Prosopagnosia involves an entire network – not just one area of the brain

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People with prosopagnosia, or “face blindness,” have trouble recognizing faces — even those of close friends and family members.

It often causes serious social problems, although some people can compensate by using clothing and other cues.

Face blindness often becomes apparent in early childhood, but people occasionally acquire it from a brain injury later in life.

A new study of people who became face-blind after a stroke, led by Alexander Cohen, MD, Ph.D., of Boston Children’s Hospital, provides clues to what goes wrong in the brain.

The findings, published in the journal Brain, indicate that no one single area is always perturbed in face blindness.

Instead, face blindness involves an entire network, where a malfunction in communication among the various components can bring the system down.

This potentially opens the door for improving face recognition by tweaking the function of different parts of the network.

Cohen, first author on the paper, believes the findings could also apply to other people with poor face-processing abilities, specifically individuals with autism, who often score very poorly on tests of face processing.

From autism to stroke and back again

Cohen began by speculating that autism could be approached not just as a holistic entity, but by studying its individual symptoms.

Those symptoms have a better chance of being localized to specific parts of the brain and could perhaps be turned into biomarkers and treatment targets.

That’s where face blindness comes in. It’s easy to test for and common in autism, seen in children as young as 2.

“In eye gaze studies, autistic kids often don’t look at the faces in a video,” Cohen says “Or they just look at one part, often the mouth, maybe because it’s giving more information about speech. Many find eye contact uncomfortable.”

Data suggest that the worse people with autism are at face processing, the worse their social communication.

“The question is, are face processing deficits causal in autism, or do they result from autism?” says Cohen.

“That’s where looking at face processing in people with stroke really helps. They have specific lesions in the brain, so there is more of a cause-and-effect relationship. If you find an abnormality involving the same brain areas in a child with autism, there’s a much higher chance that it may be driving the face processing deficit.”

Mapping brain networks

Face blindness has previously been linked to the brain’s right fusiform face area (FFA), but not everyone with face blindness shows damage there.

Cohen searched the medical literature and identified 44 people from 19 studies who developed face blindness after a stroke and who also had brain MRI data available.

Of the 44 lesions causing face blindness, only 29 involved the right FFA; the other 15 did not. To try to explain these cases, Cohen used a new method, developed by senior study author Michael Fox, MD, Ph.D., of Beth Israel Deaconess Medical Center, that draws on data from functional MRI images to create a large-scale map of brain networks, showing the relationships between different brain areas. With it, Cohen could determine which networks were consistently injured in the stroke patients that developed face blindness.

The 15 lesions that did not involve the FFA, Cohen’s team found, were in areas that were functionally connected to the right FFA, meaning that they are typically used when the FFA is being used, and become quiet when the FFA is quiet.

Surprisingly, all 44 lesion locations were also negatively connected with four additional areas in the left frontal cortex — meaning that brain activity in the four areas goes down when activity in the lesion locations goes up, and vice versa. Intriguingly, all four of the new areas belong to the left frontoparietal control network, which attends to specific features of a visual stimulus.

Based on the findings, Cohen speculates that face recognition involves two distinct brain networks. It’s not yet clear whether face blindness results from both networks being disrupted, or from an imbalance between the two.

“Maybe in face blindness, you’re using too much detail information, and are not looking at the face as a whole,” Cohen says. “That exact imbalance is something that has been seen in autism. Or, maybe you need both kinds of information to recognize a face.”

Mapping face processing in tuberous sclerosis

Based on the stroke data, Cohen now plans to delve back into face processing problems in autism spectrum disorder. Under a $100,000 two-year research award from the Child Neurology Foundation, Cohen will study children with tuberous sclerosis complex (TSC), a genetic syndrome that often includes autism and atypical face processing.

Most children with TSC have tubers (noncancerous tumors) in their brains that are thought to affect the function of nearby brain tissue. To see if they have any relationship with face processing, Cohen will recruit up to 80 children with TSC, locate their brain tubers, administer tests of face processing, and map their brain networks. He will then compare the findings with his data from the stroke study to see if common brain areas are involved.

Could face blindness be treated?

