Beau M. Ances

Paraneoplastic Encephalitis, Psychiatric Symptoms, and Hypoventilation in Ovarian Teratoma

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal‐expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two‐pore‐domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A‐purified antibodies reproduced the hippocampal immunolabeling of all patients antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune‐mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies. Ann Neurol 2005;58:594–604

Temporal dynamics of the partial pressure of brain tissue oxygen during functional forepaw stimulation in rats.

The partial pressure of tissue oxygen (pO2) was measured in rat somatosensory cortex during periodic electrical forepaw stimulation of either 1 min or 4 s in duration, and correlated with simultaneous laser Doppler flowmetry. For both stimulus durations, a transient decrease in tissue pO2 preceded blood flow changes, followed by a peak in blood flow and an overshoot in tissue pO2. With protracted stimulation, tissue pO2 remained only slightly above pre-stimulus baseline, while blood flow was maintained at a reduced plateau phase. A sustained post-stimulus undershoot in tissue pO2 was observed only for the 1 min stimulus. These findings suggest a complex dynamic relationship between oxygen utilization and blood flow.

Caudate blood flow and volume are reduced in HIV+ neurocognitively impaired patients

Objective: To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume. Methods: The authors performed continuous arterial spin labeled MRI on 42 HIV+ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups. Results: A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients (p = 0.001) with a similar decreasing trend for subsyndromic HIV+ patients (p = 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls (p = 0.010). A Jonckheere–Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group. Conclusions: Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI.

Coupling of Changes in Cerebral Blood Flow with Neural Activity: What Must Initially Dip Must Come Back Up

Activation flow coupling, increases in neuronal activity leading to changes in cerebral blood flow (CBF), is the basis of many neuroimaging methods. An early rise in deoxygenation, the “initial dip,” occurs before changes in CBF and cerebral blood volume (CBV) and may provide a better spatial localizer of early neuronal activity compared with subsequent increases in CBF. Imaging modality, anesthetic, degree of oxygenation, and species can influence the magnitude of this initial dip. The observed initial dip may reflect a depletion of mitochondrial oxygen (O2) buffers caused by increased neuronal activity. Changes in CBF mediated by nitric oxide (NO) or other metabolites and not caused by a lack of O2 or energy depletion most likely lead to an increased delivery of capillary O2 in an attempt to maintain intracellular O2 buffers.

Coupling of Neural Activation to Blood Flow in the Somatosensory Cortex of Rats Is Time-Intensity Separable, but Not Linear

Changes in cerebral blood flow (CBF) because of functional activation are used as a surrogate for neural activity in many functional neuroimaging studies. In these studies, it is often assumed that the CBF response is a linear-time invariant (LTI) transform of the underlying neural activity. By using a previously developed animal model system of electrical forepaw stimulation in rats (n = 11), laser Doppler measurements of CBF, and somatosensory evoked potentials, measurements of neural activity were obtained when the stimulus duration and intensity were separately varied. These two sets of time series data were used to assess the LTI assumption. The CBF data were modeled as a transform of neural activity (N1–P2 amplitude of the somatosensory evoked potential) by using first-order (linear) and second-order (nonlinear) components. Although a pure LTI model explained a large amount of the variance in the data for changes in stimulus duration, our results demonstrated that the second-order kernel (i.e., a nonlinear component) contributed an explanatory component that is both statistically significant and appreciable in magnitude. For variations in stimulus intensity, a pure LTI model explained almost all of the variance in the CBF data. In particular, the shape of the CBF response did not depend on intensity of neural activity when duration was held constant (time-intensity separability). These results have important implications for the analysis and interpretation of neuroimaging data.

Signal averaged laser Doppler measurements of activation-flow coupling in the rat forepaw somatosensory cortex

Regional alterations in cerebral blood flow (CBF) are widely used as a surrogate for neuronal function based on an intact coupling between changes in regional CBF and metabolism, activation-flow coupling (AFC). To further investigate parameters affecting AFC, we have implemented a rat model with electrical forepaw stimulation under alpha-chloralose anesthesia using laser Doppler (LD) measurements of flow parameters through thinned skull over contralateral somatosensory cortex. Signal averaging of the LD response was used to improve reproducibility. A characteristic flow response to electrical forepaw stimulation was reliably recorded from the somatosensory cortex using signal averaging. Stimulation at 5 Hz maximized the LD response, and constant current stimulation up to 1 mA did not induce changes in systemic blood pressure. The shape of the flow response consisted of an initial peak followed by a steady state plateau phase which was observed for stimulation durations longer than 4 s. When individual LD parameters of velocity, red blood cell concentration (CRBC), and cerebral blood flow (CBF) were compared, changes in LDCBF were primarily attributable to changes in LDvelocity rather than LDCRBC. This finding was also observed during hypercapnia. Characterization of AFC in the model provides a background for future studies of the effects of pharmacological manipulation or pathophysiological states.

