Asht M. Mishra

Demonstration of interstitial cerebral edema with diffusion tensor MR imaging in type C hepatic encephalopathy

Brain water may increase in hepatic encephalopathy (HE). Diffusion tensor imaging was performed in patients with cirrhosis with or without HE to quantify the changes in brain water diffusivity and to correlate it with neuropsychological (NP) tests. Thirty‐nine patients with cirrhosis, with minimal (MHE) or overt HE, were studied and compared to 18 controls. Mean diffusivity (MD) and fractional anisotropy (FA) were calculated in corpus callosum, internal capsule, deep gray matter nuclei, periventricular frontal, and occipital white matter regions in both cerebral hemispheres. The MD and FA values from different regions in different groups were compared using analysis of variance and Spearmans rank correlation test. In 10 patients with MHE, repeat studies were performed after 3 weeks of lactulose therapy to look for any change in MD, FA, and NP scores. Significantly increased MD was found with insignificant changes in FA in various regions of brain in patients with MHE or HE compared with controls, indicating an increase in interstitial water in the brain parenchyma without any microstructural changes. A significant correlation was found between MD values from corpus callosum, internal capsule, and NP test scores. After therapy, MD values decreased significantly and there was a corresponding improvement in NP test scores. Further analysis showed that MD values were different for different grades of minimal or overt HE. In conclusion, the increase in MD with no concomitant changes in FA in cirrhosis with minimal or early HE indicates the presence of reversible interstitial brain edema. (HEPATOLOGY 2006;43:698–706.)

Role of Diffusion-weighted Imaging and In Vivo Proton Magnetic Resonance Spectroscopy in the Differential Diagnosis of Ring-enhancing Intracranial Cystic Mass Lesions

Objectives: Proton magnetic resonance spectroscopy (PMRS) and diffusion-weighted imaging (DWI) were compared to determine which technique is more effective in the differential diagnosis of cystic intraparenchymal ring-enhancing lesions with variable perifocal edema. Methods: Fifty-two patients (abscesses [n = 29], tumor cysts [n = 20], and benign cysts [n = 3]) formed the basis for comparative evaluation in this study. The criteria for abscess diagnosis were apparent diffusion coefficient (ADC) values less than 0.9 ± 1.3 × 10−3 mm2/s and presence of lactate cytosolic amino acids (AAs) with/without succinate, acetate, alanine, and glycine on PMRS. Criteria for nonabscess cyst identification were ADC values of 1.7–3.8 × 10−3 mm2/s and presence of lactate and choline on PMRS. On the basis of these criteria, patients were categorized into abscess (n = 29) and nonabscess (n = 23) groups. Sensitivity and specificity of PMRS and DWI with respect to the final diagnosis were calculated based on the efficacy of these techniques. Results: Apparent diffusion coefficient values in 21 patients with abscesses were observed within the range of defined criteria, whereas in 8 patients, ADC values were beyond the range of defined criteria. Lactate and AAs with or without other metabolites were observed in 25 of 29 cases of abscesses on PMRS. In the nonabscess group, ADC values of cystic lesions in all patients were consistent with respect to the defined criteria. Only lactate was seen in 14 of 23 patients, whereas both lactate and choline were visible in 6 patients. In 3 patients with neurocysticercosis, AAs (n = 2), lactate (n = 3), acetate (n = 1), succinate (n = 3), choline (n = 2), and alanine (n = 3) were seen. The sensitivity of DWI and PMRS for differentiation of brain abscess from nonbrain abscess was 0.72 and 0.96, respectively, whereas the specificity was 1 for both techniques. Conclusion: Demonstration of restricted diffusion on DWI with reduced ADC is highly suggestive of brain abscess; however, in the absence of restriction, PMRS is mandatory to distinguish brain abscesses from cystic tumors.

