Norepinephrine and acetylcholine mediation of the components of reflexive attention: implications for attention deficit disorders.

Attention deficit hyperactivity disorders (ADHD) create major learning barriers for children and significant social and legal handicaps for adults worldwide. Important advances in the genetic basis of the disease have been made, but reliable, biological, diagnostic markers remain elusive. This review takes the position that future progress in treating the core symptom of attention deficits requires a clearer understanding of the neuroscience of attention in normal individuals. Two important achievements in this direction have been the development of tasks that identify activity in the orienting, alerting and conflict networks, and the identification of neurotransmitters that mediate these components. The proven ability of these tasks to identify and characterize response components of "normal" attention argues that they could be used advantageously with patient populations. The categorization of neurotransmitter abnormalities in those with ADHD could clarify whether attention deficits occur within or across attention networks. To realize these goals, we evaluate laboratory studies of attention in humans and animals that address the underlying neurotransmitter systems, primarily norepinephrine and acetylcholine. We propose that key facts about deficits in reflexive and voluntary attention may be understood by a model that includes deficits in brain norepinephrine release and its effects on cholinergic activity in the parietal cortex.

Electrical microstimulation of primate posterior parietal cortex initiates orienting and alerting components of covert attention.

The posterior parietal cortex (PPC) is implicated in the control of visuospatial orienting, including both overt saccadic eye movements and covert shifts of attention (i.e., attention to a location other than at visual fixation). Some studies have suggested that the attentional system is part of the premotor processing in the brain, while others suggest they are separate. Here, we test how the PPC controls covert attention shifts in the absence of executed eye movements. Electrical microstimulation was applied to the right PPC while monkeys performed a spatial, cued target detection task, in which they were not allowed to move their gaze. At high currents, contralateral saccades were evoked. With currents below the thresholds for eliciting saccades, microstimulation produced a purely attentional shift (as indexed by decreased target reaction time) when a cue and target were presented in the contralateral visual field. This suggests that microstimulation can move attention specifically in the absence of any overt movements of the eyes or limbs. In addition, there was a reduction in reaction times in trials that did not evoke attentional orienting, suggesting a more general alerting effect of microstimulation These data provide direct evidence that the PPC may be a source of both attentional modulation of neuronal responses and saccadic eye movements to peripheral visual stimuli.

Attention as a target of intoxication: insights and methods from studies of drug abuse.

A symposium was convened to discuss recent developments in the assessment of attention and the effects of drugs and toxic chemicals on attention at the 17th annual meeting of the Behavioral Toxicology Society on May 1, 1999, in Research Triangle Park, NC. Speakers addressed issues including the methodology of assessing cognitive function, the neurobiology of specific aspects of attention, the dual roles of attention as a target of intoxication and as a mediating variable in the development of addiction to psychoactive drugs, the changes in attention that accompany neuropsychological disorders of schizophrenia, senile dementia of the Alzheimer type and attention deficit hyperactivity disorder, and potential therapies for these disorders. This article provides an overview of the objectives of the symposium, followed by summaries of each of the talks given.

Head-related transfer functions of the Rhesus monkey.

Head-related transfer functions (HRTFs) are direction-specific acoustic filters formed by the head, the pinnae and the ear canals. They can be used to assess acoustical cues available for sound localization and to construct virtual auditory environments. We measured the HRTFs of three anesthetized Rhesus monkeys (Macaca mulatta) from 591 locations in the frontal hemisphere ranging from -90 degrees (left) to 90 degrees (right) in azimuth and -60 degrees (down) to 90 degrees (up) in elevation for frequencies between 0.5 and 15 kHz. Acoustic validation of the HRTFs shows good agreement between free field and virtual sound sources. Monaural spectra exhibit deep notches at frequencies above 9 kHz, providing putative cues for elevation discrimination. Interaural level differences (ILDs) and interaural time differences (ITDs) generally vary monotonically with azimuth between 0.5 and 8 kHz, suggesting that these two cues can be used to discriminate azimuthal position. Comparison with published subsets of HRTFs from squirrel monkeys (Saimiri sciureus) shows good agreement. Comparison with published human HRTFs from the frontal hemisphere demonstrates overall similarity in the patterns of ILD and ITD, suggesting that the Rhesus monkey is a good acoustic model for these two sound localization cues in humans. Finally, the measured ITDs in the horizontal plane agree well between -40 degrees and 40 degrees in azimuth with those calculated from a spherical head model with a radius of 52 mm, one-half the interaural distance of the monkey.

