Gene therapy of the human retina

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Gene_therapy_of_the_human_retina 

 

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber's congenital amaurosis had been successfully treated using gene therapy with adeno-associated virus (AAV). In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA. These results were widely seen as a success in the gene therapy field, and have generated excitement and momentum for AAV-mediated applications in retinal disease.

In retinal gene therapy, the most widely used vectors for ocular gene delivery are based on adeno-associated virus. The great advantage in using adeno-associated virus for the gene therapy is that it poses minimal immune responses and mediates long-term transgene expression in a variety of retinal cell types. For example, tight junctions that form the blood-retina barrier, separate subretinal space from the blood supply, providing protection from microbes and decreasing most immune-mediated damages.

Clinical trials

Leber's congenital amaurosis

Preclinical studies in mouse models of Leber's congenital amaurosis (LCA) were published in 1996 and a study in dogs published in 2001. In 2008, three groups reported results of clinical trials using adeno-associated virus for LCA. In these studies, an AAV vector encoding the RPE65 gene was delivered via a "subretinal injection", where a small amount of fluid is injected underneath the retina in a short surgical procedure. Development continued, and in December 2017 the FDA approved Voretigene neparvovec (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. People must have viable retinal cells as a prerequisite for the intraocular administration of the drug.

Age-related macular degeneration

Following the successful clinical trials in LCA, researchers have been developing similar treatments using adeno-associated virus for age-related macular degeneration (AMD). To date, efforts have focused on long-term delivery of VEGF inhibitors to treat the wet form of macular degeneration. Whereas wet AMD is currently treated using frequent injections of recombinant protein into the eyeball, the goal of these treatments is long-term disease management following a single administration. One such study is being conducted at the Lions Eye Institute in Australia in collaboration with Avalanche Biotechnologies, a US-based biotechnology start-up. Another early-stage study is sponsored by Genzyme Corporation.

Choroideremia

In October 2011, the first clinical trial was announced for the treatment of choroideremia. Dr. Robert MacLaren of the University of Oxford, who lead the trial, co-developed the treatment with Dr. Miguel Seabra of the Imperial College, London. This Phase 1/2 trial used subretinal AAV to restore the REP gene in affected patients. Initial results of the trial were reported in January 2014 as promising as all six patients had better vision.

Color blindness

Recent research has shown that AAV can successfully restore color vision to treat color blindness in adult monkeys. Although this treatment has not yet entered clinical trials for humans, this work was considered a breakthrough for the ability to target cone photoreceptors.

Mechanism

Physiological components in retinal gene therapy

The vertebrate neural retina composed of several layers and distinct cell types. A number of these cell types are implicated in retinal diseases, including retinal ganglion cells, which degenerate in glaucoma, the rod and cone photoreceptors, which are responsive to light and degenerate in retinitis pigmentosa, macular degeneration, and other retinal diseases, and the retinal pigment epithelium (RPE), which supports the photoreceptors and is also implicated in retinitis pigmentosa and macular degeneration. 

In retinal gene therapy, AAV is capable of "transducing" these various cell types by entering the cells and expressing the therapeutic DNA sequence. Since the cells of the retina are non-dividing, AAV continues to persist and provide expression of the therapeutic DNA sequence over a long time period that can last several years.

AAV tropism and routes of administration

AAV is capable of transducing multiple cell types within the retina. AAV serotype 2, the most well-studied type of AAV, is commonly administered in one of two routes: intravitreal or subretinal. Using the intravitreal route, AAV is injected in the vitreous humor of the eye. Using the subretinal route, AAV is injected underneath the retina, taking advantage of the potential space between the photoreceptors and RPE layer, in a short surgical procedure. Although this is more invasive than the intravitreal route, the fluid is absorbed by the RPE and the retina flattens in less than 14 hours without complications. Intravitreal AAV targets retinal ganglion cells and a few Muller glial cells. Subretinal AAV efficiently targets photoreceptors and RPE cells.

The reason that different routes of administration lead to different cell types being transfected (e.g., different tropism) is that the inner limiting membrane (ILM) and the various retinal layers act as physical barriers for the delivery of drugs and vectors to the deeper retinal layers. Thus overall, subretinal AAV is 5-10 times more efficient than delivery using the intravitreal route.

