The 2024 Richardson Lecture: Prosopagnosia - A Classic Neurologic Deficit Meets the Modern Era.

Acquired prosopagnosia is a rare disorder, but it serves as a model for impairments in expert-level visual processing. This review discusses five key observations made over the past 30 years. First, there are variants, an apperceptive type linked to damage to the inferior occipitotemporal cortex and an amnestic type associated with anterior temporal lesions, both either right or bilateral. Second, these variants are clustered in syndromes with other perceptual deficits, the apperceptive type with field defects, dyschromatopsia and topographagnosia, and the amnestic type with topographagnosia and the auditory disorders of phonagnosia and acquired amusia. Third, extensive testing often shows additional problems with recognizing exemplars of other objects, especially when degrees of expertise are taken into account. Fourth, the prosopagnosic impairment does not affect all facial information. For example, the perception of expression and lip-reading likely depends on other neural substrates than those for processing facial identity. Last, face perception in prosopagnosia is not immutable but can improve with extensive training, though as yet this does not represent a cure for the condition. Continuing work with neural networks and animal models will enhance our understanding of this intriguing condition and what it tells us about how our brains process vision.

James Sharpe's Contributions to Neurology and Neuro-ophthalmology: A Posthumous Tribute 10 Years On.

Dr. Sharpe was a leading eye movement researcher who had also been the editor of this journal. We wish to mark the 10th anniversary of his death by providing a sense of what he had achieved through some examples of his research.

"Looking at nothing": An implicit ocular motor index of face recognition in developmental prosopagnosia.

Subjects often look towards to previous location of a stimulus related to a task even when that stimulus is no longer visible. In this study we asked whether this effect would be preserved or reduced in subjects with developmental prosopagnosia. Participants learned faces presented in video-clips and then saw a brief montage of four faces, which was replaced by a screen with empty boxes, at which time they indicated whether the learned face had been present in the montage. Control subjects were more likely to look at the blank location where the learned face had appeared, on both hit and miss trials, though the effect was larger on hit trials. Prosopagnosic subjects showed a reduced effect, though still better on hit than on miss trials. We conclude that explicit accuracy and our implicit looking at nothing effect are parallel effects reflecting the strength of the neural activity underlying face recognition.

Visual imagery deficits in posterior cortical atrophy.

Visual imagery has a close overlapping relationship with visual perception. Posterior cortical atrophy (PCA) is a neurodegenerative syndrome marked by early impairments in visuospatial processing and visual object recognition. We asked whether PCA would therefore also be marked by deficits in visual imagery, tested using objective forced-choice questionnaires, and whether imagery deficits would be selective for certain properties. We recruited four patients with PCA and a patient with integrative visual agnosia due to bilateral occipitotemporal strokes for comparison. We administered a test battery probing imagery for object shape, size, colour lightness, hue, upper-case letters, lower-case letters, word shape, letter construction, and faces. All subjects showed significant impairments in visual imagery, with imagery for lower-case letters most likely to be spared. We conclude that PCA subjects can show severe deficits in visual imagery. Further work is needed to establish how frequently this occurs and how early it can be found.

Faces, English words and Chinese characters: a study of dual-task interference in mono-and bilingual speakers.

The many-to-many hypothesis suggests that face and visual-word processing tasks share neural resources in the brain, even though they show opposing hemispheric asymmetries in neuroimaging and neuropsychologic studies. Recently it has been suggested that both stimulus and task effects need to be incorporated into the hypothesis. A recent study found dual-task interference between face and text functions that lateralized to the same hemisphere, but not when they lateralized to different hemispheres. However, it is not clear whether a lack of interference between word and face recognition would occur for other languages, particularly those with a morpho-syllabic script, like Chinese, for which there is some evidence of greater right hemispheric involvement. Here, we used the same technique to probe for dual-task interference between English text, Chinese characters and face recognition. We tested 20 subjects monolingual for English and 20 subjects bilingual for Chinese and English. We replicated the prior result for English text and showed similar results for Chinese text with no evidence of interference with faces. We also did not find interference between Chinese and English text. The results support a view in which reading English words, reading Chinese characters and face identification have minimal sharing of neural resources.

