pre-school years. Participants were drawn from the Drakenstein Child Health Study (DCHS), an ongoing birth cohort study conducted in a peri-urban community in the Western Cape, South Africa. A total of 342 scans acquired from 237 children as neonates (N = 82 scans: 30 PAE; 52 controls) and at ages 2-3 (N = 121 scans: 27 PAE; 94 controls) and 6-7 years (N = 139 scans: 45 PAE; 94 controls) were included. Maternal alcohol use during pregnancy and other antenatal covariates were collected from 28 to 32 weeks' gestation. Linear mixed effects models with restricted maxium likelihood to accommodate missing data were implemented to investigate the effects of PAE on fractional anisotropy (FA) and mean diffusivity (MD) in specific white matter tracts over time, while adjusting for child sex and maternal education. We found significant PAE-by-time effects on trajectories of FA development in the left superior cerebellar peduncle (SCP-L: p = 0.001; survived FDR correction) and right superior longitudinal fasciculus (SLF-R: p = 0.046), suggesting altered white matter development among children with PAE. Compared with controls, children with PAE demonstrated a more rapid change in FA in these tracts from the neonatal period to 2-3 years of age, followed by a more tapered trajectory for the period from 2-3 to 6-7 years of age, with these trajectories differing from unexposed control children. Given their supporting roles in various aspects of neurocognitive functioning (i.e., motor regulation, learning, memory, language), altered patterns of maturation in the SCP and SLF may contribute to a spectrum of physical, social, emotional, and cognitive difficulties often experienced by children with PAE. This study highlights the value of repeated early imaging in longitudinal studies of PAE, and focus for early childhood as a critical window of potential susceptibility as well as an opportunity for early intervention.

Cortical mechanisms of human imitation.

How does imitation occur? How can the motor plans necessary for imitating an action derive from the observation of that action? Imitation may be based on a mechanism directly matching the observed action onto an internal motor representation of that action ("direct matching hypothesis"). To test this hypothesis, normal human participants were asked to observe and imitate a finger movement and to perform the same movement after spatial or symbolic cues. Brain activity was measured with functional magnetic resonance imaging. If the direct matching hypothesis is correct, there should be areas that become active during finger movement, regardless of how it is evoked, and their activation should increase when the same movement is elicited by the observation of an identical movement made by another individual. Two areas with these properties were found in the left inferior frontal cortex (opercular region) and the rostral-most region of the right superior parietal lobule.

Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex.

Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections.

Improved detection of focal cerebral blood flow changes using three-dimensional positron emission tomography.

Removal of the interplane septa and configuration of a typical multislice PET scanner to accept all possible coincidence lines of response leads to a fivefold increase in sensitivity. This can be of value in regional CBF studies using bolus 15O-labeled water injections, allowing the injected dose to be reduced by a factor of 4, while maintaining the same number of noise equivalent counts. Thus, for a given cumulative dose limit, four times as many studies can be performed in a single subject. Data from the three-dimensional Hoffman brain phantom, closely matched to count rates seen in human studies, show that for an identical cumulative dose, the noise in subtraction (stimulus minus baseline) images can be reduced by a factor of 2 using three-dimensional data acquisition, with appropriate fractionation of the dose. This improvement is dependent on axial position due to the sensitivity characteristics of three-dimensional scans; however, there is a significant gain in the signal-to-noise ratio (S/N) in all image planes. Studies performed in a human subject demonstrate how the factor of 2 gain in S/N leads to improved detectability of activation sites in PET subtraction images.

Principal component analysis and the scaled subprofile model compared to intersubject averaging and statistical parametric mapping: I. "Functional connectivity" of the human motor system studied with [15O]water PET.

Using [15O]water PET and a previously well studied motor activation task, repetitive finger-to-thumb opposition, we compared the spatial activation patterns produced by (1) global normalization and intersubject averaging of paired-image subtractions, (2) the mean differences of ANCOVA-adjusted voxels in Statistical Parametric Mapping, (3) ANCOVA-adjusted voxels followed by principal component analysis (PCA), (4) ANCOVA-adjustment of mean image volumes (mean over subjects at each time point) followed by F-masking and PCA, and (5) PCA with Scaled Subprofile Model pre- and postprocessing. All data analysis techniques identified large positive focal activations in the contralateral sensorimotor cortex and ipsilateral cerebellar cortex, with varying levels of activation in other parts of the motor system, e.g., supplementary motor area, thalamus, putamen; techniques 1-4 also produced extensive negative areas. The activation signal of interest constitutes a very small fraction of the total nonrandom signal in the original dataset, and the exact choice of data preprocessing steps together with a particular analysis procedure have a significant impact on the identification and relative levels of activated regions. The challenge for the future is to identify those preprocessing algorithms and data analysis models that reproducibly optimize the identification and quantification of higher-order sensorimotor and cognitive responses.

Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans.

BACKGROUND: Animal and human studies have demonstrated that postischemic hyperperfusion may occur both early and late timepoints following acute cerebral ischemia. OBJECTIVE: To use diffusion-perfusion MRI to characterize hyperperfusion in humans following intra-arterial thrombolysis. METHODS: MRI were performed before treatment, several hours following vessel recanalization, and at day 7 in patients successfully recanalized with intra-arterial thrombolytics. RESULTS: Hyperperfusion was visualized in 5 of 12 patients within several hours after recanalization (mean volume, 18 mL; range, 7 to 40 mL), and in 6 of 11 patients at day 7 (mean volume, 28 mL; range, 4 to 45 mL). Within the core region of hyperperfusion, mean cerebral blood flow was 2.1 times greater than in the contralateral homologous region at the early time point, and 3.1 times greater at day 7. Seventy-nine percent of voxels with hyperperfusion at day 7 demonstrated infarction at day 7, whereas only 36% of voxels (within the initial hypoperfusion region) not showing hyperperfusion at day 7 demonstrated infarction at day 7. Mean pretreatment apparent diffusion coefficient (ADC) and perfusion values were more impaired in voxels that subsequently developed hyperperfusion compared with other at-risk voxels (all p values < 0.0001). There were no significant differences in the degree of clinical improvement in patients with regions of hyperperfusion versus those without, although sample size limited power to detect group differences. CONCLUSIONS: Postischemic hyperperfusion, visualized with perfusion MRI in humans following recanalization by intra-arterial thrombolytic therapy, occurred in about 40% of patients within hours and in about 50% of patients at day 7. Hyperperfusion developed mainly in regions that went on to infarction. Compared with other abnormal regions, tissues that developed postischemic hyperperfusion had greater bioenergetic compromise in pretreatment apparent diffusion coefficient values and greater impairment in pretreatment blood flow measures.

Improved signal-to-noise in PET activation studies using switched paradigms.

UNLABELLED: PET activation studies employing the autoradiographic technique and 15O-water or 15O-butanol use the difference between images acquired under baseline conditions and during activation to detect focal changes in cerebral blood flow which occur upon stimulus presentation. Typically, the activating task or baseline conditions are maintained throughout the entire imaging period. Simulations of the kinetics of these freely diffusible tracers suggest there may be an advantage to switching between activation and baseline conditions during the course of the study which results in images which maximize the difference signal rather than seeking to quantitate blood flow. We examine the potential of these switched protocols to increase signal-to-noise (S/N) in PET activation studies. METHODS: We examined S/N in activation studies using both-standard and switched paradigms with a simple switched protocol and dynamic three-dimensional PET data from human subjects. With tracer kinetic simulations, we investigated the sensitivity of the S/N gain to factors such as the shape of the input function, the time at which the conditions are switched and the magnitude of the activation. RESULTS: In human studies of activation sites in the visual cortex, primary motor and premotor areas, S/N improvements of 20%-30% were detected using the switched paradigms. Simulations show that this gain is virtually independent of activation magnitude and that there is a broad time window of 20 sec for making the switch between conditions. To obtain the highest S/N gain, a rapid bolus injection is required. CONCLUSION: Switched paradigms have the potential to significantly increase S/N in PET activation studies. In human studies, the S/N increase averaged 25% which is equivalent to increasing the number of counts collected by 50%. Switched paradigms can be used to maximize the difference signal in many activation studies, and do not preclude the absolute quantitation of blood flow using the standard autoradiographic technique.

Topographical and temporal specificity of human intraoperative optical intrinsic signals.

The goal of this study was to determine the topographical and temporal specificity of neuronal and vascular responses using an intraoperative optical technique (iOIS). The face, thumb, index, and middle fingers were stimulated individually to obtain separate maps of cortical activation. Peak optical responses provided unique, non-overlapping cortical brain maps. Non-peak signals were more dispersed and produced overlapping responses from different digits. Peak iOIS responses colocalized with electrocortical stimulation mapping and evoked potentials. Temporally, we observed statistically significant specificity corresponding to sequential cortical activation during early optical signals (500-1750 ms), but later perfusion responses were non-specific. To our knowledge, this is the first report of either topographical specificity in overlapping spatial patterns, and/or temporal specificity in early perfusion profiles. These results therefore may have significant implications for other perfusion dependent functional imaging techniques.

Functional MR and PET imaging of rolandic and visual cortices for neurosurgical planning.