Tropism modification and novel AAV vectors

One important factor in gene delivery is developing altered cell tropisms to narrow or broaden rAAV-mediated gene delivery and to increase its efficiency in tissues. Specific properties like capsid conformation, cell targeting strategies can determine which cell types are affected and also the efficiency of the gene transfer process. Different kinds of modification can be undertaken. For example, modification by chemical, immunological or genetic changes that enables the AAV2 capsid to interact with specific cell surface molecules.

Initial studies with AAV in the retina have utilized AAV serotype 2. Researchers are now beginning to develop new variants of AAV, based on naturally-occurring AAV serotypes and engineered AAV variants.

Several naturally-occurring serotypes of AAV have been isolated that can transduce retinal cells. Following intravitreal injection, only AAV serotypes 2 and 8 were capable of transducing retinal ganglion cells. Occasional Muller cells were transduced by AAV serotypes 2, 8, and 9. Following subretinal injection, serotypes 2, 5, 7, and 8 efficiently transduced photoreceptors, and serotypes 1, 2, 5, 7, 8, and 9 efficiently transduce RPE cells.

One example of an engineered variant has recently been described that efficiently transduces Muller glia following intravitreal injection, and has been used to rescue an animal model of aggressive, autosomal-dominant retinitis pigmentosa.

AAV and immune privilege in the retina

Importantly, the retina is immune-privileged, and thus does not experience a significant inflammation or immune-response when AAV is injected. Immune response to gene therapy vectors is what has caused previous attempts at gene therapy to fail, and is considered a key advantage of gene therapy in the eye. Re-administration has been successful in large animals, indicating that no long-lasting immune response is mounted.

Recent data indicates that the subretinal route may be subject to a greater degree of immune privilege compared to the intravitreal route.

Promoter sequence

Expression in various retinal cell types can be determined by the promoter sequence. In order to restrict expression to a specific cell type, a tissue-specific or cell-type specific promoter can be used.

For example, in rats the murine rhodopsin gene drive the expression in AAV2, GFP reporter product was found only in rat photoreceptors, not in any other retinal cell type or in the adjacent RPE after subretinal injection. On the other hand, if ubiquitously expressed immediate-early cytomegalovirus (CMV) enhancer-promoter is expressed in a wide variety of transfected cell types. Other ubiquitous promoters such as the CBA promoter, a fusion of the chicken-actin promoter and CMV immediate-early enhancer, allows stable GFP reporter expression in both RPE and photoreceptor cells after subretinal injections.

Modulation of expression

Sometimes modulation of transgene expression may be necessary since strong constitutive expression of a therapeutic gene in retinal tissues could be deleterious for long-term retinal function. Different methods have been utilized for the expression modulation. One way is using exogenously regulatable promoter system in AAV vectors. For example, the tetracycline-inducible expression system uses a silencer/transactivator AAV2 vector and a separate inducible doxycycline-responsive coinjection. When induction occurs by oral doxycycline, this system shows tight regulation of gene expression in both photoreceptor and RPE cells.

Examples and animal models

Targeting RPE

One study that was done by Royal College of Surgeons (RCS) in rat model shows that a recessive mutation in a receptor tyrposine kinase gene, mertk results in a premature stop codon and impaired phagocytosis function by RPE cells. This mutation causes the accumulation of outer segment debris in the subretinal space, which causes photoreceptor cell death. The model organism with this disease received a subretinal injection of AAV serotype 2 carrying a mouse Mertk cDNA under the control of either the CMV or RPE65 promoters. This treatment was found to prolong photoreceptor cell survival for several months and also the number of photoreceptor was 2.5 fold higher in AAV-Mertk- treated eyes compared with controls 9 weeks after injection, also they found decreased amount of debris in the subretinal space.

The protein RPE65 is used in the retinoid cycle where the all-trans-retinol within the rod outer segment is isomerized to its 11-cis form and oxidized to 11-cis retinal before it goes back to the photoreceptor and joins with opsin molecule to form functional rhodopsin. In animal knockout model (RPE65-/-), gene transfer experiment shows that early intraocular delivery of human RPE65 vector on embryonic day 14 shows efficient transduction of retinal pigment epithelium in the RPE65-/- knockout mice and rescues visual functions. This shows successful gene therapy can be attributed to early intraocular deliver to the diseased animal.

Targeting of photoreceptors

Juvenile retinoschisis is a disease that affects the nerve tissue in the eye. This disease is an X-linked recessive degenerative disease of the central macula region, and it is caused by mutation in the RSI gene encoding the protein retinoschisin. Retinoschisin is produced in the photoreceptor and bipolar cells and it is critical in maintaining the synaptic integrity of the retina.

