2023

1. 

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

   Whitney S. Griggs*, Sumner L. Norman*, Thomas Deffieux, Florian Segura, Bruno-Félix Osmanski, Geeling Chau, Vasileios Christopoulos, Charles Liu, Mickael Tanter, Mikhail G. Shapiro, and Richard A. Andersen

   Nature Neuroscience Nov 2023

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   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.

2. 

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

   Claire Rabut*, Sumner L. Norman*, Whitney S. Griggs*, Jonathan J. Russin, Kay Jann, Vasileios Christopoulos, Charles Liu, Richard A. Andersen, and Mikhail G. Shapiro

   BioRxiv Jun 2023

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   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 (200μm) and large-scale (50mmx38mm) brain imaging through a permanent acoustic window.

3. Ph.D. Dissertation

   Listening to the Internal Representation of Actions Within the Posterior Parietal Cortex

   Whitney S. Griggs

   California Institute of Technology - Biology PhD May 2023

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   More than 5.4 million people in the United States live with chronic paralysis and roughly 20 million people worldwide live with spinal cord injuries. Brain-machine interfaces (BMIs) can be transformative for these people, enabling them to control computers, robots, and more with only thought. State-of-the-art BMIs have already made this future a reality in limited clinical trials. However, these state-of-the-art BMIs have shortcomings that limit user adoption; high-performance BMIs currently require highly invasive electrodes above or in the brain; device degradation limits longevity to about 5 years; and their field of view is small, restricting the number, and type, of applications possible. This illustrates the need for a new generation of BMIs with a brain recording modality that is longer lasting, less invasive, and scalable to sense activity from large regions of the brain. Functional ultrasound imaging (fUSI) is a recently developed technique that meets these criteria. fUSI measures cerebral hemodynamics with exceptional spatiotemporal resolution (<100 µm; ~100 ms) and a large field of view (several cm)—specifications ideally suited to recording detailed activity of entire cortical regions in parallel. In a series of novel results, we work towards developing the first high-performance ultrasonic BMI for human use. We first demonstrate that posterior parietal cortex (PPC), an area important for sensorimotor transformation, contains mesoscopic populations tuned to the intended movement direction. Using offline recorded data from several rhesus macaque monkeys, we can decode intended movement direction, task state, and expected action reward magnitude on a single trial basis. Having demonstrated that we could decode a variety of motor and cognitive variables using offline data, we developed a real-time, closed-loop ultrasonic BMI capable of decoding up to eight directions of intended movement with high accuracy. Finally, we began to translate these results into human applications and demonstrate the ability to measure changes in cerebral hemodynamics with high sensitivity through an acoustically transparent skull replacement in human subjects. Taken together, our work is a novel characterization of how functional ultrasound neuroimaging may enable a new generation of BMIs. Additionally, this work reinforces the validity of fUSI as a robust and accessible neuroimaging technique for future neuroscience questions about mesoscopic populations and their interrelationships throughout the brain.

2021

1. 

   Single-trial decoding of movement intentions using functional ultrasound neuroimaging

   Sumner L. Norman*, David Maresca*, Vassilios N. Christopoulos*, Whitney S. Griggs, Charlie Demene, Mickael Tanter, Mikhail G. Shapiro, and Richard A. Andersen

   Neuron Mar 2021

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   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.

2020

1. Current Biology

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

   Hyoung F. Kim, Whitney S. Griggs, and Okihide Hikosaka

   Current Biology Aug 2020

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   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.

2. Cereb Cortex Comm

   Brain networks sensitive to object novelty, value, and their combination

   Ali Ghazizadeh, Mohammad Amin Fakharian, Arash Amini, Whitney Griggs, David A. Leopold, and Okihide Hikosaka

   Cerebal Cortex Communications Aug 2020

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   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.

2018

1. 

   Parallel basal ganglia circuits for decision making

   Okihide Hikosaka, Ali Ghazizadeh, Whitney Griggs, and Hidetoshi Amita

   Journal of Neural Transmission Mar 2018

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   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.

2. 

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

   Ali Ghazizadeh, Whitney Griggs, David A. Leopold, and Okihide Hikosaka

   Proceedings of the National Academy of Sciences Feb 2018

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   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.

3. 

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

   Whitney S. Griggs, Hidetoshi Amita, Atul Gopal, and Okihide Hikosaka

   Frontiers in Neuroscience Feb 2018

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   The superior colliculus (SC) is an important structure in the mammalian brain that orients the animal towards 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 (\textgreater10 days) to saccade to multiple fractal objects, half of which were consistently associated with large reward while other half were associated with small reward. 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 (\textgreater1 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.

2017

1. 

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

   Whitney S. Griggs, Hyoung F. Kim, Ali Ghazizadeh, M. Gabriela Costello, Kathryn M. Wall, and Okihide Hikosaka

   Frontiers in Neuroanatomy Nov 2017

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   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.

2016

1. 

   Object-finding skill created by repeated reward experience

   Ali Ghazizadeh, Whitney Griggs, and Okihide Hikosaka

   Journal of Vision Aug 2016

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   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.

2. 

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

   Ali Ghazizadeh, Whitney Griggs, and Okihide Hikosaka

   Frontiers in Neuroscience Aug 2016

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   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.

2013

1. Honors Thesis

   Eliminating Intersubject Variability of Large Amplitude Gaze Metrics by Reducing the Visual Field

   Whitney Griggs, and Thomas Knight

   Whitman College - Biochemistry, Biophysics and Molecular Biology Major May 2013
2. Thesis

   Penalized spline regression and its applications

   Whitney Griggs, and Kelly McConville

   Whitman College - Applied Mathematics Major May 2013

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