Eventually, Cohen hopes to do a larger study of brain connectivity and face processing in children with garden-variety (non-syndromic) autism. “Just as many disorders can be affected by multiple genes, it may take a whole network of brain regions to cause a symptom,” he says.

This shows brain scans from the study

Brain lesions from 44 stroke patients who developed prosopagnosia. As shown, 29 of these lesions intersected with the right fusiform face area (FFA; shown in blue outline), which is known to be associated with face blindness.

The other 15 lesions did not intersect with the FFA. However, all 44 lesions were in areas that were functionally connected to the right FFA, meaning that these regions are typically used when the FFA is being used, and become quiet when the FFA is quiet. The image is credited to Cohen AL; et al. Brain 2019.

If all roads in that network lead to a specific area in the brain, that area could potentially be treated by methods to increase or decrease its activity. Even addressing face processing in isolation could improve the quality of life in children with autism — and others with face blindness.

“We could try to modulate activity in that spot — with novel therapies like transcranial magnetic stimulation or functional-MRI-based neurofeedback — and see if it affects behavior,” Cohen says. “If this works, we aim to expand this methodology to many other symptoms in autism as well.”.

Funding: The stroke study was funded by the National Institutes of Health (T32MH112510, F32EY023479, K23NS083741), a Canada Research Chair (950-228984), the Canadian Institutes of Health Research (MOP-102567), the Marianne Koerner Chair in Brain Disease, the Sidney R. Baer, Jr. Foundation, the Dystonia Foundation, and the Nancy Lurie Marks Foundation.

Coauthors on the Brain paper were Louis Soussand, Harvard Medical School; Sherryse Corrow, Bethel University; Olivier Martinaud, University Hospital of Rouen, France; and Jason Barton, University of British Columbia.


The face is a complex structure. It has a complicated three-dimensional shape, a substantial degree of mobility, and structural constraints that make all faces fairly similar; all of these issues present challenges to a perceptual system.

Nevertheless, perhaps because of the social importance of faces, humans have developed the ability to recognize faces rapidly and accurately and with seemingly little effort. Indeed, recent estimates are that the typical person can remember and recognize about 5000 faces 1.

However, for some people, face recognition is not so easy. Prosopagnosia is a condition marked by the loss of familiarity for faces and the consequent inability to identify people by their faces 2.

Although prosopagnosic subjects frequently turn to other cues such as voice, hairstyle, or anomalous facial features, these strategies have their limitations; as a result, prosopagnosic subjects still often find social situations stressful, and recent work has shown that they can suffer from anxiety, depression, and social withdrawal 34.

Studies of prosopagnosia have a time-honoured place in research on face recognition. Neuropsychological observations have played key roles in the development of cognitive models of face processing 5 and pointed to the cerebral substrates of face recognition 67. Even in an era when advances in face research are coming from psychophysics, functional neuroimaging, and primate neurophysiology, there are still important contributions from work on prosopagnosia. This has been spurred particularly by the recognition of a developmental variant 8. Although acquired prosopagnosia is rare, developmental prosopagnosia appears to be more common but debate on its exact prevalence continues 9.

Nevertheless, the greater availability of developmental subjects has led to an increase in the number of prosopagnosic studies. In this review, we focus on four areas of recent progress in the fields of acquired and developmental prosopagnosia.Go to:

The diagnosis of prosopagnosia

Uniform definitions are a critical starting point for research into a condition. The core defects in prosopagnosia are the loss of familiarity for previously known faces and the inability to learn to recognize new faces. In the past, this was often shown by tests using famous faces or in case studies by demonstrations that the subject could not recognize friends or family members. However, it is difficult to derive uniform diagnostic criteria from such tests.

Familiarity for famous faces is affected by the subject’s age, culture, education, and interests, for example, and carefully matched controls are essential for interpreting the results of such tests. This has led to supplementation of famous face tests by the increasing use of tests that assess short-term familiarity.

These show faces in a learning phase and then present these “target” faces along with new “distractor” faces in a test phase in which subjects are asked to indicate which were the faces they had learned.

The most well-known examples are the Warrington Recognition Memory Test 10 and the Cambridge Face Memory Test 11, the latter of which has the desirable feature of testing recognition across changes in pose or lighting. Compared with tests that use famous or personally known faces, tests of short-term familiarity provide limited exposure and lack the semantic and perceptual richness of long experience but have the advantage of uniformity in the degree of learning and testing.