Specifically the AAV 5 vector containing the wild-type human RSI cDNA driven by a mouse opsin promoter showed long-term retinal functional and structural recovery. Also the retinal structural reliability improved greatly after the treatment, characterized by an increase in the outer nuclear layer thickness.

Retinitis pigmentosa

Retinitis pigmentosa is an inherited disease which leads to progressive night blindness and loss of peripheral vision as a result of photoreceptor cell death. Most people who suffer from RP are born with rod cells that are either dead or dysfunctional, so they are effectively blind at nighttime, since these are the cells responsible for vision in low levels of light. What follows often is the death of cone cells, responsible for color vision and acuity, at light levels present during the day. Loss of cones leads to full blindness as early as five years old, but may not onset until many years later. There have been multiple hypotheses about how the lack of rod cells can lead to the death of cone cells. Pinpointing a mechanism for RP is difficult because there are more than 39 genetic loci and genes correlated with this disease. In an effort to find the cause of RP, there have been different gene therapy techniques applied to address each of the hypotheses.

Different types of inheritance can attribute to this disease; autosomal recessive, autosomal dominant, X-linked type, etc. The main function of rhodopsin is initiating the phototransduction cascade. The opsin proteins are made in the photoreceptor inner segments, then transported to the outer segment, and eventually phagocytized by the RPE cells. When mutations occur in the rhodopsin the directional protein movement is affected because the mutations can affect protein folding, stability, and intracellular trafficking. One approach is introducing AAV-delivered ribozymes designed to target and destroy a mutant mRNA.

The way this system operates was shown in animal model that have a mutant rhodopsin gene. The injected AAV-ribozymes were optimized in vitro and used to cleave the mutant mRNA transcript of P23H (where most mutation occur) in vivo.

Another mutation in the rhodopsin structural protein, specifically peripherin 2 which is a membrane glycoprotein involved in the formation of photoreceptor outersegment disk, can lead to recessive RP and macular degeneration in human (19). In a mouse experiment, AAV2 carrying a wild-type peripherin 2 gene driven by a rhodopsin promoter was delivered to the mice by subretinal injection. The result showed improvement in photoreceptor structure and function which was detected by ERG (electroretinogram). The result showed improvement of photoreceptor structure and function which was detected by ERG. Also peripherin 2 was detected at the outer segment layer of the retina 2 weeks after injection and therapeutic effects were noted as soon as 3 weeks after injection. A well-defined outer segment containing both peripherin2 and rhodopsin was present 9-month after injection.

Since apoptosis can be the cause of photoreceptor death in most of the retinal dystrophies. It has been known that survival factors and antiapoptoic reagents can be an alternative treatment if the mutation is unknown for gene replacement therapy. Some scientists have experimented with treating this issue by injecting substitute trophic factors into the eye. One group of researchers injected the rod derived cone viability factor (RdCVF) protein (encoded for by the Nxnl1 (Txnl6) gene) into the eye of the most commonly occurring dominant RP mutation rat models. This treatment demonstrated success in promoting the survival of cone activity, but the treatment served even more significantly to prevent progression of the disease by increasing the actual function of the cones. Experiments were also carried out to study whether supplying AAV2 vectors with cDNA for glial cell line-derived neurotrophic factor (GDNF) can have an anti-apoptosis effect on the rod cells. In looking at an animal model, the opsin transgene contains a truncated protein lacking the last 15 amino acids of the C terminus, which causes alteration in rhodopsin transport to the outer segment and leads to retinal degeneration. When the AAV2-CBA-GDNF vector is administered to the subretinal space, photoreceptor stabilized and rod photoreceptors increased and this was seen in the improved function of the ERG analysis. Successful experiments in animals have also been carried out using ciliary neurotrophic factor (CNTF), and CNTF is currently being used as a treatment in human clinical trials.

AAV-based treatment for retinal neovascular diseases

Ocular neovascularization (NV) is the abnormal formation of new capillaries from already existing blood vessels in the eye, and this is a characteristics for ocular diseases such as diabetic retinopathy (DR), retinopathy of prematurity (ROP) and (wet form) age-related macular degeneration (AMD). One of the main players in these diseases is VEGF (Vascular endothelial growth factor) which is known to induce vessel leakage and which is also known to be angiogenic. In normal tissues VEGF stimulates endothelial cell proliferation in a dose dependent manner, but such activity is lost with other angiogenic factors.