Local infusion of scopolamine into intraparietal cortex slows covert orienting in rhesus monkeys.

There is accumulating evidence to suggest that cholinergic neurotransmission may play an important role in visuospatial attention, but the brain sites at which acetylcholine modulates attention are not well understood. The present work tested the hypothesis that the cholinergic influences within the intraparietal cortex are necessary for normal attentional shifting (covert orienting) in nonhuman primates. Two rhesus monkeys were trained to perform a visual, cued target detection task for liquid reinforcement. The animals pressed a lever to produce a visual display in which a central fixation point was flanked by two circles. Shortly after fixation was established, one of the circles brightened (cue), and a target appeared subsequently within one of the circles. Detection was signaled by a manual response and the reaction time to the appearance of the target was recorded. Four types of trials were presented. For valid cue trials, the cue and target were at the same spatial location; for invalid cues, cue and target were in opposite hemifields; for double cues, both cues were brightened but the target appeared in either the left or right circle; in no-cue trials, the cue was omitted. We localized the intraparietal region by recording attention-related, cellular activity with intracerebral microelectrodes. Among visually responsive cells in this area, valid cues presented to the receptive fields of visual neurons enhanced the responses to target stimuli in about half the cells and inhibited those responses in the remainder. In addition, some cells showed longer response latencies to invalid cues than to valid cues. We then infused scopolamine into attention-related activity sites and assessed its effect on performance. Scopolamine produced a dose-dependent increase in reaction times and decrease in performance accuracy that lasted more than 1 h. Neither vehicle injections in the same locations nor scopolamine outside the physiologically defined area produced any significant change in behavior. Under our conditions of measurement, we conclude that activity mediated by muscarinic cholinergic receptors within the intraparietal cortex is necessary for normal covert orienting.

Scopolamine slows the orienting of attention in primates to cued visual targets.

The cholinergic agonist nicotine facilitates visuospatial attention shifting, but the role of muscarinic cholinergic drugs in this behavior is unclear. In order to establish the generality of cholinergic action in attention shifting, we administered the muscarinic antagonist scopolamine to two rhesus monkeys trained to perform a cued target detection (Posner) task. In this task, monkeys signaled the detection of a peripheral visual target by releasing a switch and their reaction times were measured. The location of the target's appearance was preceded by a cue that was either valid (target and cue in the same spatial location), invalid (target and cue to opposite hemifields), spatially uninformative (cues in both hemifields, target to one hemifield), or omitted altogether. Scopolamine produced a dose-dependent increase in all reaction times and a decrease in accuracy. The slowing was most prominent for valid cues in either visual field. However, slowing did not occur in trials whose cues lacked spatial information, or in tasks in which attention was directed to events at the fixation point, whether or not peripheral distractors were present. These results provide additional support for the hypothesis that acetylcholine plays a key role in reflexive attention shifting to peripheral visual targets.

Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting.

Experiments were conducted to elucidate the role of the noradrenergic neurotransmitter system in arousal and the orienting of attention. Rhesus monkeys were trained to perform a peripherally cued, covert orienting task for juice reward, and their manual reaction times (RTs) to visual stimuli were measured. The effects of parenteral injections of the alpha-2 adrenergic agonists clonidine and guanfacine, and normal saline were compared on the covert task. We assessed 1) overall error rates, 2) the difference in RTs between validly and invalidly cued trials (validity effect), 3) the difference in RTs between neutral and no-cue trials (alerting effect), 4) target location (visual field), and 5) cue-target interval. Changes in noradrenaline levels produced by clonidine (and to a lesser extent guanfacine) significantly decreased the alerting effect, and lowered RTs to stimuli in the left visual field, but did not change the validity effect, suggesting that noradrenaline is involved in maintaining non-spatial, sensory readiness to external cues but not in the shifting of the attentional focus.