The impact of simulated hemianopia on visual search for faces, words, and cars.

Tests of visual search can index the effects of perceptual load and compare the processing efficiency for different object types, particularly when one examines the set-size effect, the increase in search time for each additional stimulus in an array. Previous studies have shown that the set-size effect is increased by manoeuvres that impede object processing, and in patients with object processing impairments. In this study, we examine how the low-level visual impairment of hemianopia affects visual search for complex objects, using a virtual paradigm. Forty-two healthy subjects performed visual search for faces, words, or cars with full-viewing as well as gaze-contingent simulations of complete left or right hemianopia. Simulated hemianopia lowered accuracy and discriminative power and increased response times and set-size effects, similarly for faces, words and cars. A comparison of set-size effects between target absent and target present trials did not show a difference between full-view and simulated hemianopic conditions, and a model of decision-making suggested that simulated hemianopia reduced the rate of accumulation of perceptual data, but did not change decision thresholds. We conclude that simulated hemianopia reduces the efficiency of visual search for complex objects, and that such impairment should be considered when interpreting results from high-level object processing deficits.

Oblique saccades in internuclear ophthalmoplegia.

PURPOSE: Oblique saccades often display component stretching, in which the shorter vector in one cardinal direction is slowed so that its duration matches that of the longer vector in the orthogonal direction, resulting in a straighter trajectory. In internuclear ophthalmoplegia, adducting saccades are typically slowed while vertical saccades are unaffected. It is not known whether these slowed adducting movements are accompanied by adaptive component stretching of the vertical vector during oblique saccades. This was a cross-sectional study. We recorded the saccadic eye movement in 5 patients with right or bilateral internuclear ophthalmoplegia from multiple sclerosis and 17 healthy controls, using an EyeLink 1000 machine. The target stimulus was located at varying angles (0-360) and amplitudes (4, 8, 12 degrees). For each saccade we have calculated the curvature index as the main outcome measure, which is the area between the actual and ideal straight trajectory for oblique saccadic eye movements, divided by the square of the length of the straight trajectory, to give a unit-less metric for curvature. In the 17 control subjects, curvature showed a strong positive correlation between adducting saccades and the yoked abducting saccades of the other eye. In internuclear ophthalmoplegia, adducting saccades showed a strong curvature concave to the horizontal meridian, indicating inadequate component stretching, while abducting saccades did not differ from controls. This new sign of oblique saccadic curvature in internuclear ophthalmoplegia indicates a limitation of the range of central adaptive changes in response to distal lesions affecting transmission of the saccadic command.

The inversion effect in word recognition: The effect of language familiarity and handwriting.

Humans have expertise with visual words and faces. One marker of this expertise is the inversion effect. This is attributed to experience with those objects being biased towards a canonical orientation, rather than some inherent property of object structure or perceptual anisotropy. To confirm the role of experience, we measured inversion effects in word matching for familiar and unfamiliar languages. Second, we examined whether there may be more demands on reading expertise with handwritten stimuli rather than computer font, given the greater variability and irregularities in the former, with the prediction of larger inversion effects for handwriting. We recruited two cohorts of subjects, one fluent in Farsi and the other in Punjabi, neither of whom were able to read the other's language. Subjects performed a match-to-sample task with words in either computer fonts or handwritings. Subjects were more accurate and faster with their familiar language, even when it was inverted. Inversion effects were present for the familiar but not the unfamiliar language. The inversion effect in accuracy for handwriting was larger than that for computer fonts in the familiar language. We conclude that the word inversion effect is generated solely by orientation-biased experience, and that demands on this expertise are greater with handwriting than computer font.

Contrasting domain-general and domain-specific accounts in cognitive neuropsychology: An outline of a new approach with developmental prosopagnosia as a case.

