Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2-0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

Detection thresholds for spiral Glass patterns.

We measured thresholds for the detection of spiral Glass patterns in the presence of random noise. The patterns were constructed so that the orientation content did not vary as a function of spiral angle or signal level. We found that spiral patterns had higher thresholds than either radial or concentric Glass patterns. The results support the idea that the human visual system is specialized to detect radial and concentric patterns.

On the gap effect for saccades evoked by electrical microstimulation of frontal eye fields in monkeys.

To investigate the mechanisms of fixation disengagement and saccade initiation, we electrically stimulated the macaque frontal eye fields (FEF) while monkeys performed a visual fixation task. We tested the effect of introducing a temporal gap between fixation target offset and the onset of the electrical stimulus. We found that the duration of the gap had a pronounced effect on the probability of producing electrically evoked saccades at a given current level. The highest probability was found for gaps of 200 ms duration. There were also effects of gap duration on saccade latency and amplitude for most of the stimulation sites. The increase in saccade probability may be associated with lower current thresholds for evoking saccades.

Task-dependent modulation of the sensorimotor transformation for smooth pursuit eye movements.

To investigate the transformation of retinal image velocity into smooth pursuit eye velocity, eye movements were measured in the presence of two moving targets. In the first experiment, the targets were identical in all respects except for direction of motion, and the monkey was not cued to attend to either target. In this experiment, smooth pursuit eye velocity elicited by two targets was the vector average of the response evoked by each target alone. In subsequent experiments, we examined the effects of stimulus and task parameters on the selectivity of pursuit. When the targets were made different colors and monkeys were cued for the color of the rewarded target, their pursuit eye movements were biased in the direction of the rewarded target, but still showed a substantial influence of the nonrewarded target (distractor). It did not matter whether the same target color was used for an entire session or whether the color was randomized from trial to trial. Reducing uncertainty about the axis of motion of the rewarded target also had little effect. However, the pattern of image motion appeared to have a substantial effect; radial image motion favored averaging, and winner-take-all pursuit was found only with nonradial image motion. We conclude that the sensorimotor interface for pursuit uses a flexible decision rule that can vary continuously from vector averaging to winner-take-all. We present a simple recurrent network model that reflects this range of behavior. The model has allowed us to identify three computational elements (selection bias, competitive inhibition, and response normalization) that should be taken into consideration in future models of smooth pursuit.

Activity of prefrontal neurons during location and color delayed matching tasks.

Many cells in prefrontal cortex show enhanced activity prior to movement onset in delayed or memory-guided saccade tasks. This activity is a possible neural correlate of spatial attention and working memory. The goal of this study was to determine whether delay activity is evoked when non-spatial cues such as color are used to guide saccades. Monkeys were trained on a saccade target selection task in which they were cued for either the location or color of the rewarded target. When the location of the target was specified explicitly, many cells showed visual responses and delay activity that were spatially selective. Color selective visual responses or delay activity were both rare and weak. However, for many cells, spatially selective delay activity could be evoked when color was used to specify the location of the target. These results indicate that color is capable of eliciting spatially selective activity from cells that have no overt color selectivity.

Neuronal responses in visual areas MT and MST during smooth pursuit target selection.

We recorded the activity of single neurons in the middle temporal (MT) and middle superior temporal (MST) visual areas in two macaque monkeys while the animals performed a smooth pursuit target selection task. The monkeys were presented with two moving stimuli of different colors and were trained to initiate smooth pursuit to the stimulus that matched the color of a previously given cue. We designed these experiments so that we could separate the component of the neuronal response that was driven by the visual stimulus from an extraretinal component that predicted the color or direction of the selected target. We found that for all cells in MT and MST the response was primarily determined by the visual stimulus. However, 14% (8 of 58) of MT neurons and 26% (22 of 84) of MST neurons had a small predictive component that was significant at the P < or = 0.05 level. In some cells, the predictive component was clearly related to the color of the intended target, but more often it was correlated with the direction of the target. We have previously documented a systematic shift in the latency of smooth pursuit that depends on the relative direction of motion of the two stimuli. We found that neither the latency nor the amplitude of neuronal responses in MT or MST was correlated with behavioral latency. These results are consistent with a model for target selection in which a weak selection bias for the intended target is amplified by a competitive network that suppresses motion signals related to the nonintended stimulus. It is possible that the predictive component of neuronal responses in MT and MST contributes to the selection bias. However, the strength of the selection bias in MT and MST is not sufficient to account for the high degree of selectivity shown by pursuit behavior.

Vector averaging for smooth pursuit eye movements initiated by two moving targets in monkeys.