Effects of altering brain cholinergic activity on covert orienting of attention: comparison of monkey and human performance.

Experiments were conducted to elucidate the role of the cholinergic neurotransmitter system in arousal and the orienting of attention to peripheral targets. Rhesus monkeys and humans fixated a visual stimulus and responded to the onset of visual targets presented randomly in two visual field locations. The target was preceded by a valid cue (cue and target at the same location), an invalid cue (cue and target to opposite locations), a double cue (cues to both spatial locations, target to one), or, the cue was omitted (no-cue, target to either location). Reaction times (RTs) to the onset of the target were recorded. For monkeys, systemic injections of nicotine (0.003-0.012 mg/kg) or atropine (0.001-0.01 mg/kg), but not saline control injections, reduced mean RTs for all trials, indicating general behavioral stimulation. In addition, nicotine significantly reduced RTs for invalid trials but had little additional effect on those for valid, double, or no-cue trials. Virtually identical effects were observed for human chronic tobacco smokers in performing the same task following cigarette smoking. Injections of atropine in monkeys had no effect on RTs for valid or invalid trials but significantly slowed RTs in double-cue trials that did not require the orienting of attention. These results suggest that in both species, the nicotinic cholinergic system may play a role in automatic sensory orienting. In addition, the muscarinic system may play a role in alerting to visual stimuli in monkeys.

Visual orienting and alerting in rhesus monkeys: comparison with humans.

The behavioral capacities of the rhesus monkey for several sensory and cognitive tasks appear quite similar to those of humans. To evaluate the monkey's attentional capacities, we have compared monkey and human performance on a visuospatial attentional task, the cued target detection (CTD) paradigm. Animals were trained to fixate a small spot of light while a cue and a subsequent target, are flashed in the visual periphery. In valid trials, the cue and target appeared in the same spatial location; in invalid trials, the cue and target appeared in the opposite location; in double trials, two cues were presented and the target appeared in one of their locations; in no-cue trials, the cue was omitted and the target appeared in one location. In addition, we varied cognitive control over the task initiation by making the trial onset either self-paced or computer-paced. Reaction times (RTs) to target presentation, response accuracy, and frequency of aborted trials were measured for all subjects. No significant species differences were found for the patterns of RTs for different trial types or for attentional dynamics, as indexed by the decreases in RT with increasing cue-target interval. However, humans and non-human primates reacted differently to changes in cognitive control. Humans shows significant increases in no-cue trial RTs in the auto-paced task compared to the self-paced, but no differences in overall RT between tasks; monkeys showed a significant faster overall RT for the self-paced than the computer-paced task, but no difference between no-cue RTs. The performance differences between species may be related to the training history of the animals or to known anatomical differences in cortical organization, especially in the parietal lobe.

The influence of the visual cortex on the spatiotemporal response properties of lateral geniculate nucleus cells.

Previous studies of the cortical input to the mammalian dorsal lateral geniculate nucleus (LGN) have identified a number of possible functions for the corticogeniculate pathway, including alteration of LGN spatial frequency selectivity and facilitation of both binocular interactions and orientation selectivity. These changes may be due to either a tonic or a phasic cortical facilitation or both. The temporal differences between each of these inputs suggests that their impact on LGN cell temporal tuning should be unique. To test this hypothesis, we reversibly blocked the visual cortex (VI) and measured the effects on several indices of the temporal properties of LGN cells, including peak frequency, bandwidth, and response phase. Macaque monkeys were anesthetized and paralyzed during single cell recording from the LGN while area VI was cryogenically deactivated. Single-cell responses were visually evoked with drifting, luminance-modulated, sine-wave gratings and discrete-Fourier analyzed. Cortical cooling produced statistically significant increases or decreases in response amplitude in 64% of cells recorded. In most cases, alterations in response amplitude occurred for stimuli that varied in spatial as well as temporal frequency. For those cells influenced by changes in stimulus temporal frequency, the majority showed changes over a broad range of frequencies. A minority of cells showed changes in either peak temporal tuning or temporal frequency bandwidth. Response phase angles for all temporal frequencies tested were unaffected by cortical cooling. Overall, these results suggest that the cortical input may alter the temporal response properties of LGN cells, perhaps by tonic, but not exclusively excitatory, corticofugal influences.

