Non-invasive Blood-Brain Barrier Disruption using Acoustic Holography with a Clinical Focused Ultrasound System.

OBJECTIVE: Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption. METHODS: With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption. RESULTS: This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

Feature-selective responses in macaque visual cortex follow eye movements during natural vision.

In natural vision, primates actively move their eyes several times per second via saccades. It remains unclear whether, during this active looking, visual neurons exhibit classical retinotopic properties, anticipate gaze shifts or mirror the stable quality of perception, especially in complex natural scenes. Here, we let 13 monkeys freely view thousands of natural images across 4.6 million fixations, recorded 883 h of neuronal responses in six areas spanning primary visual to anterior inferior temporal cortex and analyzed spatial, temporal and featural selectivity in these responses. Face neurons tracked their receptive field contents, indicated by category-selective responses. Self-consistency analysis showed that general feature-selective responses also followed eye movements and remained gaze-dependent over seconds of viewing the same image. Computational models of feature-selective responses located retinotopic receptive fields during free viewing. We found limited evidence for feature-selective predictive remapping and no viewing-history integration. Thus, ventral visual neurons represent the world in a predominantly eye-centered reference frame during natural vision.

A Whole-Brain Topographic Ontology.

It is a common view that the intricate array of specialized domains in the ventral visual pathway is innately prespecified. What this review postulates is that they are not. We explore the origins of domain specificity, hypothesizing that the adult brain emerges from an interplay between a domain-general map-based architecture, shaped by intrinsic mechanisms, and experience. We argue that the most fundamental innate organization of cortex in general, and not just the visual pathway, is a map-based topography that governs how the environment maps onto the brain, how brain areas interconnect, and ultimately, how the brain processes information. Expected final online publication date for the Annual Review of Neuroscience, Volume 47 is July 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

When the whole is only the parts: non-holistic object parts predominate face-cell responses to illusory faces.

Humans are inclined to perceive faces in everyday objects with a face-like configuration. This illusion, known as face pareidolia, is often attributed to a specialized network of 'face cells' in primates. We found that face cells in macaque inferotemporal cortex responded selectively to pareidolia images, but this selectivity did not require a holistic, face-like configuration, nor did it encode human faceness ratings. Instead, it was driven mostly by isolated object parts that are perceived as eyes only within a face-like context. These object parts lack usual characteristics of primate eyes, pointing to the role of lower-level features. Our results suggest that face-cell responses are dominated by local, generic features, unlike primate visual perception, which requires holistic information. These findings caution against interpreting neural activity through the lens of human perception. Doing so could impose human perceptual biases, like seeing faces where none exist, onto our understanding of neural activity.

The neural code for "face cells" is not face-specific.

Face cells are neurons that respond more to faces than to non-face objects. They are found in clusters in the inferotemporal cortex, thought to process faces specifically, and, hence, studied using faces almost exclusively. Analyzing neural responses in and around macaque face patches to hundreds of objects, we found graded response profiles for non-face objects that predicted the degree of face selectivity and provided information on face-cell tuning beyond that from actual faces. This relationship between non-face and face responses was not predicted by color and simple shape properties but by information encoded in deep neural networks trained on general objects rather than face classification. These findings contradict the long-standing assumption that face versus non-face selectivity emerges from face-specific features and challenge the practice of focusing on only the most effective stimulus. They provide evidence instead that category-selective neurons are best understood by their tuning directions in a domain-general object space.

Look twice: A generalist computational model predicts return fixations across tasks and species.