The visual input for pursuit eye movements is represented in the cerebral cortex as the distributed activity of neurons that are tuned for both the direction and speed of target motion. To probe how the motor system uses this distributed code to compute a command for smooth eye movements, we have recorded the initiation of pursuit for 150 msec presentations of two spots moving at different speeds and/or in different directions. With equal probability, one of the two spots continued to move at the same speed and in the same direction and became the tracking target, whereas the other disappeared and served as a distractor. We measured eye acceleration in the interval from 110 to 206 msec after the onset of spot motion, within both the open-loop interval for pursuit and the interval during which eye motion was affected by the two spots. Our results demonstrate that weighted vector averaging is used to combine the responses to two moving spots. We found only a minute number of responses that were consistent with either vector summation or winner-take-all computations. In addition, our data show that it is difficult for the monkey to defeat vector averaging without extended training on the use of an explicit cue about which spot will become the target. We argue that our experiment reveals the computations done by the pursuit system in the absence of attentional bias and that vector averaging is normally used to read the distributed code of image motion when there is only one target.

The effect of a moving distractor on the initiation of smooth-pursuit eye movements.

As a step toward understanding the mechanism by which targets are selected for smooth-pursuit eye movements, we examined the behavior of the pursuit system when monkeys were presented with two discrete moving visual targets. Two rhesus monkeys were trained to select a small moving target identified by its color in the presence of a moving distractor of another color. Smooth-pursuit eye movements were quantified in terms of the latency of the eye movement and the initial eye acceleration profile. We have previously shown that the latency of smooth pursuit, which is normally around 100 ms, can be extended to 150 ms or shortened to 85 ms depending on whether there is a distractor moving in the opposite or same direction, respectively, relative to the direction of the target. We have now measured this effect for a 360 deg range of distractor directions, and distractor speeds of 5-45 deg/s. We have also examined the effect of varying the spatial separation and temporal asynchrony between target and distractor. The results indicate that the effect of the distractor on the latency of pursuit depends on its direction of motion, and its spatial and temporal proximity to the target, but depends very little on the speed of the distractor. Furthermore, under the conditions of these experiments, the direction of the eye movement that is emitted in response to two competing moving stimuli is not a vectorial combination of the stimulus motions, but is solely determined by the direction of the target. The results are consistent with a competitive model for smooth-pursuit target selection and suggest that the competition takes place at a stage of the pursuit pathway that is between visual-motion processing and motor-response preparation.

Attention and target selection for smooth pursuit eye movements.

Two rhesus monkeys were trained to track a small moving target in the presence of a moving distractor. The target and distractor were distinguished by their color. Smooth pursuit eye movements were quantified in terms of the latency of the eye movement and the open-loop eye acceleration profile. Smooth pursuit latencies for single targets were on the order of 100 msec. When the target was paired with a distractor moving in the same direction as the target, pursuit latencies decreased to roughly 85 msec. When the target was paired with a distractor moving in the opposite direction, pursuit latencies increased to roughly 150 msec. The motion of the distractor had no significant effect on the eye acceleration profile. Experiments were performed to dissociate visual search for the target from pursuit initiation by providing a spatial cue rather than the color cue. These experiments showed that visual search necessarily preceded pursuit initiation only when the distractor moved in the opposite direction relative to the target. In this case, visual search contributed about 25 msec to the overall latency of pursuit. Control experiments showed that the monkey need not attend to the distractor in order for it to influence the latency of pursuit. A network model was developed in which units that represent the motions of the target and distractor compete against one another. Attention serves to bias the outcome of this competition toward the direction of the selected target. The performance of this network exhibits a striking parallel to the effect of the distractor on smooth pursuit latency.

A reduction in the number of directionally selective neurons extends the spatial limit for global motion perception.

Dynamic random-dot targets were used to study neural mechanisms underlying motion perception. Performance of cats with severely reduced numbers of cortical directionally selective neurons (reduced DS) was compared to that of normal animals. We assessed the spatial properties of the residual motion mechanism by measuring direction discriminations at various dot displacements. At small displacements, reduced DS cats' motion integration thresholds for opposite direction discrimination were nearly normal. At larger displacements, their thresholds surpassed those of normal cats and their upper displacement limit (dmax) was increased by 0.35 deg. The accuracy of direction discrimination was reduced at small displacements, but at larger displacements direction difference thresholds of reduced DS cats approached or surpassed those of normals. These data were compared to the performance of humans who showed an extension of dmax for peripherally viewed targets. The data support the hypothesis that expansion in spatial scale of the motion mechanism may contribute to extension of dmax. Additional support for this hypothesis is provided by a modified direction discriminating line-element model. The model also suggests that changes in sampling of motion mechanisms in the reduced DS system may play a role.

Responses of neurons in the parietal and temporal visual pathways during a motion task.

