Anterior White Matter Research Articles

Edge density imaging: Mapping the anatomic embedding of the structural connectome within the white matter of the human brain

The structural connectome has emerged as a powerful tool to characterize the network architecture of the human brain and shows great potential for generating important new biomarkers for neurologic and psychiatric disorders. The edges of the cerebral graph traverse white matter to interconnect cortical and subcortical nodes, although the anatomic embedding of these edges is generally overlooked in the literature. Mapping the paths of the connectome edges could elucidate the relative importance of individual white matter tracts to the overall network topology of the brain and also lead to a better understanding of the effect of regionally-specific white matter pathology on cognition and behavior. In this work, we introduce edge density imaging (EDI), which maps the number of network edges that pass through every white matter voxel. Test–retest analysis shows good to excellent reliability for edge density (ED) measurements, with consistent results using different cortical and subcortical parcellation schemes and different diffusion MR imaging acquisition parameters. We also demonstrate that ED yields complementary information to both traditional and emerging voxel-wise metrics of white matter microstructure and connectivity, including fractional anisotropy, track density, fiber orientation dispersion and neurite density. Our results demonstrate spatially ordered variations of ED throughout the white matter, notably including greater ED in posterior than anterior cerebral white matter. The EDI framework is employed to map the white matter regions that are enriched with pathways connecting rich club nodes and also those with high densities of intra-modular and inter-modular edges. We show that periventricular white matter has particularly high ED and high densities of rich club edges, which is significant for diseases in which these areas are selectively affected, ranging from white matter injury of prematurity in infants to leukoaraiosis in the elderly. Using edge betweenness centrality, we identify specific white matter regions involved in a large number of shortest paths, some containing highly connected rich club edges while others are relatively isolated within individual modules. Overall, these findings reveal an intricate relationship between white matter anatomy and the structural connectome, motivating further exploration of EDI for biomarkers of cognition and behavior.

In Patients With Idiopathic Normal Pressure Hydrocephalus Postoperative Cerebral Perfusion Changes Measured by Dynamic Susceptibility Contrast Magnetic Resonance Imaging Correlate With Clinical Improvement.

To explore relationships between clinical improvement and relative cerebral blood flow (rCBF) changes after shunt-insertion in idiopathic normal pressure hydrocephalus (iNPH) as measured by dynamic susceptibility contrast magnetic resonance imaging. In 20 idiopathic normal pressure hydrocephalus patients rCBF was measured preoperatively and 3 months postoperatively. Because of shunt-induced right-sided artefacts, evaluation was restricted to 12 left-sided cortical, subcortical, and periventricular regions of interest. Correlations between rCBF and clinical symptoms were analyzed in shunt responders. In responders, the postoperative regions of interest-based rCBF increase of 2% to 9% was significant in the parenchyma, the hippocampus, and the anterior periventricular white matter. Perfusion improvement in the cingulus, caudate head, and thalamus correlated with decreased disturbance in one or more of the domains neuropsychology, gait, balance, and total performance. Apparently, dynamic susceptibility contrast magnetic resonance imaging can measure postoperative perfusion changes in responders. Postoperatively, perfusion increase in some grey matter structures seems to determine the degree of clinical improvement.

Dissociating prefrontal circuitry in intelligence and memory: neuropsychological correlates of magnetic resonance and diffusion tensor imaging.

We examined intelligence and memory in 25 healthy participants who had both prior magnetic resonance imaging (MRI) of gray matter volumes of medial orbital frontal cortex (mOFC) and rostral anterior cingulate cortex (rACC), along with diffusion tensor imaging (DTI) of posterior and anterior mOFC-rACC white matter microstructure, as assessed by fractional anisotropy (FA). Results showed distinct relationships between these basic structural brain parameters and higher cognition, highlighted by a highly significant correlation of left rACC gray matter volume with memory, and to a lesser extent, though still statistically significant, correlation of left posterior mOFC-rACC FA with intelligence. Regression analyses showed that left posterior mOFC-rACC connections and left rACC gray matter volume each contributed to intelligence, with left posterior mOFC-rACC FA uniquely accounting for between 20.43 and 24.99% of the variance in intelligence, in comparison to 13.54 to 17.98% uniquely explained by left rACC gray matter volume. For memory, only left rACC gray matter volume explained neuropsychological performance, uniquely accounting for a remarkably high portion of individual variation, ranging from 73.61 to 79.21%. These results pointed to differential contributions of white mater microstructure connections and gray matter volumes to individual differences in intelligence and memory, respectively.