The backbone of cognitive neuropsychology is the observation of (double) dissociations in performance between patients, suggesting some degree of independence between cognitive processes (domain specificity). In comparison, observations of associations between disorders/deficits have been deemed less evidential in neuropsychological theorizing about cognitive architecture. The reason is that associations can reflect damage to independent cognitive processes that happen to be mediated by structures commonly affected by the same brain disorder rather than damage to a shared (domain-general) mechanism. Here we demonstrate that it is in principle possible to discriminate between these alternatives by means of a procedure involving large unbiased samples. We exemplify the procedure in the context of developmental prosopagnosia (DP), but the procedure is in principle applicable to all neuropsychological deficits/disorders. A simulation of the procedure on a dataset yields estimates of dissociations/associations that are well in line with existing DP-studies, and also suggests that seemingly selective disorders can reflect damage to both domain-general and domain-specific cognitive processes. However, the simulation also highlights some limitations that should be considered if the procedure is to be applied prospectively. The main advantage of the procedure is that allows for examination of both associations and dissociations in the same sample. Hence, it may help even the balance in the use of associations and dissociations as grounds for neuropsychological theorizing.

Vision Therapy: Ocular Motor Training in Mild Traumatic Brain Injury.

Vision therapy in the form of ocular motor training is increasingly used to treat visual complaints, particularly in the setting of persistent symptoms after mild traumatic brain injury (mTBI). In this review, we discuss the rationale behind this intervention and the evidence for its utility. Although the efficacy of exercises for primary convergence insufficiency is plausible and supported by data, there is not yet strong evidence of benefit for the post-traumatic variant. It is not established that abnormalities in fixation, pursuit, and saccades in mTBI are the cause of post-concussive symptoms, or that these abnormalities arise from ocular motor damage rather than being secondary effects of cognitive problems with attention or executive control. The few studies to date have significant methodological weaknesses. More substantial evidence is required before vision therapy can be accepted as a useful tool in the rehabilitation of patients with brain trauma. ANN NEUROL 2020;88:453-461.

Whole-object effects in visual word processing: Parallels with and differences from face recognition.

Visual words and faces differ in their structural properties, but both are objects of high expertise. Holistic processing is said to characterize expert face recognition, but the extent to which whole-word processes contribute to word recognition is unclear, particularly as word recognition is thought to proceed by a component-based process. We review the evidence for experimental effects in word recognition that parallel those used to support holistic face processing, namely inversion effects, the part-whole task, and composite effects, as well as the status of whole-word processing in pure alexia and developmental dyslexia, contrasts between familiar and unfamiliar languages, and the differences between handwriting and typeset font. The observations support some parallels in whole-object influences between face and visual word recognition, but do not necessarily imply similar expert mechanisms. It remains to be determined whether and how the relative balance between part-based and whole-object processing differs for visual words and faces.

Search for Face Identity or Expression: Set Size Effects in Developmental Prosopagnosia.

The set size effect during visual search indexes the effects of processing load and thus the efficiency of perceptual mechanisms. Our goal was to investigate whether individuals with developmental prosopagnosia show increased set size effects when searching faces for face identity and how this compares to search for face expression. We tested 29 healthy individuals and 13 individuals with developmental prosopagnosia. Participants were shown sets of three to seven faces to judge whether the identities or expressions of the faces were the same across all stimuli or if one differed. The set size effect was the slope of the linear regression between the number of faces in the array and the response time. Accuracy was similar in both controls and prosopagnosic participants. Developmental prosopagnosic participants displayed increased set size effects in face identity search but not in expression search. Single-participant analyses reveal that 11 developmental prosopagnosic participants showed a putative classical dissociation, with impairments in identity but not expression search. Signal detection theory analysis showed that identity set size effects were highly reliable in discriminating prosopagnosic participants from controls. Finally, the set size ratios of same to different trials were consistent with the predictions of self-terminated serial search models for control participants and prosopagnosic participants engaged in expression search but deviated from those predictions for identity search by the prosopagnosic cohort. We conclude that the face set size effect reveals a highly prevalent and selective perceptual inefficiency for processing face identity in developmental prosopagnosia.

Looking beyond the face area: lesion network mapping of prosopagnosia.