For the Cambridge Face Memory Test, there has also been substantial normative work showing good internal consistency (Cronbach’s alpha ranges from 0.83 to 0.89) and no effects of intelligence or the ethnic mix of faces in the subject’s life experience. There is a very modest advantage for women but a more significant effect of age in that accuracy declines for those over the age of 50 11– 13. Also, versions of this test have been developed for use in children 14.

There are many other tests of face processing and these were recently reviewed in detail and categorized 15. Diagnostic tests can be divided into three main types:

(a) tests of face perception, which can include detecting faces in arrays or discriminating or matching simultaneously seen faces;

(b) tests of face recognition, such as the tests for short- and long-term familiarity which were discussed above; and

(c) tests of face identification, which involve naming or providing other information learned about the person whose face is shown.

Prosopagnosic subjects are impaired on both recognition and identification.

Performance on tests of face perception can be used to differentiate between prosopagnosic subjects who have an apperceptive variant, in which there is an under-specification of facial structure by perceptual processing, or an associative or amnestic variant, in which the problem is not perception but the ability of perceptual information to access facial memories 16.

Examples of tests assessing face perception are the Benton Facial Recognition Test 17, the Cambridge Face Perception Test 18, the Glasgow Face Matching Test 19, and the Caledonian Face Test 20. Tests of face imagery have also been used to clarify the status of facial memories and diagnose the amnestic variant 21.

Self-report questionnaires are becoming more common tools in diagnosing prosopagnosia. They are quick and easy, do not require equipment, do not need to be done in person and hence can be used to screen a large number of subjects, even at a distance. Among those are the Kennerknecht 15-item questionnaire 22, the 20-item Prosopagnosia Index 23, and the Cambridge Face Memory Questionnaire 24.

A potential concern is that individuals may have only modest insight into their face recognition abilities 2526, particularly children 27, although some studies suggest that this might not be the case for adults using the Prosopagnosia Index 2829.

This concern might account for the fact that questionnaires may have high reliability but only modest sensitivity and specificity for diagnosing prosopagnosia 24. Because of these concerns, some have advocated that questionnaires always be supplemented by objective tests for diagnosis 92430.

Recent reviews have discussed how to incorporate these various instruments into a diagnostic approach. This may be less of an issue for acquired prosopagnosia, in which the combination of an appropriate lesion on imaging, the subject’s awareness of a change in face recognition after lesion onset, and poor performance on an objective test of face recognition makes the diagnosis plausible.

For developmental prosopagnosia, there are no definite structural or genetic markers at present and so its diagnosis still rests solely on behavioural tests. One review pointed out the wide variations between studies in the types of tests, the number of tests, and the statistical cutoffs used 9.

This creates variable confidence in the diagnosis and introduces heterogeneity that can confound comparisons across groups and studies, an obstacle to scientific progress. As a result, there have been proposals for more uniform diagnostic criteria 931.

These include (i) subjective difficulty recognizing faces in daily life; (ii) objectively impaired face recognition on at least two tests of face recognition and criteria of at least 2 standard deviations below control means; (iii) intact general perceptual and memory function; and (iv) exclusion of other disorders associated with impaired face recognition, such as autism spectrum disorders.

Although reaching a firm diagnosis of developmental prosopagnosia has its hurdles, a recent study using qualitative methods suggested that screening for it may be possible with a simple list of 16 “hallmark symptoms” from experiences in daily life, which anyone can review 27. The utility and sensitivity of this approach need to be explored.Go to:

The neural basis of prosopagnosia

The older literature has shown that lesions of acquired prosopagnosia are bilateral 67 or limited to the right hemisphere 3233, and reports of left-sided lesions alone are rare 34– 36. This is consistent with evidence from functional neuroimaging that face processing induces greater activation in the right hemisphere 37. The areas involved are the ventral occipito-temporal and fusiform cortex or anterior temporal cortex or both.

These anatomic variants may correspond to functional variants 16. Individuals with occipito-temporal or fusiform lesions are more likely to have an apperceptive variant 38, whereas those with anterior temporal lesions have an amnestic variant along with better perceptual function and more difficulty with face imagery 39.

