Functional ultrasound neuroimaging reveals mesoscopic organization of saccades in the lateral intraparietal area of posterior parietal cortex.

The lateral intraparietal cortex (LIP) located within the posterior parietal cortex (PPC) is an important area for the transformation of spatial information into accurate saccadic eye movements. Despite extensive research, we do not fully understand the functional anatomy of intended movement directions within LIP. This is in part due to technical challenges. Electrophysiology recordings can only record from small regions of the PPC, while fMRI and other whole-brain techniques lack sufficient spatiotemporal resolution. Here, we use functional ultrasound imaging (fUSI), an emerging technique with high sensitivity, large spatial coverage, and good spatial resolution, to determine how movement direction is encoded across PPC. We used fUSI to record local changes in cerebral blood volume in PPC as two monkeys performed memory-guided saccades to targets throughout their visual field. We then analyzed the distribution of preferred directional response fields within each coronal plane of PPC. Many subregions within LIP demonstrated strong directional tuning that was consistent across several months to years. These mesoscopic maps revealed a highly heterogenous organization within LIP with many small patches of neighboring cortex encoding different directions. LIP had a rough topography where anterior LIP represented more contralateral upward movements and posterior LIP represented more contralateral downward movements. These results address two fundamental gaps in our understanding of LIP's functional organization: the neighborhood organization of patches and the broader organization across LIP. These findings were achieved by tracking the same LIP populations across many months to years and developing mesoscopic maps of direction specificity previously unattainable with fMRI or electrophysiology methods.

Functional ultrasound imaging of human brain activity through an acoustically transparent cranial window.

Visualization of human brain activity is crucial for understanding normal and aberrant brain function. Currently available neural activity recording methods are highly invasive, have low sensitivity, and cannot be conducted outside of an operating room. Functional ultrasound imaging (fUSI) is an emerging technique that offers sensitive, large-scale, high-resolution neural imaging; however, fUSI cannot be performed through the adult human skull. Here, we used a polymeric skull replacement material to create an acoustic window compatible with fUSI to monitor adult human brain activity in a single individual. Using an in vitro cerebrovascular phantom to mimic brain vasculature and an in vivo rodent cranial defect model, first, we evaluated the fUSI signal intensity and signal-to-noise ratio through polymethyl methacrylate (PMMA) cranial implants of different thicknesses or a titanium mesh implant. We found that rat brain neural activity could be recorded with high sensitivity through a PMMA implant using a dedicated fUSI pulse sequence. We then designed a custom ultrasound-transparent cranial window implant for an adult patient undergoing reconstructive skull surgery after traumatic brain injury. We showed that fUSI could record brain activity in an awake human outside of the operating room. In a video game "connect the dots" task, we demonstrated mapping and decoding of task-modulated cortical activity in this individual. In a guitar-strumming task, we mapped additional task-specific cortical responses. Our proof-of-principle study shows that fUSI can be used as a high-resolution (200 µm) functional imaging modality for measuring adult human brain activity through an acoustically transparent cranial window.

Decoding motor plans using a closed-loop ultrasonic brain-machine interface.

Brain-machine interfaces (BMIs) enable people living with chronic paralysis to control computers, robots and more with nothing but thought. Existing BMIs have trade-offs across invasiveness, performance, spatial coverage and spatiotemporal resolution. Functional ultrasound (fUS) neuroimaging is an emerging technology that balances these attributes and may complement existing BMI recording technologies. In this study, we use fUS to demonstrate a successful implementation of a closed-loop ultrasonic BMI. We streamed fUS data from the posterior parietal cortex of two rhesus macaque monkeys while they performed eye and hand movements. After training, the monkeys controlled up to eight movement directions using the BMI. We also developed a method for pretraining the BMI using data from previous sessions. This enabled immediate control on subsequent days, even those that occurred months apart, without requiring extensive recalibration. These findings establish the feasibility of ultrasonic BMIs, paving the way for a new class of less-invasive (epidural) interfaces that generalize across extended time periods and promise to restore function to people with neurological impairments.