Damage to the right fusiform face area can disrupt the ability to recognize faces, a classic example of how damage to a specialized brain region can disrupt a specialized brain function. However, similar symptoms can arise from damage to other brain regions, and face recognition is now thought to depend on a distributed brain network. The extent of this network and which regions are critical for facial recognition remains unclear. Here, we derive this network empirically based on lesion locations causing clinically significant impairments in facial recognition. Cases of acquired prosopagnosia were identified through a systematic literature search and lesion locations were mapped to a common brain atlas. The network of brain regions connected to each lesion location was identified using resting state functional connectivity from healthy participants (n = 1000), a technique termed lesion network mapping. Lesion networks were overlapped to identify connections common to lesions causing prosopagnosia. Reproducibility was assessed using split-half replication. Specificity was assessed through comparison with non-specific control lesions (n = 135) and with control lesions associated with symptoms other than prosopagnosia (n = 155). Finally, we tested whether our facial recognition network derived from clinically evident cases of prosopagnosia could predict subclinical facial agnosia in an independent lesion cohort (n = 31). Our systematic literature search identified 44 lesions causing prosopagnosia, only 29 of which intersected the right fusiform face area. However, all 44 lesion locations fell within a single brain network defined by connectivity to the right fusiform face area. Less consistent connectivity was found to other face-selective regions. Surprisingly, all 44 lesion locations were also functionally connected, through negative correlation, with regions in the left frontal cortex. This connectivity pattern was highly reproducible and specific to lesions causing prosopagnosia. Positive connectivity to the right fusiform face area and negative connectivity to left frontal regions were independent predictors of prosopagnosia and predicted subclinical facial agnosia in an independent lesion cohort. We conclude that lesions causing prosopagnosia localize to a single functionally connected brain network defined by connectivity to the right fusiform face area and to left frontal regions. Implications of these findings for models of facial recognition deficits are discussed.

Win-Concurrent Sensory Cues Can Promote Riskier Choice.

Reward-related stimuli can potently influence behavior; for example, exposure to drug-paired cues can trigger drug use and relapse in people with addictions. Psychological mechanisms that generate such outcomes likely include cue-induced cravings and attentional biases. Recent animal data suggest another candidate mechanism: reward-paired cues can enhance risky decision making, yet whether this translates to humans is unknown. Here, we examined whether sensory reward-paired cues alter decision making under uncertainty and risk, as measured respectively by the Iowa Gambling Task and a two-choice lottery task. In the cued versions of both tasks, gain feedback was augmented with reward-concurrent audiovisual stimuli. Healthy human volunteers (53 males, 78 females) performed each task once, one with and the other without cues (cued Iowa Gambling Task/uncued Vancouver Gambling Task: n = 63; uncued Iowa Gambling Task/cued Vancouver Gambling Task: n = 68), with concurrent eye-tracking. Reward-paired cues did not affect choice on the Iowa Gambling Task. On the two-choice lottery task, the cued group displayed riskier choice and reduced sensitivity to probability information. The cued condition was associated with reduced eye fixations on probability information shown on the screen and greater pupil dilation related to decision and reward anticipation. This pupil effect was unrelated to the risk-promoting effects of cues: the degree of pupil dilation for risky versus risk-averse choices did not differ as a function of cues. Together, our data show that sensory reward cues can promote riskier decisions and have additional and distinct effects on arousal.SIGNIFICANCE STATEMENT Animal data suggest that reward-paired cues can promote maladaptive reward-seeking by biasing cost-benefit decision making. Whether this finding translates to humans is unknown. We examined the effects of salient reward-paired audiovisual cues on decision making under risk and uncertainty in human volunteers. Cues had risk-promoting effects on a risky choice task and independently increased task-related arousal as measured by pupil dilation. By demonstrating risk-promoting effects of cues in human participants, our data identify a mechanism whereby cue reactivity could translate into maladaptive behavioral outcomes in people with addictions.

Object recognition in acquired and developmental prosopagnosia.