Although by definition subjects with developmental prosopagnosia do not have large visible lesions, the status of their face processing networks can be studied with more subtle neuroimaging techniques, including measures of cortical thickness, the degree of functional activation, and connectivity within the network. The results as they currently stand are not conclusive. There are two main views.

One proposes that developmental prosopagnosia is marked by alterations in various regions of the face network, particularly the fusiform gyrus, changes such as reduced cortical thickness or density 4041, reduced face selectivity of their activation 4042– 44, local white matter abnormalities on diffusion imaging 4546, or reduced feedforward connectivity from early visual to occipito-temporal cortex 47.

The second proposes a disconnection between posterior and anterior regions within the face network 4849 on the basis of observations of preserved activation of the fusiform and ventral occipito-temporal cortex by faces 50– 52 and abnormalities in long white matter tracts that link posterior and anterior temporal cortex 5354.

Comparisons with other developmental disorders might be informative. Researchers on dyslexia have suggested a model in which a general risk for cortical anomalies is modulated by other genetic and/or environmental factors that determine the location and extent of such anomalies 55. The latter determines the specific syndrome and can explain the frequent co-association of developmental disorders. In this regard, we note recent observations of associations between congenital amusia and developmental prosopagnosia 5657. Along these lines, others have speculated that abnormal neural migration may be responsible for developmental prosopagnosia 8.

Does developmental prosopagnosia have a genetic cause? Face recognition abilities show a high degree of heritability in the general population 5859, and early observations were that developmental prosopagnosia tended to run in families 59– 63, possibly with an autosomal dominant pattern of inheritance 2264.

However, most neurodevelopmental disorders are polygenic combinations of allelic variants present in the normal population. Along these lines, a recent study of 24 subjects reported that common single-nucleotide polymorphisms in the oxytocin receptor gene are associated with developmental prosopagnosia 65. These preliminary results require replication in larger samples.Go to:

Is prosopagnosia only about faces?

A long-standing controversy is whether the impaired recognition in prosopagnosia is face-specific or affects other object types. This has important theoretical implications for how object recognition is organized in the visual system.

The distributed view suggests that object processing is performed by networks of visual regions, and that some of these regions are involved in the perception of several types of stimuli 66– 68. The modular view claims that different categories of objects—particularly faces—are processed by distinct dedicated cortical regions 69– 71.

Case studies of acquired prosopagnosia have produced mixed results; some reported normal recognition of exemplars of other objects 72– 82 and others showed impairments 808183– 88. A recent major review 89 examined 238 cases of developmental prosopagnosia in the literature. The majority of subjects had evidence of impaired object recognition, although a smaller number had reasonable evidence that object recognition was intact, given that they had both good accuracy and normal reaction times on tests.

Although the authors concluded that the frequent association of face and object impairments supported a shared mechanism for recognizing faces and other objects 89, the challenge for any comprehensive explanation is to account for both frequent associations and occasional dissociations.

One of the most useful aspects of this review was the collection of accompanying commentaries 90– 104, which suggested both various hypotheses to explain this fact and methodologic limitations in the currently available data that need to be addressed in future work to allow a more definitive set of conclusions to be drawn.

A particular object type deserves comment – namely, words. One of the difficulties in comparing faces and objects is that humans have a great deal of experience and expertise with faces but such expertise cannot be assumed for other object types. Take cars, for example. A recent study found that, as a group, subjects with developmental prosopagnosia tended to score low on the Cambridge Car Recognition Test but that individual scores ranged quite widely, from excellent to poor 105.

However, not everyone is a car expert and variable expertise could affect recognition performance. In another group of studies, when visual car recognition scores were adjusted for car expertise, as reflected by a subject’s semantic knowledge about cars, subjects with both acquired and developmental prosopagnosia tended to perform worse than expected 16106107.

In literate societies, visual words, in contrast to cars, are a category for which almost all subjects have considerable perceptual expertise. The “many-to-many hypothesis” proposes that face and visual word processing share and compete for neural resources in regions like the fusiform gyrus and that structural constraints cause visual words to be processed more on the left, in proximity to language processing, and faces secondarily to lateralize to the right 108– 111. Lateralization is incomplete, though, and functional imaging shows overlap between face- and word-activated voxels 112.

