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Activity in regions of the brain have been correlated with decision making but determining whether such relationships are correlative or causative has been challenging; using a technique to reversibly inactivate brain areas in monkeys reveals that although there is decision-related activity in the lateral intraparietal (LIP) area, LIP is not critical for the perceptual decisions studied here. Limited decision-making potential in brain area LIP Activity in 'area LIP', the lateral intraparietal cortex of the brain, has long been associated with evidence accumulation in sensory decision-making tasks, but a causal role in decision-making has never been established. Leor Katz et al . confirmed that choice-related activity occurs in area LIP and motion-stimulus-related activity in area MT (middle temporal) in rhesus monkeys performing a challenging motion discrimination task. Surprisingly, inactivation in LIP did not impair decision-making, but inactivation of neurons in area MT did. LIP inactivation did influence behaviour in a free-choice task. These findings point to a dissociation between decision-related activity in LIP and the causal role of such activity in decision-making, and indicate that recordings from area LIP in monkeys do not necessarily provide insight into computations involved in decision-making. During decision making, neurons in multiple brain regions exhibit responses that are correlated with decisions 1 , 2 , 3 , 4 , 5 , 6 . However, it remains uncertain whether or not various forms of decision-related activity are causally related to decision making 7 , 8 , 9 . Here we address this question by recording and reversibly inactivating the lateral intraparietal (LIP) and middle temporal (MT) areas of rhesus macaques performing a motion direction discrimination task. Neurons in area LIP exhibited firing rate patterns that directly resembled the evidence accumulation process posited to govern decision making 2 , 10 , with strong correlations between their response fluctuations and the animal’s choices. Neurons in area MT, in contrast, exhibited weak correlations between their response fluctuations and choices, and had firing rate patterns consistent with their sensory role in motion encoding 1 . The behavioural impact of pharmacological inactivation of each area was inversely related to their degree of decision-related activity: while inactivation of neurons in MT profoundly impaired psychophysical performance, inactivation in LIP had no measurable impact on decision-making performance, despite having silenced the very clusters that exhibited strong decision-related activity. Although LIP inactivation did not impair psychophysical behaviour, it did influence spatial selection and oculomotor metrics in a free-choice control task. The absence of an effect on perceptual decision making was stable over trials and sessions and was robust to changes in stimulus type and task geometry, arguing against several forms of compensation. Thus, decision-related signals in LIP do not appear to be critical for computing perceptual decisions, and may instead reflect secondary processes. Our findings highlight a dissociation between decision correlation and causation, showing that strong neuron-decision correlations do not necessarily offer direct access to the neural computations underlying decisions.

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ∼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography—the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function. Laser microdissection and microarrays are used to assess 900 precise subdivisions of the brains from three healthy men with 60,000 gene expression probes; the resulting atlas allows comparisons between humans and other animals, and will facilitate studies of human neurological and psychiatric diseases. Atlas of the brain High-resolution maps of genome-wide gene expression have been available for mice for a few years, but only relatively coarse equivalents have been published for the human brain because of the challenges presented by the 1,000-fold increase in size and the limited availability and quality of postmortem tissue. Now Michael Hawrylycz and colleagues at the Allen Institute for Brain Science in Seattle, Washington, have used laser microdissection and microarrays to assess 900 precise subdivisions in brains from two healthy men with 60,000 gene-expression probes. The resulting atlas, freely available at www.brain-map.org, allows comparisons between humans and other animals, and will facilitate studies of human neurological and psychiatric diseases. One early observation from the data is a human-specific pattern — compared with the mouse and rhesus monkey — for the calcium-binding protein CALB1 in the hippocampus.

Significance It is widely recognized that studying the detailed anatomy of the human brain is of great importance for neuroscience and medicine. The principal means for achieving this goal is presently diffusion magnetic resonance imaging (dMRI) tractography, which uses the local diffusion of water throughout the brain to estimate the course of long-range anatomical projections. Such projections connect gray matter regions through axons that travel in the deep white matter. The present study combines dMRI tractography with histological analysis to investigate where in the brain this method succeeds and fails. We conclude that certain superficial white matter systems pose challenges for measuring cortical connections that must be overcome for accurate determination of detailed neuroanatomy in humans. In vivo tractography based on diffusion magnetic resonance imaging (dMRI) has opened new doors to study structure–function relationships in the human brain. Initially developed to map the trajectory of major white matter tracts, dMRI is used increasingly to infer long-range anatomical connections of the cortex. Because axonal projections originate and terminate in the gray matter but travel mainly through the deep white matter, the success of tractography hinges on the capacity to follow fibers across this transition. Here we demonstrate that the complex arrangement of white matter fibers residing just under the cortical sheet poses severe challenges for long-range tractography over roughly half of the brain. We investigate this issue by comparing dMRI from very-high-resolution ex vivo macaque brain specimens with histological analysis of the same tissue. Using probabilistic tracking from pure gray and white matter seeds, we found that ∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking because of dense white matter zones just beneath the infragranular layers of the cortex. Analysis of the corresponding myelin-stained sections revealed that these zones colocalized with dense and uniform sheets of axons running mostly parallel to the cortical surface, most often in sulcal regions but also in many gyral crowns. Tracer injection into the sulcal cortex demonstrated that at least some axonal fibers pass directly through these fiber systems. Current and future high-resolution dMRI studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately.