A window to the brain: ultrasound imaging of human neural activity through a permanent acoustic window.

Recording human brain activity is crucial for understanding normal and aberrant brain function. However, available recording methods are either highly invasive or have relatively low sensitivity. Functional ultrasound imaging (fUSI) is an emerging technique that offers sensitive, large-scale, high-resolution neural imaging. However, fUSI cannot be performed through adult human skull. Here, we use a polymeric skull replacement material to create an acoustic window allowing ultrasound to monitor brain activity in fully intact adult humans. We design the window through experiments in phantoms and rodents, then implement it in a participant undergoing reconstructive skull surgery. Subsequently, we demonstrate fully non-invasive mapping and decoding of cortical responses to finger movement, marking the first instance of high-resolution (200 µm) and large-scale (50 mmx38 mm) brain imaging through a permanent acoustic window.

Single-trial decoding of movement intentions using functional ultrasound neuroimaging.

New technologies are key to understanding the dynamic activity of neural circuits and systems in the brain. Here, we show that a minimally invasive approach based on ultrasound can be used to detect the neural correlates of movement planning, including directions and effectors. While non-human primates (NHPs) performed memory-guided movements, we used functional ultrasound (fUS) neuroimaging to record changes in cerebral blood volume with 100 µm resolution. We recorded from outside the dura above the posterior parietal cortex, a brain area important for spatial perception, multisensory integration, and movement planning. We then used fUS signals from the delay period before movement to decode the animals' intended direction and effector. Single-trial decoding is a prerequisite to brain-machine interfaces, a key application that could benefit from this technology. These results are a critical step in the development of neuro-recording and brain interface tools that are less invasive, high resolution, and scalable.

Brain Networks Sensitive to Object Novelty, Value, and Their Combination.

Novel and valuable objects are motivationally attractive for animals including primates. However, little is known about how novelty and value processing is organized across the brain. We used fMRI in macaques to map brain responses to visual fractal patterns varying in either novelty or value dimensions and compared the results with the structure of functionally connected brain networks determined at rest. The results show that different brain networks possess unique combinations of novelty and value coding. One network identified in the ventral temporal cortex preferentially encoded object novelty, whereas another in the parietal cortex encoded the learned value. A third network, broadly composed of temporal and prefrontal areas (TP network), along with functionally connected portions of the striatum, amygdala, and claustrum, encoded both dimensions with similar activation dynamics. Our results support the emergence of a common currency signal in the TP network that may underlie the common attitudes toward novel and valuable objects.

Long-Term Value Memory in the Primate Posterior Thalamus for Fast Automatic Action.

The thalamus is known to process information from various brain regions and relay it to other brain regions, serving an essential role in sensory perception and motor execution. The thalamus also receives inputs from basal ganglia nuclei (BG) involved in value-based decision making, suggesting a role in the value process. We found that neurons in a particular area of the rhesus macaque posterior thalamus encoded the historical value memory of visual objects. Many of these value-coding neurons were located in the suprageniculate nucleus (SGN). This thalamic area directly received anatomical input from the superior colliculus (SC), and the neurons showed visual responses with contralateral preferences. Notably, the value discrimination activity of these thalamic neurons increased during learning, with the learned values stably retained even more than 200 days after learning. Our data indicate that single neurons in the posterior thalamus not only processed simple visual information but also represented historical values. Furthermore, our data suggest an SC-posterior thalamus-BG-SC subcortical loop circuit that encodes the historical value, enabling a quick automatic gaze by bypassing the visual cortex.

Visual Neurons in the Superior Colliculus Discriminate Many Objects by Their Historical Values.

