Michael Guiou

Linear and Nonlinear Relationships between Neuronal Activity, Oxygen Metabolism, and Hemodynamic Responses

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.

Evaluation of coupling between optical intrinsic signals and neuronal activity in rat somatosensory cortex.

We investigated the coupling between perfusion-related brain imaging signals and evoked neuronal activity using optical imaging of intrinsic signals (OIS) at 570 and 610 nm. OIS at 570 nm reflects changes in cerebral blood volume (CBV), and the 610 nm response is related to hemoglobin oxygenation changes. We assessed the degree to which these components of the hemodynamic response were coupled to neuronal activity in rat barrel, hindpaw, and forepaw somatosensory cortex by simultaneously recording extracellular evoked field potentials (EPs) and OIS while varying stimulation frequency. In all stimulation paradigms, 10 Hz stimulation evoked the largest optical and electrophysiological responses. Across all animals, the 610 late phase and 570 responses correlated linearly with sigmaEP (P < 0.05) during both whisker deflection and electrical hindpaw stimulation, but the 610 early phase did not (whisker P = 0.27, hindpaw P = 0.28). The signal-to-noise ratio (SNR) of the 610 early phase (whisker 3.1, hindpaw 5.3) was much less than that for the late phase (whisker 14, hindpaw 51) and 570 response (whisker 11, hindpaw 46). During forepaw stimulation, however, the 610 early phase had a SNR (17) higher than that during hindpaw stimulation and correlated well with neuronal activity (P < 0.05). We conclude that the early deoxygenation change does not correlate consistently with neuronal activity, possibly because of its low SNR. The robust CBV-related response, however, has a high SNR and correlates well with evoked cortical activity.

Columnar Specificity of Microvascular Oxygenation and Volume Responses: Implications for Functional Brain Mapping

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 μm. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation (“initial dip”) but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing (using ≤2-3 sec changes) is more important than etiology (oxygenation or volume).

Functional signal- and paradigm-dependent linear relationships between synaptic activity and hemodynamic responses in rat somatosensory cortex

Linear relationships between synaptic activity and hemodynamic responses are critically dependent on functional signal etiology and paradigm. To investigate these relationships, we simultaneously measured local field potentials (FPs) and optical intrinsic signals in rat somatosensory cortex while delivering a small number of electrical pulses to the hindpaw with varied stimulus intensity, number, and interstimulus interval. We used 570 and 610 nm optical signals to estimate cerebral blood volume (CBV) and oxygenation, respectively. The spatiotemporal evolution patterns and trial-by-trial correlation analyses revealed that CBV-related optical signals have higher fidelity to summed evoked FPs (ΣFPs) than oxygenation-derived signals. CBV-related signals even correlated with minute ΣFP fluctuations within trials of the same stimulus condition. Furthermore, hemodynamic signals (CBV and late oxygenation signals) increased linearly with ΣFP while varying stimulus number, but they exhibited a threshold and steeper gradient while varying stimulus intensity, suggesting insufficiency of the homogeneity property of linear systems and the importance of spatiotemporal coherence of neuronal population activity in hemodynamic response formation. These stimulus paradigm-dependent linear and nonlinear relationships demonstrate that simple subtraction-based analyses of hemodynamic signals produced by complex stimulus paradigms may not reflect a difference in ΣFPs between paradigms. Functional signal- and paradigm-dependent linearity have potentially profound implications for the interpretation of perfusion-based functional signals.

DEVELOPMENT AND VALIDATION OF A STANDARDIZED METHOD FOR CONTOURING THE BRACHIAL PLEXUS: PRELIMINARY DOSIMETRIC ANALYSIS AMONG PATIENTS TREATED WITH IMRT FOR HEAD-AND-NECK CANCER

PURPOSE Although Radiation Therapy Oncology Group protocols have proposed a limiting dose to the brachial plexus for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, essentially no recommendations exist for the delineation of this structure for treatment planning. METHODS AND MATERIALS Using anatomic texts, radiologic data, and magnetic resonance imaging, a standardized method for delineating the brachial plexus on 3-mm axial computed tomography images was devised. A neuroradiologist assisted with identification of the brachial plexus and adjacent structures. This organ at risk was then contoured on 10 consecutive patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Dose-volume histogram curves were generated by applying the proposed brachial plexus contour to the initial treatment plan. RESULTS The total dose to the planning target volume ranged from 60 to 70 Gy (median, 70). The mean brachial plexus volume was 33 +/- 4 cm(3) (range, 25.1-39.4). The mean irradiated volumes of the brachial plexus were 50 Gy (17 +/- 3 cm(3)), 60 Gy (6 +/- 3 cm(3)), 66 Gy (2 +/- 1 cm(3)), 70 Gy (0 +/- 1 cm(3)). The maximal dose to the brachial plexus was 69.9 Gy (range, 62.3-76.9) and was >/=60 Gy, >/=66 Gy, and >/=70 Gy in 100%, 70%, and 30% of patients, respectively. CONCLUSIONS This technique provides a precise and accurate method for delineating the brachial plexus organ at risk on treatment planning computed tomography scans. Our dosimetric analysis suggest that for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, brachial plexus routinely receives doses in excess of historic and Radiation Therapy Oncology Group limits.