Primates constantly explore their surroundings via saccadic eye movements that bring different parts of an image into high resolution. In addition to exploring new regions in the visual field, primates also make frequent return fixations, revisiting previously foveated locations. We systematically studied a total of 44,328 return fixations out of 217,440 fixations. Return fixations were ubiquitous across different behavioral tasks, in monkeys and humans, both when subjects viewed static images and when subjects performed natural behaviors. Return fixations locations were consistent across subjects, tended to occur within short temporal offsets, and typically followed a 180-degree turn in saccadic direction. To understand the origin of return fixations, we propose a proof-of-principle, biologically-inspired and image-computable neural network model. The model combines five key modules: an image feature extractor, bottom-up saliency cues, task-relevant visual features, finite inhibition-of-return, and saccade size constraints. Even though there are no free parameters that are fine-tuned for each specific task, species, or condition, the model produces fixation sequences resembling the universal properties of return fixations. These results provide initial steps towards a mechanistic understanding of the trade-off between rapid foveal recognition and the need to scrutinize previous fixation locations.

Triggers for mother love.

Previous studies showed that baby monkeys separated from their mothers develop strong and lasting attachments to inanimate surrogate mothers, but only if the surrogate has a soft texture; soft texture is more important for the infant's attachment than is the provision of milk. Here I report that postpartum female monkeys also form strong and persistent attachments to inanimate surrogate infants, that the template for triggering maternal attachment is also tactile, and that even a brief period of attachment formation can dominate visual and auditory cues indicating a more appropriate target.

Face neurons encode nonsemantic features.

The primate inferior temporal cortex contains neurons that respond more strongly to faces than to other objects. Termed "face neurons," these neurons are thought to be selective for faces as a semantic category. However, face neurons also partly respond to clocks, fruits, and single eyes, raising the question of whether face neurons are better described as selective for visual features related to faces but dissociable from them. We used a recently described algorithm, XDream, to evolve stimuli that strongly activated face neurons. XDream leverages a generative neural network that is not limited to realistic objects. Human participants assessed images evolved for face neurons and for nonface neurons and natural images depicting faces, cars, fruits, etc. Evolved images were consistently judged to be distinct from real faces. Images evolved for face neurons were rated as slightly more similar to faces than images evolved for nonface neurons. There was a correlation among natural images between face neuron activity and subjective "faceness" ratings, but this relationship did not hold for face neuron­evolved images, which triggered high activity but were rated low in faceness. Our results suggest that so-called face neurons are better described as tuned to visual features rather than semantic categories.

The retrocalcarine sulcus maps different retinotopic representations in macaques and humans.

Primate cerebral cortex is highly convoluted with much of the cortical surface buried in sulcal folds. The origins of cortical folding and its functional relevance have been a major focus of systems and cognitive neuroscience, especially when considering stereotyped patterns of cortical folding that are shared across individuals within a primate species and across multiple species. However, foundational questions regarding organizing principles shared across species remain unanswered. Taking a cross-species comparative approach with a careful consideration of historical observations, we investigate cortical folding relative to primary visual cortex (area V1). We identify two macroanatomical structures-the retrocalcarine and external calcarine sulci-in 24 humans and 6 macaque monkeys. We show that within species, these sulci are identifiable in all individuals, fall on a similar part of the V1 retinotopic map, and thus, serve as anatomical landmarks predictive of functional organization. Yet, across species, the underlying eccentricity representations corresponding to these macroanatomical structures differ strikingly across humans and macaques. Thus, the correspondence between retinotopic representation and cortical folding for an evolutionarily old structure like V1 is species-specific and suggests potential differences in developmental and experiential constraints across primates.

Evaluation of the impact of gastric bypass surgery on eating behaviour using objective methodologies under residential conditions: Rationale and study protocol.

