Vincent P. Ferrera

Detection of time-varying signals in event-related fMRI designs

In neuroimaging research on attention, cognitive control, decision-making, and other areas where response time (RT) is a critical variable, the temporal variability associated with the decision is often assumed to be inconsequential to the hemodynamic response (HDR) in rapid event-related designs. On this basis, the majority of published studies model brain activity lasting less than 4 s with brief impulses representing the onset of neural or cognitive events, which are then convolved with the hemodynamic impulse response function (HRF). However, electrophysiological studies have shown that decision-related neuronal activity is not instantaneous, but in fact, often lasts until the motor response. It is therefore possible that small differences in neural processing durations, similar to human RTs, will produce noticeable changes in the HDR, and therefore in the results of regression analyses. In this study we compare the effectiveness of traditional models that assume no temporal variance with a model that explicitly accounts for the duration of very brief epochs of neural activity. Using both simulations and fMRI data, we show that brief differences in duration are detectable, making it possible to dissociate the effects of stimulus intensity from stimulus duration, and that optimizing the model for the type of activity being detected improves the statistical power, consistency, and interpretability of results.

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.

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.

The dorsal medial frontal cortex is sensitive to time on task, not response conflict or error likelihood

The dorsal medial frontal cortex (dMFC) is highly active during choice behavior. Though many models have been proposed to explain dMFC function, the conflict monitoring model is the most influential. It posits that dMFC is primarily involved in detecting interference between competing responses thus signaling the need for control. It accurately predicts increased neural activity and response time (RT) for incompatible (high-interference) vs. compatible (low-interference) decisions. However, it has been shown that neural activity can increase with time on task, even when no decisions are made. Thus, the greater dMFC activity on incompatible trials may stem from longer RTs rather than response conflict. This study shows that (1) the conflict monitoring model fails to predict the relationship between error likelihood and RT, and (2) the dMFC activity is not sensitive to congruency, error likelihood, or response conflict, but is monotonically related to time on task.

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.

Noninvasive, transient and selective blood-brain barrier opening in non-human primates in vivo.

The blood-brain barrier (BBB) is a specialized vascular system that impedes entry of all large and the vast majority of small molecules including the most potent central nervous system (CNS) disease therapeutic agents from entering from the lumen into the brain parenchyma. Microbubble-enhanced, focused ultrasound (ME-FUS) has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. For the first time, the feasibility of transcranial ME-FUS BBB opening in non-human primates is demonstrated with subsequent BBB recovery. Sonications were combined with two different types of microbubbles (customized 4–5 µm and Definity®). 3T MRI was used to confirm the BBB disruption and to assess brain damage.

Estimating invisible target speed from neuronal activity in monkey frontal eye field

Working memory involves transient storage of information and the ability to manipulate that information for short-range planning and prediction. The computational aspect of working memory can be probed using dynamic sensorimotor behavior requiring complex stimulus–response mappings. Such a transformation occurs when extrapolating the future location of a moving target that is rendered temporarily invisible. Estimating the trajectory of an invisible moving target requires encoding and storing several target features, including the direction and speed of motion. We trained monkeys to make saccades to the estimated position of invisible targets moving at various speeds. The activity of neurons in the frontal eye field (FEF) was consistently modulated according to the speed of target motion. A reconstruction algorithm showed that estimates of target speed based on FEF activity were similar to behavioral speed estimates. FEF may therefore be involved in updating an internal representation of target trajectory for predictive saccades.

Feasibility of noninvasive cavitation-guided blood-brain barrier opening using focused ultrasound and microbubbles in nonhuman primates

In vivo transcranial and noninvasive cavitation detection with blood-brain barrier (BBB) opening in nonhuman primates is hereby reported. The BBB in monkeys was opened transcranically using focused ultrasound (FUS) in conjunction with microbubbles. A passive cavitation detector, confocal with the FUS transducer, was used to identify and monitor the bubble behavior. During sonication, the cavitation spectrum, which was found to be region-, pressure-, and bubble-dependent, provided real-time feedback regarding the opening occurrence and its properties. These findings demonstrate feasibility of transcranial, cavitation-guided BBB opening using FUS and microbubbles in noninvasive human applications.

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

Microstimulation of the Dorsolateral Prefrontal Cortex Biases Saccade Target Selection

A long-standing issue concerning the executive function of the primate dorsolateral prefrontal cortex is how the activity of prefrontal neurons is linked to behavioral response selection. To establish a functional relationship between prefrontal memory fields and saccade target selection, we trained three macaque monkeys to make saccades to the remembered location of a visual cue in a delayed spatial match-to-sample saccade task. We electrically stimulated sites in the prefrontal cortex with subthreshold currents during the delay epoch while monkeys performed this task. Our results show that the artificially injected signal interacts with the neural activity responsible for target selection, biasing saccade choices either towards the receptive/movement field (RF/MF) or away from the RF/MF, depending on the stimulation site. These findings might reflect a functional link between prefrontal signals responsible for the selection bias by modulating the balance between excitation and inhibition in the competitive interactions underlying behavioral selection.