The superior colliculus (SC) is an important structure in the mammalian brain that orients the animal toward distinct visual events. Visually responsive neurons in SC are modulated by visual object features, including size, motion, and color. However, it remains unclear whether SC activity is modulated by non-visual object features, such as the reward value associated with the object. To address this question, three monkeys were trained (>10 days) to saccade to multiple fractal objects, half of which were consistently associated with large rewards while other half were associated with small rewards. This created historically high-valued ('good') and low-valued ('bad') objects. During the neuronal recordings from the SC, the monkeys maintained fixation at the center while the objects were flashed in the receptive field of the neuron without any reward. We found that approximately half of the visual neurons responded more strongly to the good than bad objects. In some neurons, this value-coding remained intact for a long time (>1 year) after the last object-reward association learning. Notably, the neuronal discrimination of reward values started about 100 ms after the appearance of visual objects and lasted for more than 100 ms. These results provide evidence that SC neurons can discriminate objects by their historical (long-term) values. This object value information may be provided by the basal ganglia, especially the circuit originating from the tail of the caudate nucleus. The information may be used by the neural circuits inside SC for motor (saccade) output or may be sent to the circuits outside SC for future behavior.

Temporal-prefrontal cortical network for discrimination of valuable objects in long-term memory.

Remembering and discriminating objects based on their previously learned values are essential for goal-directed behaviors. While the cerebral cortex is known to contribute to object recognition, surprisingly little is known about its role in retaining long-term object-value associations. To address this question, we trained macaques to arbitrarily associate small or large rewards with many random fractal objects (>100) and then used fMRI to study the long-term retention of value-based response selectivity across the brain. We found a pronounced long-term value memory in core subregions of temporal and prefrontal cortex where, several months after training, fractals previously associated with high reward ("good" stimuli) elicited elevated fMRI responses compared with those associated with low reward ("bad" stimuli). Similar long-term value-based modulation was also observed in subregions of the striatum, amygdala, and claustrum, but not in the hippocampus. The value-modulated temporal-prefrontal subregions showed strong resting-state functional connectivity to each other. Moreover, for areas outside this core, the magnitude of long-term value responses was predicted by the strength of resting-state functional connectivity to the core subregions. In separate testing, free-viewing gaze behavior indicated that the monkeys retained stable long-term memory of object value. These results suggest an implicit and high-capacity memory mechanism in the temporal-prefrontal circuitry and its associated subcortical regions for long-term retention of object-value memories that can guide value-oriented behavior.

Parallel basal ganglia circuits for decision making.

The basal ganglia control body movements, mainly, based on their values. Critical for this mechanism is dopamine neurons, which sends unpredicted value signals, mainly, to the striatum. This mechanism enables animals to change their behaviors flexibly, eventually choosing a valuable behavior. However, this may not be the best behavior, because the flexible choice is focused on recent, and, therefore, limited, experiences (i.e., short-term memories). Our old and recent studies suggest that the basal ganglia contain separate circuits that process value signals in a completely different manner. They are insensitive to recent changes in value, yet gradually accumulate the value of each behavior (i.e., movement or object choice). These stable circuits eventually encode values of many behaviors and then retain the value signals for a long time (i.e., long-term memories). They are innervated by a separate group of dopamine neurons that retain value signals, even when no reward is predicted. Importantly, the stable circuits can control motor behaviors (e.g., hand or eye) quickly and precisely, which allows animals to automatically acquire valuable outcomes based on historical life experiences. These behaviors would be called 'skills', which are crucial for survival. The stable circuits are localized in the posterior part of the basal ganglia, separately from the flexible circuits located in the anterior part. To summarize, the flexible and stable circuits in the basal ganglia, working together but independently, enable animals (and humans) to reach valuable goals in various contexts.

Flexible and Stable Value Coding Areas in Caudate Head and Tail Receive Anatomically Distinct Cortical and Subcortical Inputs.