Gastric bypass surgery leads to significant and sustained weight loss and a reduction in associated health risks in individuals with severe obesity. While reduced energy intake (EI) is the primary driver of weight loss following surgery, the underlying mechanisms accounting for this energy deficit are not well understood. The evidence base has been constrained by a lack of fit-for-purpose methodology in assessing food intake coupled with follow-up studies that are relatively short-term. This paper describes the underlying rationale and protocol for an observational, fully residential study using covert, objective methodology to evaluate changes in 24-hr food intake in patients (n = 31) at 1-month pre-surgery and 3-, 12- and 24-months post-surgery, compared to weight-stable controls (n = 32). The main study endpoints included change in EI, macronutrient intake, food preferences, and eating behaviours (speed, frequency, and duration of eating). Other physiological changes that may influence EI and weight regulation including changes in body composition, circulating appetite hormones, resting metabolic rate, total energy expenditure and gastrointestinal symptoms were also evaluated. Understanding which mechanisms contribute to a reduction in EI and weight loss post-surgery could potentially help to identify those individuals who are most likely to benefit from gastric bypass surgery as well as those that may need more targeted intervention to optimise their weight loss post-surgery. Furthermore, clarification of these mechanisms may also inform targeted approaches for non-surgical treatments of obesity.

On the relationship between maps and domains in inferotemporal cortex.

How does the brain encode information about the environment? Decades of research have led to the pervasive notion that the object-processing pathway in primate cortex consists of multiple areas that are each specialized to process different object categories (such as faces, bodies, hands, non-face objects and scenes). The anatomical consistency and modularity of these regions have been interpreted as evidence that these regions are innately specialized. Here, we propose that ventral-stream modules do not represent clusters of circuits that each evolved to process some specific object category particularly important for survival, but instead reflect the effects of experience on a domain-general architecture that evolved to be able to adapt, within a lifetime, to its particular environment. Furthermore, we propose that the mechanisms underlying the development of domains are both evolutionarily old and universal across cortex. Topographic maps are fundamental, governing the development of specializations across systems, providing a framework for brain organization.

Sulcal Depth in the Medial Ventral Temporal Cortex Predicts the Location of a Place-Selective Region in Macaques, Children, and Adults.

The evolution and development of anatomical-functional relationships in the cerebral cortex is of major interest in neuroscience. Here, we leveraged the fact that a functional region selective for visual scenes is located within a sulcus in the medial ventral temporal cortex (VTC) in both humans and macaques to examine the relationship between sulcal depth and place selectivity in the medial VTC across species and age groups. To do so, we acquired anatomical and functional magnetic resonance imaging scans in 9 macaques, 26 human children, and 28 human adults. Our results revealed a strong structural-functional coupling between sulcal depth and place selectivity across age groups and species in which selectivity was strongest near the deepest sulcal point (the sulcal pit). Interestingly, this coupling between sulcal depth and place selectivity strengthens from childhood to adulthood in humans. Morphological analyses suggest that the stabilization of sulcal-functional coupling in adulthood may be due to sulcal deepening and areal expansion with age as well as developmental differences in cortical curvature at the pial, but not the white matter surfaces. Our results implicate sulcal features as functional landmarks in high-level visual cortex and highlight that sulcal-functional relationships in the medial VTC are preserved between macaques and humans despite differences in cortical folding.

Anatomical correlates of face patches in macaque inferotemporal cortex.

Primate brains typically have regions within the ventral visual stream that are selectively responsive to faces. In macaques, these face patches are located in similar parts of inferotemporal cortex across individuals although correspondence with particular anatomical features has not been reported previously. Here, using high-resolution functional and anatomical imaging, we show that small "bumps," or buried gyri, along the lower bank of the superior temporal sulcus are predictive of the location of face-selective regions. Recordings from implanted multielectrode arrays verified that these bumps contain face-selective neurons. These bumps were present in monkeys raised without seeing faces and that lack face patches, indicating that these anatomical landmarks are predictive of, but not sufficient for, the presence of face selectivity. These bumps are found across primate species that span taxonomy lines, indicating common evolutionary developmental mechanisms. The bumps emerge during fetal development in macaques, indicating that they arise from general developmental mechanisms that result in the regularity of cortical folding of the entire brain.

The neurons that mistook a hat for a face.