Arousal systems.

Recent advances in neural and behavioural pharmacology, and in intracellular recording suggest that arousal during the awake state may be regulated by multiple, interdependent neurotransmitter systems that originate in the brainstem or hypothalamus, and project to subcortical and cortical sites. We discuss efforts to determine the mechanisms by which these systems extent their effects, and the roles that they play in the control of arousal.

Biphasic striatal dopamine release during transient ischemia and reperfusion in gerbils.

To clarify the nature of ischemic striatal dopamine release during the earliest periods of neuronal injury, we used chronoamperometry to measure dopamine levels every 60 seconds during various durations of ischemia in 32 gerbils. Catecholamine-selective electrodes were implanted into the brains of anesthetized gerbils subjected to 2, 5, or 10 minutes of transient forebrain ischemia or permanent forebrain ischemia. Four control animals showed a stable chronoamperometric baseline. In the six gerbils subjected to permanent ischemia, dopamine release was rapid during early ischemia and slowed with time. The four animals subjected to 2 minutes of ischemia showed minimal dopamine release. The six gerbils subjected to 5 minutes of ischemia demonstrated a noticeable dopamine release during ischemia, and three of the six developed a massive secondary dopamine release during reperfusion. All six animals subjected to 10 minutes of ischemia demonstrated a similar biphasic dopamine release twice the size of that observed in the 5-minute group. Pretreatment with pargyline in six additional gerbils subjected to 10 minutes of ischemia failed to modify significantly this biphasic pattern of dopamine release. We conclude that dopamine release occurs very early during ischemia and that its magnitude correlates with the duration of an ischemia insult. Reperfusion is associated with an even larger striatal dopamine release. This previously unreported biphasic dopamine release phenomenon may have important clinical implications in the management of cerebral ischemia.

Predictions about chromatic receptive fields assuming random cone connections.

We hypothesize that color vision depends on random connections between cones containing different pigments and neurons at higher levels in the macaque visual system. This hypothesis predicts the same types and proportions of chromatic receptive fields reported in the physiological literature at least up through the lateral geniculate nucleus. The results suggest that the specificity of connections demanded by the labelled-line model of color coding are unnecessary to account for current physiological data.

Release of cortical catecholamines by visual stimulation requires activity in thalamocortical afferents of monkey and cat.

Catecholamine (CA) release was measured in vivo in the monkey and cat visual cortices electrochemically. Stereate-modified, graphite-paste electrodes were used to monitor changes in norepinephrine and dopamine release. Micromolar changes in CA concentration were obtained by stimulation of the eye with nonspecific (strobe) or specific (oriented bars, radial gratings) stimuli. CA release depended on which eye was illuminated. Electrodes passed tangentially through the striate area recorded release following visual stimulation of one eye or the other in succession, and the shift in eye dominance occurred at about 500 microns intervals. The magnitude of CA release was highly correlated with the ocular dominance of neuronal activity measured with tungsten microelectrodes. Light-stimulated release was not recorded in monkey area V2, V4, or somatosensory area 1, but was recorded in cat V2, suggesting that the presence of LGN afferents is associated with CA release. Results are discussed in terms of the role of geniculate activity and the specific role of CAs in cortical information processing.

Evidence for spatial structure in the cortical input to the monkey lateral geniculate nucleus.

We combined visual stimulation of the corticogeniculate pathway with cryogenic blockade of area 17 to examine the visual spatial structure of the cortical influence on single macaque LGN cells. Excitatory central areas surrounded by inhibitory regions and vice versa were found with equal frequency. Unstructured influences were also seen. The structure of the influence suggests that modulation of the spatial parameter may be an important function for the corticogeniculate pathway.

Spatial contrast sensitivity: effects of peripheral field stimulation during monocular and dichoptic viewing.