The visual cortex of macaque monkeys has been divided into two functional streams that have been characterized in terms of sensory processing (color/form vs motion) and in terms of behavioral goals (object recognition vs spatial orientation). As a step toward unifying these two views of cortical processing, we compared the behavioral modulation of sensory signals across the two streams in monkeys trained to do a visual short-term memory task. We recorded from individual neurons in areas MT, MST, 7a, and V4 while monkeys performed a delayed match-to-sample task using direction of motion as the matching criterion. This task allowed us to determine if sensory responses were modulated by extraretinal signals related to the direction of the remembered sample. We sorted neuronal responses as a function of the remembered direction and calculated a modulation index, MI = (maximum response--minimum response)/(maximum response + minimum response). In the motion pathway, we found virtually no extraretinal signals in MT (average MI = 0.11 +/- 0.01 SE, 66 cells), but progressively stronger extraretinal signals in later stages, that is, MST (average MI = 0.17 +/- 0.01 SE, 57 cells) and 7a (average MI = 0.23 +/- 0.02 SE, 46 cells). In contrast to MT, strong extraretinal signals for direction matching were found in V4 (average MI = 0.28 +/- 0.02 SE, 94 cells), a relatively early stage of the color/form pathway, even though this pathway is not generally viewed as playing a major role in motion processing. Some cells in V4 were also tested while the animals performed a color matching task. These cells showed memory-related modulation of their response when either color or direction was used as the matching criterion. We conclude that extraretinal signals related to the match-to-sample task may be stronger in the temporal (color/form) pathway than in the parietal (motion) pathway, regardless of the stimulus dimension involved. Furthermore, our results indicate that the temporal pathway is capable of making a significant contribution to motion processing in tasks where motion can be considered as a cue for the identification of object attributes.

Responses in macaque visual area V4 following inactivation of the parvocellular and magnocellular LGN pathways.

A substantial body of evidence has suggested that signals transmitted through the magnocellular and parvocellular subdivisions of the LGN remain largely segregated in visual cortex. This hypothesis can be tested directly by selectively blocking transmission through either the magnocellular or parvocellular layers with small injections of lidocaine or GABA while recording cortical responses to a visual stimulus. In a previous study, we found that responses in the middle temporal visual area (MT) were almost always greatly reduced by blocks of magnocellular LGN, but that few MT neurons were affected by parvocellular blocks. In the present study, we have examined magnocellular and parvocellular contributions to area V4, which lies at the same level of processing in the cortical hierarchy as does MT and is thought to be a major recipient of parvocellular input. We found that inactivation of parvocellular layers usually resulted in a moderate reduction of visual responses (median reduction, 36%). However, comparable reductions in V4 responses were also seen following magnocellular blocks (median reduction, 47%). Directionally selective responses in V4 were not found to depend specifically on either subdivision. We conclude that area V4, unlike MT, receives strong input from both subdivisions of the LGN. These results suggest that the relationship between the subcortical magnocellular and parvocellular pathways and the parietal and temporal streams of processing in cortex is not one-to-one.

Mixed parvocellular and magnocellular geniculate signals in visual area V4.

Visual information from the retina is transmitted to the cerebral cortex by way of the lateral geniculate nucleus (LGN) in the thalamus. In primates, most of the retinal ganglion cells that project to the LGN belong to one of two classes, P and M, whose axons terminate in the parvocellular or magnocellular subdivisions of the LGN. These cell classes give rise to two channels that have been distinguished anatomically, physiologically and behaviourally. The visual cortex also can be subdivided into two pathways, one specialized for motion processing and the other for colour and form information. Several lines of indirect evidence have suggested a close correspondence between the subcortical and cortical pathways, such that the M channel provides input to the motion pathway and the P channel drives the colour/form pathway. This hypothesis was tested directly by selectively inactivating either the magnocellular or parvocellular subdivision of the LGN and recording the effects on visual responses in the cortex. We have previously reported that, in accordance with the hypothesis, responses in the motion pathway in the cortex depend primarily on magnocellular LGN. We now report that in the colour/form pathway, visual responses depend on both P and M input. These results argue against a simple correspondence between the subcortical and cortical pathways.

A psychophysically motivated model for two-dimensional motion perception.

A quantitative model is developed to predict the perceived direction of moving two-dimensional patterns. The model incorporates both a simple motion energy pathway and a "texture boundary motion" pathway that incorporates response squaring before the extraction of motion energy. These pathways correspond to Fourier and non-Fourier motion pathways and are hypothesized to reflect processing in the V1-MT and V1-V2-MT pathway, respectively. A cosine-weighted sum of these pathways followed by competitive feedback inhibition accurately predicts the perceived direction for patterns composed of two cosine gratings at different orientations ("plaids"). The model also predicts direction discrimination, differences between foveal and peripheral viewing, changes in perceived direction with exposure duration, motion masking, and motion transparency.