Magnetic resonance (MR) imaging has recently been used to demonstrate physiological activation of the human brain. This development is of considerable interest to the neurosurgeon planning procedures near brain regions involving specific functions. In the present study, rolandic and visual cortices were imaged with a conventional 1.5-tesla clinical MR imager using a spoiled gradient-recalled acquisition in the steady state sequence. Two patients, one with a right frontal astrocytoma and the other with a left parietal meningioma, underwent MR imaging of rolandic cortex while performing a repetitive finger apposition task. Two patients with complex partial seizures referable to the temporal and occipital regions underwent MR imaging of visual cortex while exposed to repetitive photic stimulation (8.3 Hz). Significant signal intensity changes up to 15% between the activation and rest conditions were observed near the surgical targets at the expected anatomical location of the rolandic and visual cortices. In two of these cases activation measured by MR was compared and found similar to the activation measured at the same plane by H2(15)O positron emission tomography (PET). These results suggest that functional MR and PET techniques can be used to obtain preoperative brain mapping in individual patients considered for neurosurgical procedures.

Localization of motor areas adjacent to arteriovenous malformations. A positron emission tomographic study.

Motor cortex activity was localized with positron emission tomography (PET) in 4 patients with large arteriovenous malformations adjacent to or undercutting the left primary motor cortex. Relative cerebral blood flow responses were measured during execution of a visually guided motor tracking task performed with the right index finger, hand, great toe, tongue, or eyes alone (control) and mapped onto each patient's corresponding magnetic resonance imaging (MRI) scan. The relative cerebral blood flow responses in the contralateral precentral gyrus, adjacent to each arteriovenous malformation, demonstrated a normal somatotopic distribution, similar to that in a control population. In the 3 patients with preserved motor function, responses were also present in the ipsilateral primary motor cortex, bilateral supplementary motor area, and ipsilateral anterior cerebellum, similar in location to those of a control population. In the fourth patient with a hemiparesis, responses were attenuated in the primary motor cortex, increased in the supplementary motor area, and absent in the cerebellum. The results demonstrate that PET cerebral blood flow mapping can localize motor cortex despite the presence of significant blood flow abnormalities in adjacent arteriovenous malformations. The method, particularly when combined with MRI, may be used in the planning of surgical, radiation, or embolization therapy.

Electroconvulsive therapy mediates neuroplasticity of white matter microstructure in major depression.

Whether plasticity of white matter (WM) microstructure relates to therapeutic response in major depressive disorder (MDD) remains uncertain. We examined diffusion tensor imaging (DTI) correlates of WM structural connectivity in patients receiving electroconvulsive therapy (ECT), a rapidly acting treatment for severe MDD. Tract-Based Spatial Statistics (TBSS) applied to DTI data (61 directions, 2.5 mm(3) voxel size) targeted voxel-level changes in fractional anisotropy (FA), and radial (RD), axial (AD) and mean diffusivity (MD) in major WM pathways in MDD patients (n=20, mean age: 41.15 years, 10.32 s.d.) scanned before ECT, after their second ECT and at transition to maintenance therapy. Comparisons made at baseline with demographically similar controls (n=28, mean age: 39.42 years, 12.20 s.d.) established effects of diagnosis. Controls were imaged twice to estimate scanning-related variance. Patients showed significant increases of FA in dorsal fronto-limbic circuits encompassing the anterior cingulum, forceps minor and left superior longitudinal fasciculus between baseline and transition to maintenance therapy (P<0.05, corrected). Decreases in RD and MD were observed in overlapping regions and the anterior thalamic radiation (P<0.05, corrected). Changes in DTI metrics associated with therapeutic response in tracts showing significant ECT effects differed between patients and controls. All measures remained stable across time in controls. Altered WM microstructure in pathways connecting frontal and limbic areas occur in MDD, are modulated by ECT and relate to therapeutic response. Increased FA together with decreased MD and RD, which trend towards normative values with treatment, suggest increased fiber integrity in dorsal fronto-limbic pathways involved in mood regulation.

A tensor-based morphometry analysis of regional differences in brain volume in relation to prenatal alcohol exposure.