Anatomically distinct areas within the basal ganglia encode flexible- and stable-value memories for visual objects (Hikosaka et al., 2014), but an important question remains: do they receive inputs from the same or different brain areas or neurons? To answer this question, we first located flexible and stable value-coding areas in the caudate head (CDh) and caudate tail (CDt) of two rhesus macaque monkeys, and then injected different retrograde tracers into these areas of each monkey. We found that CDh and CDt received different inputs from several cortical and subcortical areas including temporal cortex, prefrontal cortex, cingulate cortex, amygdala, claustrum and thalamus. Superior temporal cortex and inferior temporal cortex projected to both CDh and CDt, with more CDt-projecting than CDh-projecting neurons. In superior temporal cortex and dorsal inferior temporal cortex, layers 3 and 5 projected to CDh while layers 3 and 6 projected to CDt. Prefrontal and cingulate cortex projected mostly to CDh bilaterally, less to CDt unilaterally. A cluster of neurons in the basolateral amygdala projected to CDt. Rostral-dorsal claustrum projected to CDh while caudal-ventral claustrum projected to CDt. Within the thalamus, different nuclei projected to either CDh or CDt. The medial centromedian nucleus and lateral parafascicular nucleus projected to CDt while the medial parafascicular nucleus projected to CDh. The inferior pulvinar and lateral dorsal nuclei projected to CDt. The ventral anterior and medial dorsal nuclei projected to CDh. We found little evidence of neurons projecting to both CDh and CDt across the brain. These data suggest that CDh and CDt can control separate functions using anatomically separate circuits. Understanding the roles of these striatal projections will be important for understanding how value memories are created and stored.

Ecological Origins of Object Salience: Reward, Uncertainty, Aversiveness, and Novelty.

Among many objects around us, some are more salient than others (i.e., attract our attention automatically). Some objects may be inherently salient (e.g., brighter), while others may become salient by virtue of their ecological relevance through experience. However, the role of ecological experience in automatic attention has not been studied systematically. To address this question, we let subjects (macaque monkeys) view a large number of complex objects (>300), each experienced repeatedly (>5 days) with rewarding, aversive or no outcome association (mere-perceptual exposure). Test of salience was done on separate days using free viewing with no outcome. We found that gaze was biased among the objects from the outset, affecting saccades to objects or fixations within objects. When the outcome was rewarding, gaze preference was stronger (i.e., positive) for objects with larger or equal but uncertain rewards. The effects of aversive outcomes were variable. Gaze preference was positive for some outcome associations (e.g., airpuff), but negative for others (e.g., time-out), possibly due to differences in threat levels. Finally, novel objects attracted gaze, but mere perceptual exposure of objects reduced their salience (learned negative salience). Our results show that, in primates, object salience is strongly influenced by previous ecological experience and is supported by a large memory capacity. Owing to such high capacity for learned salience, the ability to rapidly choose important objects can grow during the entire life to promote biological fitness.

Object-finding skill created by repeated reward experience.

For most animals, survival depends on rapid detection of rewarding objects, but search for an object surrounded by many others is known to be difficult and time consuming. However, there is neuronal evidence for robust and rapid differentiation of objects based on their reward history in primates (Hikosaka, Kim, Yasuda, & Yamamoto, 2014). We hypothesized that such robust coding should support efficient search for high-value objects, similar to a pop-out mechanism. To test this hypothesis, we let subjects (n = 4, macaque monkeys) view a large number of complex objects with consistently biased rewards with variable training durations (1, 5, or 30 + days). Following training, subjects searched for a high-value object (Good) among a variable number of low-value objects (Bad). Consistent with our hypothesis, we found that Good objects were accurately and quickly targeted, often by a single and direct saccade with a very short latency (<200 ms). The dependence of search times on display size reduced significantly with longer reward training, giving rise to a more efficient search (40 ms/item to 16 ms/item). This object-finding skill showed a large capacity for value-biased objects and was maintained in the long-term memory with no interference from reward learning with other objects. Such object-finding skill, and in particular its large capacity and long term retention, would be crucial for maximizing rewards and biological fitness throughout life where many objects are experienced continuously and/or intermittently.