Multimodal imaging of mild traumatic brain injury and persistent postconcussion syndrome.

BackgroundPersistent postconcussion syndrome (PCS) occurs in around 5–10% of individuals after mild traumatic brain injury (mTBI), but research into the underlying biology of these ongoing symptoms is limited and inconsistent. One reason for this could be the heterogeneity inherent to mTBI, with individualized injury mechanisms and psychological factors. A multimodal imaging study may be able to characterize the injury better.AimTo look at the relationship between functional (fMRI), structural (diffusion tensor imaging), and metabolic (magnetic resonance spectroscopy) data in the same participants in the long term (>1 year) after injury. It was hypothesized that only those mTBI participants with persistent PCS would show functional changes, and that these changes would be related to reduced structural integrity and altered metabolite concentrations.MethodsFunctional changes associated with persistent PCS after mTBI (>1 year postinjury) were investigated in participants with and without PCS (both n = 8) and non-head injured participants (n = 9) during performance of working memory and attention/processing speed tasks. Correlation analyses were performed to look at the relationship between the functional data and structural and metabolic alterations in the same participants.ResultsThere were no behavioral differences between the groups, but participants with greater PCS symptoms exhibited greater activation in attention-related areas (anterior cingulate), along with reduced activation in temporal, default mode network, and working memory areas (left prefrontal) as cognitive load was increased from the easiest to the most difficult task. Functional changes in these areas correlated with reduced structural integrity in corpus callosum and anterior white matter, and reduced creatine concentration in right dorsolateral prefrontal cortex.ConclusionThese data suggest that the top-down attentional regulation and deactivation of task-irrelevant areas may be compensating for the reduction in working memory capacity and variation in white matter transmission caused by the structural and metabolic changes after injury. This may in turn be contributing to secondary PCS symptoms such as fatigue and headache. Further research is required using multimodal data to investigate the mechanisms of injury after mTBI, but also to aid individualized diagnosis and prognosis.

The affective modulation of motor awareness in anosognosia for hemiplegia: Behavioural and lesion evidence

The possible role of emotion in anosognosia for hemiplegia (i.e., denial of motor deficits contralateral to a brain lesion), has long been debated between psychodynamic and neurocognitive theories. However, there are only a handful of case studies focussing on this topic, and the precise role of emotion in anosognosia for hemiplegia requires empirical investigation. In the present study, we aimed to investigate how negative and positive emotions influence motor awareness in anosognosia. Positive and negative emotions were induced under carefully-controlled experimental conditions in right-hemisphere stroke patients with anosognosia for hemiplegia (n = 11) and controls with clinically normal awareness (n = 10). Only the negative, emotion induction condition resulted in a significant improvement of motor awareness in anosognosic patients compared to controls; the positive emotion induction did not. Using lesion overlay and voxel-based lesion-symptom mapping approaches, we also investigated the brain lesions associated with the diagnosis of anosognosia, as well as with performance on the experimental task. Anatomical areas that are commonly damaged in AHP included the right-hemisphere motor and sensory cortices, the inferior frontal cortex, and the insula. Additionally, the insula, putamen and anterior periventricular white matter were associated with less awareness change following the negative emotion induction. This study suggests that motor unawareness and the observed lack of negative emotions about one's disabilities cannot be adequately explained by either purely motivational or neurocognitive accounts. Instead, we propose an integrative account in which insular and striatal lesions result in weak interoceptive and motivational signals. These deficits lead to faulty inferences about the self, involving a difficulty to personalise new sensorimotor information, and an abnormal adherence to premorbid beliefs about the body.