Perceived speed of moving two-dimensional patterns.

When two cosine gratings drifting in different directions are superimposed they can form a coherently moving two-dimensional pattern (plaid) whose resultant speed is related to the component velocities by a geometric construction known as the intersection-of-constraints (IOC). When measured against a standard which has the same spatial frequency as its components, a plaid always appears to move slower than the IOC prediction. However, the perceived speed is generally faster than would be predicted if speed were judged based on the temporal frequency of either the components or the nodes of the plaid. On the other hand, when the standard has the same spatial period as the nodes, the plaid appears to move at the same rate as the predicted IOC resultant. Furthermore, a grating with the same spatial period as the nodes appears to move slower than a grating at the component spatial frequency, just the plaid does. It is therefore likely that speed is encoded similarly for both gratings and plaids, and that the perceived speed of both is determined by the spatial periodicity of the pattern. We have previously classified 2D moving patterns as either type I (resultant lies between component directions) or type II (resultant outside of components). We find that the perceived speed of both types can be accounted for on the basis of the nodal spatial period. Finally we present a model for velocity coding which is based on the responses of spatio-temporal mechanisms.

Perceived direction of moving two-dimensional patterns.

When two drifting cosine gratings are superimposed, they will, under appropriate conditions, form a coherently moving two-dimensional pattern whose resultant direction of motion may either be between (type I), or outside (type II) the directions of the two components. We have previously shown that type I patterns produce much stronger masking than either of their components, while type II patterns do not. In this study, we measured perceived direction of motion and thresholds for discrimination of motion direction. We found that type II patterns had a perceived bias of about 7.5 deg toward the direction of their components, and had discrimination thresholds around 6.5 deg, whereas type I patterns had discrimination thresholds around 1.0 deg and no significant bias. We conclude that the neural mechanisms which compute two-dimensional image motion do not strictly implement the intersection-of-constraints construction proposed by Adelson and Movshon (1982).

Spatial frequency and orientation tuning of spatial visual mechanisms in human albinos.

A masking paradigm was used to measure the spatial frequency and orientation tuning of spatial mechanisms in the albino visual system. Threshold elevation curves obtained in this manner at test spatial frequencies of 0.25 cycles/deg (cpd), 0.50 cpd, and 1 cpd have the same shape as curves obtained from normal subjects at test frequencies two octaves higher. Additional masking studies showed that contrast processing in albinos obeys the same compressive power law as in normals. Thus, spatial mechanisms in albino central vision have normal spatial frequency and orientation bandwidths. As central cones in the albino are spaced 3-4 times further apart than in the normal fovea, these results support the hypothesis that monocular spatial vision in albinos is primarily limited by this increased receptor spacing. It is hypothesized that this, in turn, is the result of arrested development of the albino retina.

Direction specific masking and the analysis of motion in two dimensions.

We measured the effects of moving two-component cosine grating masks on the detectability of a moving spatially localized test pattern with a 1.0 octave spatial frequency bandwidth. Masking was used to distinguish between two-component patterns with fluid motion (blobs) and those with rigid motion (plaids). The two gratings which made up the two-dimensional masking patterns were always of the same spatial frequency and contrast, but moved in different directions. We find that plaid masks consistently produced threshold elevations that are 2.0-4.0 times greater than are produced by a single component mask at twice the contrast. Furthermore, this effect is nearly independent of the angle between the two mask components. For fluid motion, however, masking is determined by the mask component whose direction of motion is closest to that of the test. The results obtained with moving two-dimensional patterns demonstrate that, for blobs, the motion of the pattern as a whole has no effect on the degree of masking, whereas, for plaids, the signals arising from the two components interact in a nonlinear manner, thus producing a substantial enhancement of masking, which is clearly related to the coherent motion of the entire pattern. These data shed light on the properties of higher order motion units (possibly in MT cortex) that respond to the direction of two-dimensional pattern motion, suggesting that they combine, in a nonlinear manner, the outputs of units which respond independently to the direction of each mask component.

Spatial frequency tuning of transient non-oriented units.

Thresholds for a vertical test stimulus with a 1.0 octave bandwidth were measured as a function of the spatial frequency of a horizontal flickering cosine mask. Both test and mask were temporally modulated at 8.0 Hz, as low temporal frequencies were found to produce very little masking. Separate experiments were run at each of 10 test frequencies from 0.25 to 8.0 cycles per degree (c/deg) at 0.5 octave intervals. Masking curves thus obtained for each of three subjects were used to compute the spatial frequency sensitivities of three non-oriented mechanisms. Compared to previous masking studies of orientation selective units, non-oriented units have somewhat broader spatial frequency sensitivity curves, in agreement with primate neurophysiology.