Dynamic Changes in Cerebral Blood Flow, O2 Tension, and Calculated Cerebral Metabolic Rate of O2 During Functional Activation Using Oxygen Phosphorescence Quenching

Changes in cerebral blood flow (CBF) using laser–Doppler and microvascular O2 oxygen tension using oxygen-dependent phosphorescence quenching in the rat somatosensory cortex were obtained during electrical forepaw stimulation. The signal-averaged CBF response resulting from electrical forepaw stimulation consisted of an initial peak (t = 3.1 ± 0.8 seconds after onset of stimulation), followed by a plateau phase that was maintained throughout the length of the stimulus. In contrast, microvascular O2 tension changes were delayed, reached a plateau level (t = 23.5 ± 1.7 seconds after the onset of stimulation) that remained for the length of the stimulus and for several seconds after stimulus termination, and then returned to baseline. Using Ficks equation and these dynamic measurements, changes in the calculated cerebral metabolic rate of oxygen (CMRO2) during functional stimulation were determined. The calculated CMRO2 response initially was comparable with the CBF, but with protracted stimulation, CMRO2 changes were approximately one-third that of CBF changes. These results suggest that a complex relation exists, with comparable changes in CBF and CMRO2 initially occurring after stimulation but excessive changes in CBF compared with CMRO2 arising with protracted stimulation.

Laser doppler imaging of activation-flow coupling in the rat somatosensory cortex.

Activation-flow coupling (AFC) provides a physiological basis for mapping cerebral activation using cerebral blood flow (CBF) as a surrogate marker for neuronal function. Laser Doppler offers a minimally invasive approach for measuring changes in cerebral blood flow but the spatial resolution of this technique is limited by the number of individual probes that can be used. Recently, laser Doppler imaging (LDI) scanners, which use computer-driven optics to scan and measure LD changes in two dimensions, have successfully measured flow changes in the exposed cortex of animals. Here we demonstrate the use of an LDI device through a thinned skull to determine the spatiotemporal characteristics of AFC in alpha-chloralose anesthetized rats in response to electrical forepaw stimulation. The spatial and temporal characteristics of the AFC response measured by LDI are in agreement with prior results obtained using a single LD probe. These results suggest a promising role for LDI in the characterization of the spatiotemporal characteristics of AFC in animal models and possibly for intraoperative monitoring in the human brain.

Transcranial laser doppler mapping of activation flow coupling of the rat somatosensory cortex

Signal averaged laser Doppler (LD) through a thinned skull over the rat somatosensory cortex was used to map the spatial and temporal characteristics of activation-flow coupling, the change in regional cerebral blood flow (CBF) due to neuronal activation, in response to electrical forepaw stimulation. The location of maximal changes in amplitude of the LD response was reproducibly recorded at 4-5 mm lateral to Bregma. This location is very similar but slightly posterior and lateral to results obtained from electrophysiological, magnetic resonance imaging (MRI), and optical imaging studies. The latency of the activation-flow coupling (AFC) response was inversely correlated to response amplitude, with shorter latencies at positions of maximal amplitude.

Effects of variations in interstimulus interval on activation-flow coupling response and somatosensory evoked potentials with forepaw stimulation in the rat.

In functional neuroimaging studies, the hemodynamic response to functional activation is used as a surrogate marker for neuronal activity, typically in response to task paradigms that use periodic stimuli. With use of a model system of electrical forepaw stimulation in rats (n = 14) with laser-Doppler (LD) monitoring of cerebral blood flow (CBF) changes in the somatosensory cortex, the effects of variations in the interstimulus interval (ISI) on the hemodynamic response to periodic stimuli were examined. A characteristic peak flow response was seen for 4-second stimuli and a peak and plateau response were seen for all 8-second stimuli regardless of ISI. However, both the amplitude of the LDCBF response and the integrated response were significantly reduced for shorter ISIs, whereas the baseline flow was not altered. Somatosensory evoked potential responses were also recorded in some rats (n = 8) and remained unchanged for the various ISIs for a particular stimulus duration. These results suggest that the decrease in the LDCBF responses observed with shorter ISIs likely represents a refractoriness of the hemodynamic response and not neuronal function. These results may have important implications for the optimization and interpretation of functional activation paradigms that use periodic stimuli.