COMMENTARY Monkey neurophysiology to clinical neuroscience and back again COMMENTARY Michele A. Bassoa,1 Gustav Theodor Fechner defined the field of psycho- Our visual sense can be decomposed into many physics as the study of the relationship between the domains and subsystems. One broad domain is color physical properties of stimuli and the internal re- vision. The retina of humans and monkeys contains sponses or perceptions they evoke. Since the mid- three types of cone receptors providing us with our 19th century, psychophysics has evolved into a very daylight and color vision; they are the S-, M-, and powerful field of study exploring the inner workings L-cones, defined by the short-, medium-, and long- of the mind. Carefully designed and well-controlled wavelength stimuli that activate them maximally. The psychophysical experiments have revealed some of the S-cone system exists in nearly all mammals and is most fascinating aspects of our brains. Think about visual evolutionarily older than the M- and L-cone systems. illusions. How is it that we can “see” things that are not Interestingly, the S-cone system remains segregated there? How is it that we can look at one image and in one from the L- and M-cone systems from the retina to moment it looks like a vase and the next it looks like two visual cortex. Human studies indicate that the S-cone faces? Experiments using different visual stimuli and system contributes to color perception and not very measuring the time it takes to detect or discriminate strongly to luminance perception. It has low spatial somethingintheimageprovidecluesastohowourbrains frequency sensitivity so it is not useful for fine visual work. This understanding is not a one-way street. The real discriminations. The segregated and special nature of power of psychophysics depends on fundamental knowl- the S-cone system has made it an area of active in- edge gained by physiological experiments performed in vestigation, with an entire recent issue of Visual Neu- animals, particularly monkeys, when inferences about the roscience devoted to the topic (2). inner workings of the human mind are made. The paper by Hall and Colby in PNAS (1) shows how critically impor- Monkey Neurophysiology to Human tant basic research in monkeys is for our understanding of Psychophysics thehumanbrainandhowitgoesawryindisease. By the 1970s it was well known that retinal ganglion cells Psychophysics investigates the relationship be- provide inputs directly to the SC, but a new result at that tween sensory input and behavior. The sensory input time showed that there were relatively few projections to studied is often visual, because humans rely heavily on the SC from the S-cone system (3, 4). In fact, visual inputs this sense. Eye movements lend themselves to study to the SC seemed to contain only luminance information. as a behavioral read-out because of the ease with This observation led to the idea that the SC is colorblind which they are measured and, the relationship be- and participates in vision for action, rather than vision for tween vision and eye movements remains a pillar of perception. It is the retinal projections to the lateral ge- psychophysical investigation. A central structure in the niculate nucleus of the thalamus and then to the cere- brain involved in visual processing and eye movement bral cortex that serve visual perception. The S-cone control is the superior colliculus (SC). The SC is a struc- signals are conveyed to the cerebral cortex, where ture in the midbrain that has been the focus of studies they contribute to color perception together with the in psychophysics and neuroscience for over 40 y. M- and L-cone signals. Based on this work, we know that the SC plays a crucial This accepted view, that SC lacks S-cone input, led role in converting sensory signals, particularly visual to the clever idea of using S-cone–specific stimuli to signals, into commands to orient toward those sensory activate the cerebral cortical visual system indepen- signals. In lower mammals, orienting takes the form of dently of the subcortical visual system. This approach whole-body movements toward the stimulus. In mon- was pioneered by Sumner et al. (5), who devel- keys, as in humans, it is often just the eyes that move oped a psychophysical method in humans to define to realign the fovea—the high-acuity portion of the stimuli that activate only S-cones. Sumner and his retina—on the visual object of interest. colleagues used these calibrated S-cone stimuli in aFuster Laboratory of Cognitive Neuroscience, Departments of Psychiatry and Biobehavioral Sciences and Neurobiology, Semel Institute of Neuroscience and Human Behavior and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 Author contributions: M.A.B. wrote the paper. The author declares no conflict of interest. See companion article on page 6743. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1606344113 PNAS | June 14, 2016 | vol. 113 | no. 24 | 6591–6593 Downloaded by guest on September 26, 2021 human behavioral experiments with the expectation that S-cones can still make regular latency saccades (less accurately and with a lower would not activate subcortical visual structures, but only activate velocity than normal) but they can no longer make express saccades cerebral cortical structures. They reasoned that this stimulus (14). Recent work in the slice preparation provides support for an ex- specificity would allow them to tease apart the roles of cerebral clusive role of the SC in express saccade generation, because there are cortical and subcortical areas in perception and higher mental direct, excitatory projections from the sensory layers of the SC to the processing. The ability to isolate specific neuronal pathways motor layers of the SC whose neurons project to brainstem areas that using targeted physical stimuli is important because it would drive the extraocular motoneurons (15). Hall and Colby reasoned that allow noninvasive interrogation of the functioning of sites of if monkeys can generate express saccades to S-cone stimuli, then the damage in patients with visual deficits. A broad range of SC must be able to see S-cone stimuli. In PNAS, Hall and Colby phenomena have been tested for dependence on the SC using (1) demonstrate that monkeys make express saccades to stimuli this kind of approach, including the neural mechanisms of that activate only S-cones. A further confirmation of the role of the SC is blindsight (6) and interhemispheric transfer of information in their finding that neuronal response strength correlates with the patients without a corpus callosum (7). This influential tech- nique is currently being used in studies of face perception (8) and visual development (9). Indeed, a full review article pro- The paper by Hall and Colby in PNAS shows how moting this research strategy in humans recently appeared in critically important basic research in monkeys is the literature (10). for our understanding of the human brain and Human Psychophysics to Monkey Neurophysiology how it goes awry in disease. In parallel with the studies in humans, Hall and Colby hoped to use this behavioral approach in monkeys. If the approach worked, the latency of express saccades. This result shows solidly that that the SC could be temporarily “lesioned” on a trial-by-trial basis without SC can see stimuli that activate only S-cones. any actual damage to the brain. The strategy is to present either a So, how can there be responses to S-cone stimuli in the SC if there luminance or an S-cone stimulus on separate trials of a visual- are no retinal S-cone projections to SC? It is important to note that the oculomotor task. Because the SC is involved in visual-oculomotor work of Hall and Colby does not address how these signals get to the behavior, Hall and Colby reasoned that if performance of mon- SC, only that they do get there and they are used by the saccadic keys differed in response to the S-cone stimulus compared with system. The SC is important for visually guided action rather than the luminance stimulus, they could conclude that there was a conscious perception, and the current consensus on express saccades dependence on the SC. The argument is simple: If the SC cannot is that they rely on information provided by corticotectal projections detect the S-cone stimulus, it cannot generate a behavior that (16), a pathway that could underlie the findings of Hall and Colby. depends on it. Another important point to make clear is that just because SC Hall and Colby began by testing explicitly whether the SC is neurons discharge in relation to S-cone stimuli does not mean that blind to S-cone stimuli. They did so in three significant steps, they play a role in color vision. In other words, the results of Hall and culminating in the work described in PNAS (1). The first step Colby do not imply that the SC participates in our perception of was to invent a psychophysical method in monkeys for identi- color. SC neurons are not color-opponent and are not selective for fying visual stimuli that selectively activate S-cones (11). They specific colors. The results of Hall and Colby show that SC neurons used saccadic eye movements as the behavioral read-out of are sensitive to relative changes in retinal S-cone excitation, inde- whether or not the monkey detected a stimulus—if it could look pendent of excitation in L- and M-cones and sensitivity to cone input at the stimulus, it could see the stimulus. Both S-cones and is not equivalent to color perception.