Cocaine preferentially enhances sensory processing in the upper layers of the primary sensory cortex.

Sensory systems are believed to play an important role in drug addiction, particularly in triggering craving and relapse, and it has been shown in previous studies that administration of cocaine can enhance evoked responses in the primary sensory cortex of experimental animals. Primary sensory cortex comprises a multi-layered structure to which a variety of roles have been assigned; an understanding of how cocaine affects evoked activity in these different layers may shed light on how drug-associated sensory cues gain control over behavior. The aim of the present study was to examine how cocaine affects whisker sensory responses in different layers of the primary sensory (barrel) cortex. Field potential and multi-unit activity were recorded from the cortex of anesthetized rats using 16 channel linear probes during repetitive (air puff) stimulation of the whiskers. In control conditions (under saline, i.v.), responses strongly adapted to the repeated sensory stimulation. Following an i.v. injection of cocaine (0.5 mg/kg, i.v.), this adaptation was strongly attenuated, giving each stimulus a more equal representation and weight. Attenuation of adaptation was more marked in the upper cortical layers in both field potential and multi-unit data. Indeed, in these layers, not only was adaptation attenuated but multi-unit response amplitudes under cocaine exceeded those under saline for stimuli occurring early in the train. The results extend our previous findings concerning the enhancement by cocaine of primary sensory responses. Insofar as enhanced neural responses equate to enhanced stimulus salience, the results indicate that cocaine may play a previously under-appreciated role in the formation of associations between drug and drug-related environmental cues by enhancing stimulus salience. The associative process itself may be assisted by a preferential action in the upper cortical layers, thought to be involved in learning and plasticity.

Cocaine administration produces a protracted decoupling of neural and haemodynamic responses to intense sensory stimuli.

Evidence suggests that for relatively weak sensory stimuli, cocaine elevates background haemodynamic parameters but still allows enhanced neural responses to be reflected in enhanced haemodynamic responses. The current study investigated the possibility that for more intense stimuli, the raised background may produce a protracted attenuation of the haemodynamic response. Three experiments were performed to measure effects of i.v. cocaine administration (0.5 mg/kg) or saline on responses in rat barrel cortex to electrical stimulation of the whisker pad. The first experiment used optical imaging spectroscopy (OIS) and laser Doppler flowmetry (LDF) to measure haemodynamic changes. Cocaine caused an increase in baseline blood flow (peak approximately 90%), which lasted for the duration of the test period (25 min). Haemodynamic responses to whisker stimulation were substantially reduced throughout. The second experiment used a 16-channel multi-electrode to measure evoked potentials at 100 mum intervals through the barrel cortex. Summed neural responses (collapsed across the spatial dimension) after cocaine administration were similar to those after saline. The third experiment extended experiment 1 by examining the effects of cocaine on whisker sensory responses using functional magnetic resonance imaging (and concurrent OIS or LDF). Cocaine caused a similar increase in baseline and reduction in the evoked response to that seen in experiment 1. Together, the results of these three experiments show that cocaine produces a protracted decoupling of neural activity and haemodynamic responses to intense sensory stimulation, which suggests that imaging techniques based on changes in haemodynamic parameters may be unsuitable for studying the effects of cocaine on sensory processing in humans.

Integration of neural responses originating from different regions of the cortical somatosensory map.

The neural pathways responsible for detecting peripheral tactile stimuli are well known; however, the interactions between different somatosensory regions have been less well investigated. This study demonstrates how the contralateral sensory response of rat barrel cortex to whisker stimulation is affected by stimulation of contralateral forepaw and ipsilateral whisker and forepaw. The barrel cortex in the right hemisphere was located using optical imaging. A 16-channel multielectrode was used to measure field potentials evoked by contralateral electrical stimulation of the whisker pad. A standard response in the right barrel cortex to single pulse electrical stimulation of the contralateral whisker pad was modulated by applying conditioning stimulation to one of three other regions of the body (the ipsilateral whisker pad, the ipsilateral or contralateral forepaws). In conditions where the standard contralateral whisker stimulus preceded the conditioning pulse, the size of response was identical to when it was stimulated alone. However, when the ipsilateral whisker and contralateral forepaw conditioning stimuli preceded the contralateral whisker pad stimulation, up to a 35% reduction in the contralateral whisker response was observed. These results confirm and extend previous studies [Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 11026-11031; J. Neurosci. 21 (2001) 5251-5261], which show bilateral integration of neural activity within the rat somatosensory system. Furthermore, the longer latency of the inhibition following stimulation of the contralateral forepaw suggests the possible involvement of extracortical circuitry.

Effect of signal length on the performance of independent component analysis when extracting the lambda wave.

The aim of the study was to investigate the effect of signal length on the performance of a signal source separation method, independent component analysis (ICA), when extracting the visual evoked potential (EP) lambda wave from saccade-related electro-encephalogram (EEG) waveforms. A method was devised that enabled the effective length of the recorded EEG traces to be increased prior to processing by ICA. This involved abutting EEG traces from an appropriate number of successive trials (a trial was a set of waveforms recorded from 64 electrode locations in a study investigating saccade performance). ICA was applied to the saccade-related EEG and electro-oculogram (EOG) waveforms recorded from the electrode locations. One spatial and five temporal features of the lambda wave were monitored to assess the performance of ICA applied to both abutted and non-abutted waveforms. ICA applied to abutted trials managed to extract all six features across all seven subjects included in the study. This was not the case when ICA was applied to the non-abutted trials. It was quantitatively demonstrated that the process of abutting EEG waveforms was useful for ICA preprocessing when extracting lambda waves.