Significance Diffusion-weighted MRI (DWI) tractography is widely used to map structural connections of the human brain in vivo and has been adopted by large-scale initiatives such as the human connectome project. Our results indicate that, even with high-quality data, DWI tractography alone is unlikely to provide an anatomically accurate map of the brain connectome. It is crucial to complement tractography results with a combination of histological or neurophysiological methods to map structural connectivity accurately. Our findings, however, do not diminish the importance of diffusion MRI as a noninvasive tool that offers important quantitative measures related to brain tissue microstructure and white matter architecture. Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.

Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain.

The rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate for modeling the structure and function of the brain. Brain atlases, and particularly those based on magnetic resonance imaging (MRI), have become important tools for understanding normal brain structure, and for identifying structural abnormalities resulting from disease states, exposures, and/or aging. Diffusion tensor imaging (DTI)-based MRI brain atlases are widely used in both human and macaque brain imaging studies because of the unique contrasts, quantitative diffusion metrics, and diffusion tractography that they can provide. Previous MRI and DTI atlases of the rhesus brain have been limited by low contrast and/or low spatial resolution imaging. Here we present a microscopic resolution MRI/DTI atlas of the rhesus brain based on 10 postmortem brain specimens. The atlas includes both structural MRI and DTI image data, a detailed three-dimensional segmentation of 241 anatomic structures, diffusion tractography, cortical thickness estimates, and maps of anatomic variability among atlas specimens. This atlas incorporates many useful features from previous work, including anatomic label nomenclature and ontology, data orientation, and stereotaxic reference frame, and further extends prior analyses with the inclusion of high-resolution multi-contrast image data. [Display omitted] •We present a high-resolution DTI/MRI atlas of 10 postmortem rhesus macaque brains.•The atlas includes 3D segmentations of 241 brain regions, and 42 tracts.•We analyze morphometric variation and cortical thickness across the atlas group.

The idling brain Studies of brain function tend to measure activity during specific tasks or in response to specific stimuli. Yet most of the brain's time and energy is not devoted to these activities. Functional magnetic resonance imaging now shows that the monkey brain is constantly cycling through elaborate, distributed patterns of activity of a type previously associated with sensory, motor or cognitive phenomena. The fluctuations are present even during anaesthesia-induced unconsciousness, and correspond to underlying patterns of anatomical connection. These neural circuits may represent the underlying structure that makes perception and thought possible. Intriguingly, the templates are similar (but not identical) in monkeys and humans, suggesting that this structure is conserved across primate species. The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain’s energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour 1 . Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks 2 , 3 , 4 , 5 , 6 . Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the ‘default’ system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.

It has been suggested that working memory representations of visual features are encoded by neurons in the areas of the early visual cortex. In this study, the authors show that sustained spiking activity in the macaque during a delayed match-to-sample task is actually absent from the middle temporal area but is instead observed in the medial superior temporal region and the lateral prefrontal cortex. Sustained activity encoding visual working memory representations has been observed in several cortical areas of primates. Where along the visual pathways this activity emerges remains unknown. Here we show in macaques that sustained spiking activity encoding memorized visual motion directions is absent in direction-selective neurons in early visual area middle temporal (MT). However, it is robustly present immediately downstream, in multimodal association area medial superior temporal (MST), as well as and in the lateral prefrontal cortex (LPFC). This sharp emergence of sustained activity along the dorsal visual pathway suggests a functional boundary between early visual areas, which encode sensory inputs, and downstream association areas, which additionally encode mnemonic representations. Moreover, local field potential oscillations in MT encoded the memorized directions and, in the low frequencies, were phase-coherent with LPFC spikes. This suggests that LPFC sustained activity modulates synaptic activity in MT, a putative top-down mechanism by which memory signals influence stimulus processing in early visual cortex.

The rhesus macaque is a prime model animal in neuroscience. A comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain is key to a deeper understanding of the brain. Here we characterize the transcriptome of 416 brain samples from 52 regions of 8 rhesus macaque brains. We identify gene modules associated with specific brain regions like the cerebral cortex, pituitary, and thalamus. In addition, we discover 9703 novel intergenic transcripts, including 1701 coding transcripts and 2845 lncRNAs. Most of the novel transcripts are only expressed in specific brain regions or cortical regions of specific individuals. We further survey the open chromatin regions in the hippocampal CA1 and several cerebral cortical regions of the rhesus macaque brain using ATAC-seq, revealing CA1- and cortex-specific open chromatin regions. Our results add to the growing body of knowledge regarding the baseline transcriptomic and open chromatin profiles in the brain of the rhesus macaque. Non-human primates share many features with humans and are an important animal model in neuroscience. Here, the authors present a comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain.

Here the authors describe a set of new optogenetic tools for use in primates that are meant to address the unique constraints of working with this species. They characterize opsin expression, the reliability of optogenetic stimulation and its effect on behavior, and methods for determining localization and expression levels prior to the completion of experiments. Optogenetics is a technique for controlling subpopulations of neurons in the intact brain using light. This technique has the potential to enhance basic systems neuroscience research and to inform the mechanisms and treatment of brain injury and disease. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. We assessed the safety and efficiency of two viral vector systems (lentivirus and adeno-associated virus), two human promoters (human synapsin ( hSyn ) and human thymocyte-1 ( hThy-1 )) and three excitatory and inhibitory mammalian codon-optimized opsins (channelrhodopsin-2, enhanced Natronomonas pharaonis halorhodopsin and the step-function opsin), which we characterized electrophysiologically, histologically and behaviorally in rhesus monkeys ( Macaca mulatta ). We also introduced a new device for measuring in vivo fluorescence over time, allowing minimally invasive assessment of construct expression in the intact brain. We present a set of optogenetic tools designed for optogenetic experiments in the non-human primate brain.