Despite evidence that context promotes the visual recognition of objects, decades of research have led to the pervasive notion that the object processing pathway in primate cortex consists of multiple areas that each process the intrinsic features of a few particular categories (e.g. faces, bodies, hands, objects, and scenes). Here we report that such category-selective neurons do not in fact code individual categories in isolation but are also sensitive to object relationships that reflect statistical regularities of the experienced environment. We show by direct neuronal recording that face-selective neurons respond not just to an image of a face, but also to parts of an image where contextual cues-for example a body-indicate a face ought to be, even if what is there is not a face.

Body map proto-organization in newborn macaques.

Topographic sensory maps are a prominent feature of the adult primate brain. Here, we asked whether topographic representations of the body are present at birth. Using functional MRI (fMRI), we find that the newborn somatomotor system, spanning frontoparietal cortex and subcortex, comprises multiple topographic representations of the body. The organization of these large-scale body maps was indistinguishable from those in older monkeys. Finer-scale differentiation of individual fingers increased over the first 2 y, suggesting that topographic representations are refined during early development. Last, we found that somatomotor representations were unchanged in 2 visually impaired monkeys who relied on touch for interacting with their environment, demonstrating that massive shifts in early sensory experience in an otherwise anatomically intact brain are insufficient for driving cross-modal plasticity. We propose that a topographic scaffolding is present at birth that both directs and constrains experience-driven modifications throughout somatosensory and motor systems.

The neurovascular response is attenuated by focused ultrasound-mediated disruption of the blood-brain barrier.

Focused ultrasound (FUS)-induced disruption of the blood-brain barrier (BBB) is a non-invasive method to target drug delivery to specific brain areas that is now entering into the clinic. Recent studies have shown that the method has several secondary effects on local physiology and brain function beyond making the vasculature permeable to normally non-BBB penetrant molecules. This study uses functional MRI methods to investigate how FUS BBB opening alters the neurovascular response in the rat brain. Nine rats underwent actual and sham FUS induced BBB opening targeted to the right somatosensory cortex (SI) followed by four runs of bilateral electrical hind paw stimulus-evoked fMRI. The neurovascular response was quantified using measurements of the blood oxygen level dependent (BOLD) signal and cerebral blood flow (CBF). An additional three rats underwent the same FUS-BBB opening followed by stimulus-evoked fMRI with high resolution BOLD imaging and BOLD imaging of a carbogen-breathing gas challenge. BOLD and CBF measurements at two different stimulus durations demonstrate that the neurovascular response to the stimulus is attenuated in both amplitude and duration in the region targeted for FUS-BBB opening. The carbogen results show that the attenuation in response amplitude, but not duration, is still present when the signaling mechanism originates from changes in blood oxygenation instead of stimulus-induced neuronal activity. There is some evidence of non-local effects, including a possible global decrease in baseline CBF. All effects are resolved by 24 h after FUS-BBB opening. Taken together, these results suggest that FUS-BBB opening alters that state of local brain neurovascular physiology in such a way that hinders its ability to respond to demands for increased blood flow to the region. The mechanisms for this effect need to be elucidated.

Universal Mechanisms and the Development of the Face Network: What You See Is What You Get.

Our assignment was to review the development of the face-processing network, an assignment that carries the presupposition that a face-specific developmental program exists. We hope to cast some doubt on this assumption and instead argue that the development of face processing is guided by the same ubiquitous rules that guide the development of cortex in general.

Evolving Images for Visual Neurons Using a Deep Generative Network Reveals Coding Principles and Neuronal Preferences.

What specific features should visual neurons encode, given the infinity of real-world images and the limited number of neurons available to represent them? We investigated neuronal selectivity in monkey inferotemporal cortex via the vast hypothesis space of a generative deep neural network, avoiding assumptions about features or semantic categories. A genetic algorithm searched this space for stimuli that maximized neuronal firing. This led to the evolution of rich synthetic images of objects with complex combinations of shapes, colors, and textures, sometimes resembling animals or familiar people, other times revealing novel patterns that did not map to any clear semantic category. These results expand our conception of the dictionary of features encoded in the cortex, and the approach can potentially reveal the internal representations of any system whose input can be captured by a generative model.

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.