Model estimation of cerebral hemodynamics between blood flow and volume changes: a data-based modeling approach.

It is well known that there is a dynamic relationship between cerebral blood flow (CBF) and cerebral blood volume (CBV). With increasing applications of functional MRI, where the blood oxygen-level-dependent signals are recorded, the understanding and accurate modeling of the hemodynamic relationship between CBF and CBV becomes increasingly important. This study presents an empirical and data-based modeling framework for model identification from CBF and CBV experimental data. It is shown that the relationship between the changes in CBF and CBV can be described using a parsimonious autoregressive with exogenous input model structure. It is observed that neither the ordinary least-squares (LS) method nor the classical total least-squares (TLS) method can produce accurate estimates from the original noisy CBF and CBV data. A regularized total least-squares (RTLS) method is thus introduced and extended to solve such an error-in-the-variables problem. Quantitative results show that the RTLS method works very well on the noisy CBF and CBV data. Finally, a combination of RTLS with a filtering method can lead to a parsimonious but very effective model that can characterize the relationship between the changes in CBF and CBV.

Fine detail of neurovascular coupling revealed by spatiotemporal analysis of the hemodynamic response to single whisker stimulation in rat barrel cortex.

The spatial resolution of hemodynamic-based neuroimaging techniques, including functional magnetic resonance imaging, is limited by the degree to which neurons regulate their blood supply on a fine scale. Here we investigated the spatial detail of neurovascular events with a combination of high spatiotemporal resolution two-dimensional spectroscopic optical imaging, multichannel electrode recordings and cytochrome oxidase histology in the rodent whisker barrel field. After mechanical stimulation of a single whisker, we found two spatially distinct cortical hemodynamic responses: a transient response in the "upstream" branches of surface arteries and a later highly localized increase in blood volume centered on the activated cortical column. Although the spatial representation of this localized response exceeded that of a single "barrel," the spread of hemodynamic activity accurately reflected the neural response in neighboring columns rather than being due to a passive "overspill." These data confirm hemodynamics are capable of providing accurate "single-condition" maps of neural activity.

Neurovascular coupling investigated with two-dimensional optical imaging spectroscopy in rat whisker barrel cortex.

Optical imaging slit spectroscopy is a powerful method for estimating quantitative changes in cerebral haemodynamics, such as deoxyhaemoglobin, oxyhaemoglobin and blood volume (Hbr, HbO2 and Hbt, respectively). Its disadvantage is that there is a large loss of spatial data as one image dimension is used to encode spectral wavelength information. Single wavelength optical imaging, on the other hand, produces high-resolution spatiotemporal maps of brain activity, but yields only indirect measures of Hbr, HbO2 and Hbt. In this study we perform two-dimensional optical imaging spectroscopy (2D-OIS) in rat barrel cortex during contralateral whisker stimulation to obtain two-dimensional maps over time of Hbr, HbO2 and Hbt. The 2D-OIS was performed by illuminating the cortex with four wavelengths of light (575, 559, 495 and 587 nm), which were presented sequentially at a high frame rate (32 Hz). The contralateral whisker pad was stimulated using two different durations: 1 and 16 s (5 Hz, 1.2 mA). Control experiments used a hypercapnic (5% CO2) challenge to manipulate baseline blood flow and volume in the absence of corresponding neural activation. The 2D-OIS method allowed separation of artery, vein and parenchyma regions. The magnitude of the haemodynamic response elicited varied considerably between different vascular compartments; the largest responses in Hbt were in the arteries and the smallest in the veins. Phase lags in the HbO2 response between arteries and veins suggest that a process of upstream signalling maybe responsible for dilating the arteries. There was also a consistent increase in Hbr from arterial regions after whisker stimulation.

Haemodynamic responses to sensory stimulation are enhanced following acute cocaine administration.

Cocaine enhances neural activity in response to sensory stimulation, an effect that may play a role in the development of drug craving. However, cocaine-induced sensory enhancement may be difficult to study in humans using neuroimaging if the global increases in baseline haemodynamic parameters, which cocaine produces, interfere with the ability of enhanced sensory-related neural activity to lead to enhanced haemodynamic responses. To investigate the effect of cocaine-induced baseline haemodynamic changes on sensory-related haemodynamic (and electrophysiological) responses, field potential (FP) and haemodynamic responses (obtained using optical imaging spectroscopy and laser-Doppler flowmetry) in the barrel cortex of the anaesthetised rat were measured during mechanical whisker stimulation following cocaine (0.5 mg/kg) or saline administration. During cocaine infusion, the relationship between blood flow and volume transiently decoupled. Following this, cocaine caused large baseline increases in blood flow (133%) and volume (33%), which peaked after approximately 6 min and approached normal levels again after 25 min. During the peak baseline increases, FP responses to whisker stimulation were similar to saline whereas several haemodynamic response parameters were slightly reduced. After the peak, significant increases in FP responses were observed, accompanied by significantly enhanced haemodynamic responses, even though the haemodynamic baselines remained elevated. Hence, the haemodynamic response to sensory stimulation is transiently reduced in the presence of large increases in baseline but, after the baseline peak, enhanced neural responses are faithfully accompanied by enhanced haemodynamic responses. The findings suggest that any cocaine-induced enhancement of sensory-related neural activity in humans is likely to be detectable by neuroimaging.