CADASIL and Autoimmunity: Coexistence in a Family with the R169C Mutation at Exon 4 of the NOTCH3 Gene

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations of the NOTCH3 gene, which result in degeneration of vascular smooth muscle cells, arteriolar stenosis, and impaired cerebral blood flow. For clinicians this is the commonest hereditary adult-onset condition causing stroke and vascular dementia at middle age. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Coexistence of autoimmunity is atypical and has been described only in occasional patients. Methods: Three members of a Greek family from the island of Lesvos of North East Greece were evaluated. The patients come from a four-generation family in which there were at least seven members with clinical data suggestive of CADASIL. We describe here the clinical, imaging and biochemical findings in this family with R169C mutation at exon 4 and presenting additional clinical and biochemical findings suggestive of autoimmune disorder. DNA was extracted from whole blood using standard procedures for sequencing. Results: Three affected members of this family carried the R169C. In a phenotypic analysis of affected individuals from four generations with CADASIL, the disease was characterized by migraine attacks, recurrent subcortical infarcts, and cognitive decline with typical anterior temporal lobe white matter lesions. At least 3 mutation carriers from two generations had increased antinuclear antibody (ANA) titers and various combinations of rash, joint pains, photosensitivity, and renal involvement. Conclusion: This is a rare description of the coexistence of autoimmunity in CADASIL patients with possible worsening clinical effects. The study extends the spectrum of atypical presentation of CADASIL. The coexistence of autoimmunity does not necessarily exclude CADASIL, but may cause an additional diagnostic and therapeutic challenge. This autoimmune disorder may have increased the severity of the disease and, additionally, may be related to the pathogenetic mechanisms of CADASIL. It is possible that the NOTCH3 mutation alone is not enough to trigger autoimmunity since, in the case of our family, the R169C mutation has already been described in other families with no evidence of coexistent autoimmunity. Other genetic or environmental factors or interactions and/or common pathways between the vascular and immune systems are probably co-operating. Further, prospective studies are needed to clarify the prevalence and types of autoimmune disorders present in CADASIL families.

Encéphalomyélite aiguë disséminée post-vaccination antirabique : à propos d’un cas

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system. It is a disease whose incidence is not precisely known. The presumed mechanism is demyelination of the immune-mediated central nervous system. There is no pathognomonic clinical presentation in ADEM. The combination of multifocal neurological disorders arising in the aftermath of an infection or vaccination should alert the clinician. We report a case of ADEM in an 8-year-old child occurring after antirabies vaccination. The diagnosis was made by nuclear magnetic resonance imaging (bilateral and multifocal lesions in the subcortical occipitoparietal and frontal left anterior white matter with involvement of U fibers) and a history of antirabies vaccination. The clinical course was marked by the appearance of motor and visual effects.

Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder.

Functional neuroimaging studies implicate anterior cingulate and limbic dysfunction in major depressive disorder (MDD) and responsiveness to antidepressants. Diffusion tensor imaging (DTI) enables characterisation of white matter tracts that relate to these regions. To examine whether DTI measures of anterior cingulate and limbic white matter are useful prognostic biomarkers for MDD. Of the 102 MDD out-patients from the International Study to Predict Optimized Treatment for Depression (iSPOT-D) who provided baseline magnetic resonance imaging (MRI) data, 74 completed an 8-week course of antidepressant medication (randomised to escitalopram, sertraline or extended-release venlafaxine) and were included in the present analyses. Thirty-four matched controls also provided DTI data. Fractional anisotropy was measured for five anterior cingulate-limbic white matter tracts: cingulum cingulate and hippocampus bundle, fornix, stria terminalis and uncinate fasciculus. (Trial registered at ClinicalTrials.gov: NCT00693849.) A cross-validated logistic regression model demonstrated that altered connectivity for the cingulum part of the cingulate and stria terminalis tracts significantly predicted remission independent of demographic and clinical measures with 62% accuracy. Prediction improved to 74% when age was added to this model. Anterior cingulate-limbic white matter is a useful predictor of antidepressant treatment outcome in MDD.