Whether face and object recognition are dissociated in prosopagnosia continues to be debated: a recent review highlighted deficiencies in prior studies regarding the evidence for such a dissociation. Our goal was to study cohorts with acquired and developmental prosopagnosia with a complementary battery of tests of object recognition that address prior limitations, as well as evaluating for residual effects of object expertise. We studied 15 subjects with acquired and 12 subjects with developmental prosopagnosia on three tests: the Old/New Tests, the Cambridge Bicycle Memory Test, and the Expertise-adjusted Test of Car Recognition. Most subjects with developmental prosopagnosia were normal on the Old/New Tests: for acquired prosopagnosia, subjects with occipitotemporal lesions often showed impairments while those with anterior temporal lesions did not. Ten subjects showed a putative classical dissociation between the Cambridge Face and Bicycle Memory Tests, seven of whom had normal reaction times. Both developmental and acquired groups showed reduced car recognition on the expertise-adjusted test, though residual effects of expertise were still evident. Two subjects with developmental prosopagnosia met criteria for normal object recognition across all tests. We conclude that strong evidence for intact object recognition can be found in a few subjects but the majority show deficits, particularly those with the acquired form. Both acquired and developmental forms show residual but reduced object expertise effects.

The effects of enhanced attention and working memory on smooth pursuit eye movement.

It has long been suggested that increasing attentional demands can alter smooth pursuit eye movements, but the precise nature of the changes generated is not clear. Our goal was to examine smooth pursuit with a task that enhanced attention to the target and that increased demands on working memory, without distracting from the target. 15 subjects tracked a target moving around a predictable circular trajectory at a constant tangential velocity. An n-back task with two levels of additional working memory load was integrated into the pursuit target to increase cognitive demands. In the single-task conditions, subjects either performed pursuit alone or the n-back task with a stationary target. In the dual-task conditions, pursuit and the n-back task were performed together. Performance of the n-back tasks was not impaired by simultaneous smooth pursuit. The n-back tasks had negligible effects on horizontal or vertical pursuit gain, but generated increased phase lag and reduced the variability of position error during pursuit. Increasing the difficulty of the n-back task further reduced the variability of position errors. We conclude that enhanced attention does not alter the velocity gain of smooth pursuit but rather improves its consistency. As long as attention remains focused on the target, increased attentional demands further reduce pursuit variability. Increases in phase lag may serve to improve attentional processing of the target.

Diagnosing Prosopagnosia: The Utility of Visual Noise in the Cambridge Face Recognition Test.

Adding visual noise to facial images has been used to increase reliance on configural processing. Whether this enhances the ability of tests to diagnose prosopagnosia is not known. We examined 15 subjects with developmental prosopagnosia, 13 subjects with acquired prosopagnosia, and 38 control subjects with the Cambridge Face Memory Test. We compared their performance on the second phase, without visual noise, and on the third phase, which adds visual noise. We analyzed the results with signal detection theory methods. The performance of controls worsened more than did that of prosopagnosic subjects when noise was added. The second phase showed better ability to discriminate between prosopagnosic and control subjects than did the third phase. For developmental prosopagnosia, a test using only the 48 trials of the first and second phases yielded sensitivity of 88% and specificity of 91% with a criterion of 33/48 correct, performance characteristics that are similar for a criterion of 43/72 for the whole test. We conclude that a shortened Cambridge Face Memory Test without the noisy images may be a quicker yet equally effective instrument for diagnosing prosopagnosia. The theoretical advantage of noisy images is outweighed by the poorer performance of control subjects with visual noise.

Perceptual Learning of Faces: A Rehabilitative Study of Acquired Prosopagnosia.

Despite many studies of acquired prosopagnosia, there have been only a few attempts at its rehabilitation, all in single cases, with a variety of mnemonic or perceptual approaches, and of variable efficacy. In a cohort with acquired prosopagnosia, we evaluated a perceptual learning program that incorporated variations in view and expression, which was aimed at training perceptual stages of face processing with an emphasis on ecological validity. Ten patients undertook an 11-week face training program and an 11-week control task. Training required shape discrimination between morphed facial images, whose similarity was manipulated by a staircase procedure to keep training near a perceptual threshold. Training progressed from blocks of neutral faces in frontal view through increasing variations in view and expression. Whereas the control task did not change perception, training improved perceptual sensitivity for the trained faces and generalized to new untrained expressions and views of those faces. There was also a significant transfer to new faces. Benefits were maintained over a 3-month period. Training efficacy was greater for those with more perceptual deficits at baseline. We conclude that perceptual learning can lead to persistent improvements in face discrimination in acquired prosopagnosia. This reflects both acquisition of new skills that can be applied to new faces as well as a degree of overlearning of the stimulus set at the level of 3-D expression-invariant representations.