Remote Effects of Focal Hippocampal Seizures on the Rat Neocortex

Seizures have both local and remote effects on nervous system function. Whereas propagated seizures are known to disrupt cerebral activity, little work has been done on remote network effects of seizures that do not propagate. Human focal temporal lobe seizures demonstrate remote changes including slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. Ictal neocortical slow waves have been interpreted as seizure propagation; however, we hypothesize that they reflect a depressed cortical state resembling sleep or coma. To investigate this hypothesis, we performed multimodal studies of partial and secondarily generalized limbic seizures in rats. Video/EEG monitoring of spontaneous seizures revealed slow waves in the frontal cortex during behaviorally mild partial seizures, contrasted with fast polyspike activity during convulsive generalized seizures. Seizures induced by hippocampal stimulation produced a similar pattern, and were used to perform functional magnetic resonance imaging weighted for blood oxygenation and blood volume, demonstrating increased signals in hippocampus, thalamus and septum, but decreases in orbitofrontal, cingulate, and retrosplenial cortex during partial seizures, and increases in all of these regions during propagated seizures. Combining these results with neuronal recordings and CBF measurements, we related neocortical slow waves to reduced neuronal activity and cerebral metabolism during partial seizures, but found increased neuronal activity and metabolism during propagated seizures. These findings suggest that ictal neocortical slow waves represent an altered cortical state of depressed function, not propagated seizure activity. This remote effect of partial seizures may cause impaired cerebral functions, including loss of consciousness.

Cortical Deactivation Induced by Subcortical Network Dysfunction in Limbic Seizures

Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model that, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional magnetic resonance imaging (fMRI) that electrically stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, whereas frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged on by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures.

Cytotoxic Edema Is Responsible for Raised Intracranial Pressure in Fulminant Hepatic Failure: In Vivo Demonstration Using Diffusion-Weighted MRI in Human Subjects

It is not clear whether cerebral edema in fulminant hepatic failure is predominantly vasogenic or cytotoxic, though cytotoxic edema due to astrocyte swelling is more likely. Diffusion-weighted magnetic resonance imaging can differentiate vasogenic from cytotoxic edema. We performed diffusion-weighted imaging in patients with fulminant hepatic failure to clarify the issue by measuring apparent diffusion coefficient, which quantifies movement of water molecule across cell membrane. Seven patients with fulminant hepatic failure underwent conventional and diffusion-weighted magnetic resonance imaging. Apparent diffusion coefficient was measured in four cortical areas and 12 deep white and gray matter regions in both cerebral hemispheres. Thirteen healthy subjects served as controls. The apparent diffusion coefficient values in patients and controls were compared using Wilcoxon signed rank test. Two patients who survived underwent repeat imaging using same protocol. Patients with FHF had significantly lower apparent diffusion coefficient in all cortical and deep white and gray matter regions of interest compared to controls (p < 0.001), suggesting cytotoxic cell swelling. In two survivors with repeat imaging, one showed complete resolution while the changes persisted in the other, suggesting ischemic injury. Cerebral edema in fulminant hepatic failure is predominantly due to cytotoxic edema.

Biological correlates of diffusivity in brain abscess

Restricted diffusion in brain abscess is assumed to be due to a combination of inflammatory cells, necrotic debris, viscosity, and macromolecules present in the pus. We performed diffusion‐weighted imaging (DWI) on 41 patients with proven brain abscesses (36 pyogenic and five tuberculous), and correlated the apparent diffusion coefficient (ADC) from the abscess cavity with viable cell density, viscosity, and extracellular‐protein content quantified from the pus. On the basis of the correlation between cell density and ADC in animal tumor models and human tumors in the literature, we assumed that the restricted ADC represents the cellular portion in the abscess cavity. We calculated restricted and unrestricted lesion volumes, and modeled cell density over the restricted area with viable cell density per mm3 obtained from the pus. The mean restricted ADC in the cavity (0.65 ± 0.01 × 10–3 mm2/s) correlated inversely with restricted cell density in both the pyogenic (r = −0.90, P = <0.05) and tuberculous (0.60 ± 0.04 × 10–3 mm2/s, r = −0.94, P = <0.05) abscesses. We conclude that viable cell density is the main biological parameter responsible for restricted diffusion in brain abscess, and it is not influenced by the etiological agents responsible for its causation. Magn Reson Med, 2005.

Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij Rat

The relationship between neuronal activity and hemodynamic changes plays a central role in functional neuroimaging. Under normal conditions and in neurological disorders such as epilepsy, it is commonly assumed that increased functional magnetic resonance imaging (fMRI) signals reflect increased neuronal activity and that fMRI decreases represent neuronal activity decreases. Recent work suggests that these assumptions usually hold true in the cerebral cortex. However, less is known about the basis of fMRI signals from subcortical structures such as the thalamus and basal ganglia. We used WAG/Rij rats (Wistar albino Glaxo rats of Rijswijk), an established animal model of human absence epilepsy, to perform fMRI studies with blood oxygen level-dependent and cerebral blood volume (CBV) contrasts at 9.4 tesla, as well as laser Doppler cerebral blood flow (CBF), local field potential (LFP), and multiunit activity (MUA) recordings. We found that, during spike-wave discharges, the somatosensory cortex and thalamus showed increased fMRI, CBV, CBF, LFP, and MUA signals. However, the caudate–putamen showed fMRI, CBV, and CBF decreases despite increases in LFP and MUA signals. Similarly, during normal whisker stimulation, the cortex and thalamus showed increases in CBF and MUA, whereas the caudate–putamen showed decreased CBF with increased MUA. These findings suggest that neuroimaging-related signals and electrophysiology tend to agree in the cortex and thalamus but disagree in the caudate–putamen. These opposite changes in vascular and electrical activity indicate that caution should be applied when interpreting fMRI signals in both health and disease from the caudate–putamen, as well as possibly from other subcortical structures.

DTI abnormalities in anterior corpus callosum of rats with spike-wave epilepsy.

OBJECTIVE Absence epilepsy is a common seizure disorder in children which can produce chronic psychosocial sequelae. Human patients and rat absence models show bilateral spike-wave discharges (SWD) in cortical regions. We employed diffusion tensor imaging (DTI) in rat absence models to detect abnormalities in white matter pathways connecting regions of seizure activity. METHODS We studied Wistar albino Glaxo rats of Rijswijk (WAG/Rij), genetic absence epilepsy rats of Strasbourg (GAERS), and corresponding nonepileptic control strains. Ex vivo DTI was performed at 9.4 T with diffusion gradients applied in 16 orientations. We compared fractional anisotropy (FA), perpendicular (lambda(perpendicular)) and parallel (lambda(||)) diffusivity between groups using t-maps and region of interest (ROI) measurements. RESULTS Adult epileptic WAG/Rij rats exhibited a localized decrease in FA in the anterior corpus callosum. This area was confirmed by tractography to interconnect somatosensory cortex regions most intensely involved in seizures. This FA decrease was not present in young WAG/Rij rats before onset of SWD. GAERS, which have more severe SWD than WAG/Rij, exhibited even more pronounced callosal FA decreases. Reduced FA in the epileptic animals originated from an increased lambda(perpendicular) with no significant changes in lambda(||). INTERPRETATION Reduced FA with increased lambda(perpendicular) suggests that chronic seizures cause reduction in myelin or decreased axon fiber density in white matter pathways connecting regions of seizure activity. These DTI abnormalities may improve the understanding of chronic neurological difficulties in children suffering with absence epilepsy, and may also serve as a noninvasive biomarker for monitoring beneficial effects of treatment.

Decreased Subcortical Cholinergic Arousal in Focal Seizures

Impaired consciousness in temporal lobe seizures has a major negative impact on quality of life. The prevailing view holds that this disorder impairs consciousness by seizure spread to the bilateral temporal lobes. We propose instead that seizures invade subcortical regions and depress arousal, causing impairment through decreases rather than through increases in activity. Using functional magnetic resonance imaging in a rodent model, we found increased activity in regions known to depress cortical function, including lateral septum and anterior hypothalamus. Importantly, we found suppression of intralaminar thalamic and brainstem arousal systems and suppression of the cortex. At a cellular level, we found reduced firing of identified cholinergic neurons in the brainstem pedunculopontine tegmental nucleus and basal forebrain. Finally, we used enzyme-based amperometry to demonstrate reduced cholinergic neurotransmission in both cortex and thalamus. Decreased subcortical arousal is a critical mechanism for loss of consciousness in focal temporal lobe seizures.

Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.