Compensation or inhibitory failure? Testing hypotheses of age-related right frontal lobe involvement in verbal memory ability using structural and diffusion MRI

Functional neuroimaging studies report increased right prefrontal cortex (PFC) involvement during verbal memory tasks amongst low-scoring older individuals, compared to younger controls and their higher-scoring contemporaries. Some propose that this reflects inefficient use of neural resources through failure of the left PFC to inhibit non-task-related right PFC activity, via the anterior corpus callosum (CC). For others, it indicates partial compensation – that is, the right PFC cannot completely supplement the failing neural network, but contributes positively to performance. We propose that combining structural and diffusion brain MRI can be used to test predictions from these theories which have arisen from fMRI studies. We test these hypotheses in immediate and delayed verbal memory ability amongst 90 healthy older adults of mean age 73 years. Right hippocampus and left dorsolateral prefrontal cortex (DLPFC) volumes, and fractional anisotropy (FA) in the splenium made unique contributions to verbal memory ability in the whole group. There was no significant effect of anterior callosal white matter integrity on performance. Rather, segmented linear regression indicated that right DLPFC volume was a significantly stronger positive predictor of verbal memory for lower-scorers than higher-scorers, supporting a compensatory explanation for the differential involvement of the right frontal lobe in verbal memory tasks in older age.

Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides.

Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified ("resting") microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.

Dilated Perivascular Spaces in Small-Vessel Disease: A Study in CADASIL

Background and Aim: Dilated perivascular spaces (dPVS) have previously been associated with aging and hypertension-related cerebral microangiopathy. However, their risk factors, radiological features and clinical relevance have been poorly evaluated in CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology of ischemic small-vessel disease. The purpose of this study was to investigate these different aspects in a large cohort of patients with this disorder. Methods: Demographic and MRI data of 344 patients from a prospective cohort study were analyzed. The severity of dPVS was evaluated separately in the anterior temporal lobes, subinsular areas, basal ganglia and white matter, using validated semiquantitative scales. Logistic and multiple linear regression models were used to determine the risk factors associated with the severity of dPVS in these different regions and their relationships with cognition, disability and the MRI markers of the disease (white matter hyperintensities (WMH) lacunar infarcts, microbleeds and brain parenchymal fraction (BPF)). Results: The severity of dPVS was found to increase with age regardless of cerebral area (p < 0.001). In contrast with dPVS in other locations, the severity of dPVS in the temporal lobes or subinsular areas was also found strongly and specifically related to the extent of WMH (p < 0.001). Conversely, no significant association was detected with lacunar volume, number of microbleeds or BPF. A high degree of dPVS in the white matter was associated with lower cognitive performances independently of age and other MRI markers of the disease including BPF (p ≤ 0.04). Conclusions: In CADASIL, the progression of the hereditary microangiopathy with aging may promote the dilation of perivascular spaces throughout the whole brain but with variable extent according to cerebral location. In temporal lobes and subinsular areas, dPVS are common MRI features and may share a similar pathogenesis with the extension of WMH during the course of the disease. dPVS may also participate in the development of cognitive decline in this model of small-vessel disease, and their large number in white matter may alert clinicians to a higher risk of cognitive decline in CADASIL.

Effects of visuoauditive integration on motor system in speech perception: A TMS study