Spatiotemporal Evolution of Functional Hemodynamic Changes and Their Relationship to Neuronal Activity

Brain imaging techniques such as functional magnetic resonance imaging (fMRI) have provided a wealth of information about brain organization, but their ability to investigate fine-scale functional architecture is limited by the spatial specificity of the hemodynamic responses upon which they are based. We investigated the spatiotemporal evolution of hemodynamic responses in rat somatosensory cortex to electrical hindpaw stimulation. We combined the advantages of optical intrinsic signal imaging and spectroscopy to produce high-resolution two-dimensional maps of functional changes in tissue oxygenation and blood volume. Cerebral blood flow changes were measured with laser-Doppler flowmetry, and simultaneously recorded field potentials allowed comparison between hemodynamic changes and underlying neuronal activity. For the first 2 to 3 secs of activation, hemodynamic responses overlapped in a central parenchymal focus. Over the next several seconds, cerebral blood volume changes propagated retrograde into feeding arterioles, and oxygenation changes anterograde into draining veins. By 5 to 6 secs, responses localized primarily in vascular structures distant from the central focus. The peak spatial extent of the hemodynamic response increased linearly with synaptic activity. This spatial spread might be because of lateral subthreshold activation or passive vascular overspill. These results imply early microvascular changes in volume and oxygenation localize to activated neural columns, and that spatial specificity will be optimal within a 2- to 3-sec window after neuronal activation.

Near-infrared spectroscopy (NIRS) in cognitive neuroscience of the primate brain

We describe the use of near-infrared spectroscopy (NIRS) as a suitable means of assessing hemodynamic changes in the cerebral cortex of awake and behaving monkeys. NIRS can be applied to animals performing cognitive tasks in conjunction with electrophysiological methods, thus offering the possibility of investigating cortical neurovascular coupling in cognition. Because it imposes fewer constraints on behavior than fMRI, NIRS appears more practical than fMRI for certain studies of cognitive neuroscience on the primate cortex. In the present study, NIRS and field potential signals were simultaneously recorded from the association cortex (posterior parietal and prefrontal) of monkeys performing two delay tasks, one spatial and the other non-spatial. Working memory was accompanied by an increase in oxygenated hemoglobin mirrored by a decrease in deoxygenated hemoglobin. Both the trends and the amplitudes of these changes differed by task and by area. Field potential records revealed slow negative potentials that preceded the task trials and persisted during their memory period. The negativity during that period was greater in prefrontal than in parietal cortex. Between tasks, the potential differences were less pronounced than the hemodynamic differences. The present feasibility study lays the groundwork for future correlative studies of cognitive function and neurovascular coupling in the primate.

Cortical spreading depression produces long-term disruption of activity-related changes in cerebral blood volume and neurovascular coupling

Cortical spreading depression (CSD) is a pronounced depolarization of neurons and glia that spreads slowly across the cortex followed by a period of depressed electrophysiological activity. The vascular changes associated with CSD are a large transient increase in blood flow followed by a prolonged decrease lasting greater than 1 h. Currently, the profile of functional vascular activity during this hypovolemic period has not been well characterized. Perfusion-based imaging techniques such as functional magnetic resonance imaging (fMRI) assume a tight coupling between changes in neuronal and vascular activity. Under normal conditions, these variables are well correlated. Characterizing the effect of CSD on this relationship is an important step to understand the impact acute pathophysiological events may have on neurovascular coupling. We examine the effect of CSD on functional changes in cerebral blood volume (CBV) evoked by cortical electrophysiological activity for 1 h following CSD induction. CBV signal amplitude, duration, and time to peak show little recovery at 60 min post-induction. Analysis of spontaneous vasomotor activity suggests a decrease in vascular reactivity may play a significant role in the disruption of normal functional CBV responses. Electrophysiological activity is also attenuated but to a lesser degree. CBV and evoked potentials are not well correlated following CSD, suggesting a breakdown of the neurovascular coupling relationship.

PRIMARY RADIATION THERAPY FOR HEAD-AND-NECK CANCER IN THE SETTING OF HUMAN IMMUNODEFICIENCY VIRUS

PURPOSE To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). METHODS AND MATERIALS The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. RESULTS The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. CONCLUSIONS Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.