This report examines whether a radial grating with a blank 2 deg central aperture viewed with one eye can affect contrast sensitivity for foveally-viewed, counterphasing or stationary, sine-wave gratings seen with the other eye. We find that the moving radial grating preferentially raises the threshold for the low spatial frequencies of the counterphasing but not the stationary foveal stimulus. These results closely parallel recent primate electrophysiological work which suggests that visual stimulation of the peripheral field with a moving radial grating can activate inhibitory corticofugal influences on lateral geniculate neurons. The current data are evaluated in terms of a model which suggests that the peripheral stimulus activates corticofugal mechanisms.

Visual cortical input alters spatial tuning in monkey lateral geniculate nucleus cells.

The response of monkey lateral geniculate nucleus (l.g.n.) cells to flashing spots, annuli, and drifting sine-wave gratings were recorded with tungsten micro-electrodes. These stimuli were presented (a) monocularly, through an aperture in the centre of a radial grating, or (b) dichoptically, in which the spots or drifting gratings were presented to the dominant eye's receptive field, while the centre of the radial grating was positioned on the corresponding retinal location of the other eye. Movement of the radial grating produced changes in the l.g.n. cell responses evoked by the spots and sine-wave gratings. These changes were reversed by cryogenic blockade of the striate cortex. Therefore, radial grating movement altered the responses of l.g.n. cells by activating the corticogeniculate (c.g.) pathway. In about half of all cells, radial grating-induced alterations of centre, or surround, or both responses to spots and annuli were produced. By adopting a simple spatial filtering model of the centre and surround mechanisms, it was possible to predict how these alterations in centre/surround balance would affect the cell's responses to sine-wave gratings. Alterations were observed in the peak and band width of the spatial and/or temporal tuning curves. The radial gratings did not alter the spatial summation properties of cells. Minor alterations in the spectral neutral points of chromatically opponent neurones were occasionally found. These results are interpreted as support for the view that spatial and temporal tuning are dynamic properties of some l.g.n. neurones by virtue of descending input from the visual cortex.

Spatial summation and conduction latency classification of cells of the lateral geniculate nucleus of macaques.

Cells in the lateral geniculate nucleus (LGN) of the macaque monkey were investigated with microelectrodes in an attempt to develop an overall classification scheme. We classified cells in the parvocellular (P) and magnocellular (M) layers according to (non)linearity of spatial summation, shock latency, and chromatic organization of center and surround. We also measured the spatial and temporal tuning to counterphasing and drifting sine wave gratings and tested for periphery effects. Our results showed that no strict laminar segregation existed for any cell property studied. Our results can be summarized as follows: 1. Most P layer cells showed a linear summation (98%) and color-opponent responses (80%), while other cells showed a nonlinear summation (Y-cells, 2%) and broad band responses (28%). In contrast, 37% of the M layer cells were linear summators and the remainder were nonlinear. Therefore, there are overlapping distributions of X- and Y-cells in P and M layers but not a strict segregation. 2. P layer cells had longer shock latencies than M layer cells. X-cells conducted more slowly (2.4 +/- 0.7 msec) than Y-cells (1.6 +/- 0.8 msec), but there were overlapping distributions. Latency shortened gradually, rather than abruptly, with increasing depth. 3. The first harmonic of X- and Y-cell responses was maximally sensitive to spatial frequencies of about 2 cycles/deg. Each type of cell modulated about a mean rate to a drifting grating, although Y-cells had higher distortion than X-cells. Response amplitudes to drifting gratings were higher for MX- and MY- than for PX-cells. No DC elevation to high spatial frequencies was seen. Spatial bandwidths averaged 2 to 5 octaves. X-cells were maximally tuned to temporal frequencies around 11 Hz, and Y-cells were tuned to about 19 Hz;. temporal bandwidths for both averaged 2.8 octaves. 4. Periphery effects were detected in 4% of the X-cells and 25% of the Y-cells. 5. These data indicate that gradual changes occur between dorsal and ventral layers: summation changes from linear to nonlinear; conduction latencies shorten; peak temporal tuning increases; response amplitudes increase; the periphery effect becomes more prevalent. Spatial tuning does not change. No strict laminar segregation or specificity exists for any of the properties that we studied.