Unilateral spatial neglect frequently occurs after right-hemisphere stroke. It represents a major problem in the domain of public health, since it prevents patients from orienting or responding to left-sided stimuli. The exact anatomical location of lesions underlying the manifestation of this syndrome is currently debated (Bartolomeo, 2012). In the present study, we used a longitudinal approach in order to identify the lesional predictors of chronic neglect in longrange white matter bundles. We present a longitudinal study of 37 patients with right-hemisphere damage, tested at the acute/subacute phase and at more than 1 year after the stroke. 27 patients presented signs of spatial neglect in the acute/subacute phase. Each patient underwent a radiological assessment including a DTI sequence, (50 directions; bvalue of 1000 mm2/s). Voxelwise statistical analysis of the fractional anisotropy (FA) data was carried out using TBSS (Tract-Based Spatial Statistics, Smith, 2006). The longitudinal follow-up revealed that only 10 patients (27%) recovered from neglect at retest. In acute/subacute neglect, a lower FAwas found in the way of the right Superior Longitudinal fasciculus (SLF II and III) and of the corpus callosum. In the chronic phase, TBSS analysis showed the implication of the posterior portion of the corpus callosum (splenium) and of SLF II & III. The voxelwise correlation between a cancellation task (Bells test) and FA maps found a lower FA in the way of the anterior corpus callosum, local frontal and fronto-parietal white matter (SLF II and III), and in the thalamus. Our results confirm a key role of fronto-parietal disconnection in the emergence and chronic persistence of neglect (Thiebaut de Schotten et al., 2012). Moreover, we demonstrated an implication of interhemispheric disconnection (splenium and forceps major) in chronic neglect. These findings support the hypothesis that interhemispheric disconnection may deprive the right frontoparietal pathway of visual inputs, amputing the brain reconstruction of the left hemi-space (Tomaiuolo et al., 2010), and that chronic neglect at least in part results from the activity of an isolated left hemisphere (Bartolomeo et al., 2007).

Midlife measurements of white matter microstructure predict subsequent regional white matter atrophy in healthy adults.

Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval. Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables. Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P < 0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (P < 0.001, uncorrected for multiple comparisons). Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases.

Increased nuclear Olig1-expression in the pregenual anterior cingulate white matter of patients with major depression: A regenerative attempt to compensate oligodendrocyte loss?

BackgroundStructural and functional oligodendrocyte deficits as well as impaired myelin integrity have been described in affective disorders and schizophrenia, and may disturb the connectivity between disease-relevant brain regions. Olig1, an oligodendroglial transcription factor, might be important in this context, but has not been systematically studied so far. MethodsNissl- and Olig1-stained oligodendrocytes were quantified in the pregenual anterior cingulate (pACC)/dorsolateral prefrontal cortex (DLPFC), and adjacent white matter of patients with major depressive disorder (MDD, n = 9), bipolar disorder (BD, n = 8), schizophrenia (SZ, n = 13), and matched controls (n = 16). Potential downstream effects of increased Olig1-expression were analyzed. Antidepressant drug effects on Olig1-expression were further explored in OLN-93 oligodendrocyte cultures. ResultsNissl-stainings of both white matter regions showed a 19–27% reduction of total oligodendrocyte densities in MDD and BD, but not in SZ. In contrast, nuclear Olig1-immunoreactivity was elevated in MDD in the pACC-adjacent white matter (left: p = 0.008; right: p = 0.018); this effect tended to increase with antidepressant dosage (r = 0.631, p = 0.069). This reactive increase of Olig1 was confirmed by partly dose-dependent effects of imipramine and amitriptyline in oligodendrocyte cultures. Correspondingly, MBP expression in the pACC-adjacent white matter tended to increase with antidepressant dosage (r = 0.637, p = 0.065). Other tested brain regions showed no diagnosis-dependent differences regarding Olig1-immunoreactivity. ConclusionsSince nuclear Olig1-expression marks oligodendrocyte precursor cells, its increased expression along with reduced total oligodendrocyte densities (Nissl-stained) in the pACC-adjacent white matter of MDD patients might indicate a (putatively medication-boosted) regenerative attempt to compensate oligodendrocyte loss.