As a consequence, the hypothesis predicts that prosopagnosia from right lesions should be accompanied by mild reading deficits in the processing of words and that alexia from left lesions should be accompanied by mild face recognition problems 108. Whereas one study of three subjects with acquired prosopagnosia did show mild word recognition deficits 113, other studies of visual word processing in acquired prosopagnosia from right-sided lesions alone have not found impaired reading 114115 and the same is true for developmental prosopagnosia 116– 118.

On the other hand, the type of processing that is performed on words and faces may differ by hemisphere. Although subjects with acquired prosopagnosia from right-sided lesions may read normally, they often have trouble recognizing handwriting or font 119– 121, and subjects with alexia may recognize face identity 122 but have trouble with lip reading 119123124.Go to:

Can prosopagnosia be treated?

Spontaneous resolution of acquired prosopagnosia is rare 125– 127, and developmental prosopagnosia is a lifelong disorder. Hence, means of improving face recognition skills in these populations are of clinical interest.

But can it be done? Neuroimaging shows that face processing activates a widely distributed network, including occipito-temporal, superior temporal, anterior temporal, and inferior frontal regions in both hemispheres, though more on the right 128.

It is highly unlikely that acquired lesions will eliminate all components of this network; furthermore, some studies in developmental prosopagnosia continue to show activation of this network by faces 50– 52.

The open question is whether surviving components of the face network in a given prosopagnosic subject have any capacity for functional reorganization or modulation that could allow face recognition to improve through a rehabilitative approach 129.

Most work has focused on behavioural interventions, although there is one intriguing report of transient improvement of developmental prosopagnosia after intranasal inhalation of oxytocin 130.

These rehabilitative attempts have been reviewed in detail 129131132. Approaches can be divided into compensatory strategies, which aim to achieve person recognition by circumventing the face processing impairment, and remediation, which aims to improve that impairment.

In terms of the process targeted, they can also be divided into those that focus on enhancing mnemonic function, which has been used in a few case studies 133– 135, and those that target perceptual function. As examples of the latter, a few older case studies attempted to enhance attention to facial features, though results on face recognition were variable 134136– 138.

The most significant recent advances have been trials of perceptual learning in groups rather than single cases of prosopagnosia.

In one study of 24 subjects with developmental prosopagnosia 139, subjects learned over the course of 2 weeks to discriminate distances between facial features, namely the distance between the eyes and eyebrows or between the nose and the mouth.

These “spatial relations” can be thought of as indices of the complex geometry of faces, and studies show that some people with prosopagnosia are impaired in perceiving them 38.

This trial found improved face perception (but only if the test faces had a similar frontal view) and some modest improvements in subjective reports of daily experience with faces. A second study of 10 subjects with acquired prosopagnosia 132 used morphed faces to train subjects over the course of 11 weeks to perceive finer and finer differences in facial shape; at the same time, the study introduced irrelevant variations in the expression and viewpoint of the face.

In these subjects, compared with a control condition, there was a 21% absolute increase in perceptual sensitivity to facial shape after training, which generalized over new views and expressions. Importantly, there was also a 10% increase for new faces on which subjects had not trained, indicating that subjects were acquiring new skills rather than just learning a set of faces.

The effects of training were still evident 3 months later. Although some but not all subjects related anecdotes pointing to improved face recognition in daily life, future studies will require formal evaluation of real-life benefit before such methods are translated to the clinic.

These rehabilitative studies represent a starting point. Although neither training method represents a “cure”, they provide evidence that face processing can be changed in prosopagnosia.

They also suggest that there may be individual differences in training potential. Further work is required to determine whether the perceptual gains from learning can be augmented further by better training design or the use of adjunctive methods to promote plasticity during learning.


Source:
Boston Children’s Hospital
Media Contacts:
Bethany Tripp – Boston Children’s Hospital
Image Source:
The image is credited to Cohen AL; et al. Brain 2019.

Original Research: Closed access
“Looking beyond the face area: lesion network mapping of prosopagnosias”. Alexander L Cohen et al.
Brain doi:10.1093/brain/awz332.

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