Reductions in brain volumes represent a neurobiological signature of fetal alcohol spectrum disorders (FASD). Less clear is how regional brain tissue reductions differ after normalizing for brain size differences linked with FASD and whether these profiles can predict the degree of prenatal exposure to alcohol. To examine associations of regional brain tissue excesses/deficits with degree of prenatal alcohol exposure and diagnosis with and without correction for overall brain volume, tensor-based morphometry (TBM) methods were applied to structural imaging data from a well-characterized, demographically homogeneous sample of children diagnosed with FASD (n = 39, 9.6-11.0 years) and controls (n = 16, 9.5-11.0 years). Degree of prenatal alcohol exposure was significantly associated with regionally pervasive brain tissue reductions in: (1) the thalamus, midbrain, and ventromedial frontal lobe, (2) the superior cerebellum and inferior occipital lobe, (3) the dorsolateral frontal cortex, and (4) the precuneus and superior parietal lobule. When overall brain size was factored out of the analysis on a subject-by-subject basis, no regions showed significant associations with alcohol exposure. FASD diagnosis was associated with a similar deformation pattern, but few of the regions survived FDR correction. In data-driven independent component analyses (ICA) regional brain tissue deformations successfully distinguished individuals based on extent of prenatal alcohol exposure and to a lesser degree, diagnosis. The greater sensitivity of the continuous measure of alcohol exposure compared with the categorical diagnosis across diverse brain regions underscores the dose dependence of these effects. The ICA results illustrate that profiles of brain tissue alterations may be a useful indicator of prenatal alcohol exposure when reliable historical data are not available and facial features are not apparent.

Gender effects on cortical thickness and the influence of scaling.

Using magnetic resonance imaging and well-validated computational cortical pattern matching methods in a large and well-matched sample of healthy subjects (n = 60), we analyzed the regional specificity of gender-related cortical thickness differences across the lateral and medial cortices at submillimeter resolution. To establish the influences of brain size correction on gender effects, comparisons were performed with and without applying affine transformations to scale each image volume to a template. We revealed significantly greater cortical thickness in women compared to men, after correcting for individual differences in brain size, while no significant regional thickness increases were observed in males. The pattern and direction of the results were similar without brain size correction, although effects were less pronounced and a small cortical region in the lateral temporal lobes showed greater thickness in males. Our gender-specific findings support a dimorphic organization in male and female brains that appears to involve the architecture of the cortical mantle and that manifests as increased thickness in female brains. This sexual dimorphism favoring women, even without correcting for brain size, may have functional significance and possibly account for gender-specific abilities and/or behavioral differences between sexes.

Mapping cortical gray matter in the young adult brain: effects of gender.

Using magnetic resonance imaging and well-validated computational cortical pattern matching methods in a large and well-matched sample of healthy subjects, we analyzed the effects of gender on regional gray matter (GM) concentration across the cortex. To clarify discrepancies in previous reports, we also examined sexual dimorphisms for whole-brain tissue volumes with and without controlling for brain size differences. In addition, we generated spatially detailed maps of average GM distributions and variability across the entire cortex given that these descriptors are not well characterized in the normative literature. After brain size correction, we detected numerous cortical regions showing significantly increased GM concentration in females compared to males, but no regionally increased GM concentration in males. Permutation testing confirmed the statistical significance of these findings. Locally increased concentration of cortical GM in females corroborates findings of larger global GM volumes in females after correcting for individual brain sizes. Larger global volumes of GM, white matter and CSF, however, are observed in males when individual brain volumes are not taken into account. Our results show that gender is a major contributor to regional and global GM differences between individuals, although the nature of these effects depend on whether brain size is taken into account.

Modeling for intergroup comparisons of imaging data.

Intergroup comparisons pose unique challenges in the analysis of functional imaging data. Imperfections in intersubject stereotaxis can give rise to artifactual results and make it particularly important to allow for intersubject differences in task-related changes when formulating statistical models. Because intergroup comparisons generally involve inferences about the populations from which the subjects were drawn rather than inferences about the particular subjects themselves, subjects must be treated as random rather than fixed effects in the statistical model. These requirements, when combined with the need to adjust for multiple spatial comparisons, result in low statistical power when the number of subjects in each group is small. Functional imaging studies to identify differences between groups generally require many more subjects than other types of functional imaging studies and require careful advance planning to maximize the likelihood of reaching meaningful conclusions.

Brain injury, handedness, and speech lateralization in a series of amobarbital studies.

Data on handedness and speech lateralization in patients selected for amobarbital studies have frequently been extrapolated to the normal population, despite the high frequency of brain injuries which might alter lateralization in these patients. To achieve a better definition of the relationships between brain injury, handedness, and speech lateralization, we reviewed the records of 237 consecutive patients who underwent amobarbital testing. Brain injuries sufficient to cause right hemiparesis were strongly associated with left handedness and atypical (right hemisphere or bilateral) speech representation. Among nonhemiparetic patients, abnormal extratemporal radiological findings were associated with an increased incidence of left handedness and atypical speech lateralization. It was not possible to demonstrate any alteration in handedness or speech representation resulting from abnormalities restricted to the temporal lobes, although such alterations could not be excluded. Handedness and speech lateralization established using amobarbital studies in neurosurgical patients may not be representative of the normal population.