Toll-Like Receptor 3 Expression in Glia and Neurons Alters in Response to White Matter Injury in Preterm Infants

Toll-like receptors (TLRs) are members of the pattern recognition receptor family that detect components of foreign pathogens or endogenous molecules released in response to injury. Recent studies demonstrate that TLRs also have a functional role in regulating neuronal proliferation in the developing brain. This study investigated cellular expression of TLR3 using immunohistochemistry on human brain tissue. The tissue sections analysed contained anterior and lateral periventricular white matter from the frontal and parietal lobes in post-mortem neonatal cases with a postmenstrual age range of 23.6-31.4 weeks. In addition to preterm brains without overt pathology (control), preterm pathology cases with evidence of white matter injuries (WMI) were also examined. In order to identify TLR-positive cells, we utilized standard double-labelling immunofluorescence co-labelling techniques and confocal microscopy to compare co-expression of TLR3 with a neuronal marker (NeuN) or with glial markers (GFAP for astrocytes, Iba-1 for microglia and Olig2 for oligodendrocytes). We observed an increase in the neuronal (28 vs. 17%) and astroglial (38 vs. 21%) populations in the WMI group compared to controls in the anterior regions of the periventricular white matter in the frontal lobe. The increase in neurons and astrocytes in the WMI cases was associated with an increase in TLR3 immunoreactivity. This expression was significantly increased in the astroglia. The morphology of the TLR3 signal in the control cases was globular and restricted to the perinuclear region of the neurons and astrocytes, whilst in the cases of WMI, both neuronal, axonal and astroglial TLR3 expression was more diffuse (i.e., a different intracellular distribution) and could be detected along the extensions of the processes. This study demonstrates for the first time that neurons and glial cells in human neonatal periventricular white matter express TLR3 during development. The patterns of TLR3 expression were altered in the presence of WMI, which might influence normal developmental processes within the immature brain. Identifying changes in TLR3 expression during fetal development may be key to understanding the reduced volumes of grey matter and impaired cortical development seen in preterm infants.

Brain Perfusion in Encephalopathic Newborns after Therapeutic Hypothermia

Cerebral perfusion patterns in neonates with HIE after therapeutic hypothermia have not been well described. The objectives of this study were to compare global and regional perfusion between infants with HIE and neonate controls and to relate measures of cerebral perfusion to brain injury on conventional MR imaging in neonates with HIE. Term encephalopathic neonates meeting criteria for hypothermia between June 2011 and January 2012 were enrolled in this prospective observational study. MR imaging-ASL was performed in the second week of life. Comparisons were made with data from neonate controls who underwent the same imaging protocol. NIRS measures of cerebral oxygenation during and immediately after hypothermia were also evaluated in a subset of patients. Secondary analyses were performed to assess cerebral perfusion and oxygenation differences by pattern of injury on qualitative MR imaging interpretation. We enrolled 18 infants with HIE and 18 control infants. Mean global CBF and regional CBF in the basal ganglia, thalamus, and anterior white matter were higher in cases compared with controls. Infants with HIE with injury on MR imaging, however, had lower CBF (significant in the thalamus) compared with those with normal MR imaging. Decreased FTOE by NIRS further differentiated patients with HIE with injury on MR imaging. Disturbed cerebral perfusion is observed in the second week of life in some babies with HIE despite treatment with hypothermia. Infants with HIE with injury on MR imaging have lower regional CBF in the thalamus compared with those without injury, possibly representing pseudonormalization of CBF and low metabolic demand after progression to irreversible brain injury.

Altered Brain Microstructure Assessed by Diffusion Tensor Imaging in Patients With Diabetes and Gastrointestinal Symptoms

OBJECTIVEIn patients with long-standing diabetes mellitus (DM), there is increasing evidence for abnormal processing of gastrointestinal sensations in the central nervous system. Using magnetic resonance diffusion tensor imaging, we characterized brain microstructure in areas involved in visceral sensory processing and correlated these findings to clinical parameters.RESEARCH DESIGN AND METHODSTwenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the “sensory matrix” (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum.RESULTSPatients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula).CONCLUSIONSThe findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.

Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex

Prenatal stress has been widely demonstrated to have links with behavioral problems in clinical populations and animal models, however, few investigations have examined the immediate developmental events that are affected by prenatal stress. Here, we utilize GAD67GFP transgenic mice in which GABAergic progenitors express green fluorescent protein (GFP) to examine the impact of prenatal stress on the development of these precursors to inhibitory neurons. Pregnant female mice were exposed to restraint stress three times daily from embryonic day 12 (E12) onwards. Their offspring demonstrated changes in the distribution of GFP-positive (GFP+) GABAergic progenitors in the telencephalon as early as E13 and persisting until postnatal day 0. Changes in distribution reflected alterations in tangential migration and radial integration of GFP+ cells into the developing cortical plate. Fate mapping of GAD67GFP+ progenitors with bromodeoxyuridine injected at E13 demonstrated a significant increase of these cells at P0 in anterior white matter. An overall decrease in GAD67GFP+ progenitors at P0 in medial frontal cortex could not be attributed to a reduction in cell proliferation. Significant changes in dlx2, nkx2.1 and their downstream target erbb4, transcription factors which regulate interneuron migration, were found within the prenatally stressed developing forebrain, while no differences were seen in mash1, a determinant of interneuron fate, bdnf, a maturation factor for GABAergic cells or fgf2, an early growth/differentiation factor. These results demonstrate that early disruption in GABAergic progenitor migration caused by prenatal stress may be responsible for neuronal defects in disorders with GABAergic abnormalities like schizophrenia.

Anterior temporal lobe white matter abnormal signal (ATLAS) as an indicator of seizure focus laterality in temporal lobe epilepsy: comparison of double inversion recovery, FLAIR and T2W MR imaging

To investigate the diagnostic capability of anterior temporal lobe white matter abnormal signal (ATLAS) for determining seizure focus laterality in temporal lobe epilepsy (TLE) by comparing different MR sequences. This prospective study was approved by the institutional review board and written informed consent was obtained. Three 3D sequences (double inversion recovery (DIR), fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging (T2WI)) and two 2D sequences (FLAIR and T2WI) were acquired at 3 T. Signal changes in the anterior temporal white matter of 21 normal volunteers were evaluated. ATLAS laterality was evaluated in 21 TLE patients. Agreement of independent evaluations by two neuroradiologists was assessed using κ statistics. Differences in concordance between ATLAS laterality and clinically defined seizure focus laterality were analysed using McNemar's test with multiple comparisons. Pre-amygdala high signals (PAHS) were detected in all volunteers only on 3D-DIR. Inter-evaluator agreement was moderate to almost perfect for each sequence. Correct diagnosis of seizure laterality was significantly more frequent on 3D-DIR than on any other sequences (P ≤ 0.031 for each evaluator). The most sensitive sequence for detecting ATLAS laterality was 3D-DIR. ATLAS laterality on 3D-DIR can be a good indicator for determining seizure focus localization in TLE.

Abnormalities of magnetic resonance spectroscopy and diffusion tensor imaging are correlated with executive dysfunction in patients with ischemic leukoaraiosis

Abnormal diffusion tensor imaging (DTI) results have been observed in the periventricular white matter in patients with ischemic leukoaraiosis (ILA). However, the underlying pathological changes and their relationship to cognitive impairments are obscure. In addition, damage in the thalamus, an important structure in the executive function network, has been suggested in ILA, but is poorly understood. Twenty patients with ILA and 20 healthy volunteers with similar ages and educational histories underwent DTI, magnetic resonance spectroscopy (MRS) and a neuropsychological assessment. In patients with ILA, we observed an increased mean diffusivity (MD) and decreased levels of N-acetylaspartate (NAA)/creatine (Cr) in the anterior and posterior periventricular region and the thalamus, as well as decreased fractional anisotropy (FA) in the anterior and posterior periventricular regions. MD and NAA/Cr levels in the anterior and posterior periventricular white matter and NAA/Cr levels in the thalamus were correlated with executive function. DTI and MRS abnormalities were consistent with axonal and/or neuronal loss and dysfunction in the anterior and posterior periventricular white matter and the thalamus. This study demonstrates that DTI and MRS techniques can be used to investigate pathological changes in the anterior and posterior periventricular white matter and the thalamus; these changes may be correlated with executive functional changes in patients with ILA.