Many angiostatic factors have been shown to counteract the effect of increasing local VEGF. The naturally occurring form of soluble Flt-1 has been shown to reverse neovascularization in rats, mice, and monkeys.

Pigment epithelium-derived factor (PEDF) also acts as an inhibitor of angiogenesis. The secretion of PEDF is noticeably decreased under hypoxic conditions allowing the endothelial mitogenic activity of VEGF to dominate, suggesting that the loss of PEDF plays a central role in the development of ischemia-driven NV. One clinical finding shows that the levels of PEDF in aqueous humor of human are decreased with increasing age, indicating that the reduction may lead to the development of AMD. In animal model, an AAV with human PEDF cDNA under the control of the CMV promoter prevented choroidal and retinal NV(24). 

The finding suggests that the AAV-mediated expression of angiostatic factors can be implemented to treat NV. This approach could be useful as an alternative to frequent injections of recombinant protein into the eye. In addition, PEDF and sFlt-1 may be able to diffuse through sclera tissue, allowing for the potential to be relatively independent of the intraocular site of administration.

Biometrics

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Biometrics 

At Walt Disney World in Lake Buena Vista, Florida, biometric measurements are taken from the fingers of guests to ensure that a ticket is used by the same person from day to day

 

Biometrics is the technical term for body measurements and calculations. It refers to metrics related to human characteristics. Biometrics authentication (or realistic authentication) is used in computer science as a form of identification and access control. It is also used to identify individuals in groups that are under surveillance.

Biometric identifiers are the distinctive, measurable characteristics used to label and describe individuals. Biometric identifiers are often categorized as physiological versus behavioral characteristics. Physiological characteristics are related to the shape of the body. Examples include, but are not limited to fingerprint, palm veins, facerecognition, DNA, palmprint, handgeometry, irisrecognition, retina and odour/scent. Behavioral characteristics are related to the pattern of behavior of a person, including but not limited to typing rhythm, gait, and voice. Some researchers have coined the term behaviometrics to describe the latter class of biometrics.

More traditional means of access control include token-based identification systems, such as a driver's license or passport, and knowledge-based identification systems, such as a password or personal identification number. Since biometric identifiers are unique to individuals, they are more reliable in verifying identity than token and knowledge-based methods; however, the collection of biometric identifiers raises privacy concerns about the ultimate use of this information.

Biometric functionality

Many different aspects of human physiology, chemistry or behavior can be used for biometric authentication. The selection of a particular biometric for use in a specific application involves a weighting of several factors. Jain et al. (1999) identified seven such factors to be used when assessing the suitability of any trait for use in biometric authentication.

• Universality means that every person using a system should possess the trait.
• Uniqueness means the trait should be sufficiently different for individuals in the relevant population such that they can be distinguished from one another.
• Permanence relates to the manner in which a trait varies over time. More specifically, a trait with 'good' permanence will be reasonably invariant over time with respect to the specific matching algorithm.
• Measurability (collectability) relates to the ease of acquisition or measurement of the trait. In addition, acquired data should be in a form that permits subsequent processing and extraction of the relevant feature sets.
• Performance relates to the accuracy, speed, and robustness of technology used (see performance section for more details).
• Acceptability relates to how well individuals in the relevant population accept the technology such that they are willing to have their biometric trait captured and assessed.
• Circumvention relates to the ease with which a trait might be imitated using an artifact or substitute.

Proper biometric use is very application dependent. Certain biometrics will be better than others based on the required levels of convenience and security. No single biometric will meet all the requirements of every possible application.

The block diagram illustrates the two basic modes of a biometric system. First, in verification (or authentication) mode the system performs a one-to-one comparison of a captured biometric with a specific template stored in a biometric database in order to verify the individual is the person they claim to be. Three steps are involved in the verification of a person. In the first step, reference models for all the users are generated and stored in the model database. In the second step, some samples are matched with reference models to generate the genuine and impostor scores and calculate the threshold. The third step is the testing step. This process may use a smart card, username or ID number (e.g. PIN) to indicate which template should be used for comparison. 'Positive recognition' is a common use of the verification mode, "where the aim is to prevent multiple people from using the same identity".

Second, in identification mode the system performs a one-to-many comparison against a biometric database in an attempt to establish the identity of an unknown individual. The system will succeed in identifying the individual if the comparison of the biometric sample to a template in the database falls within a previously set threshold. Identification mode can be used either for 'positive recognition' (so that the user does not have to provide any information about the template to be used) or for 'negative recognition' of the person "where the system establishes whether the person is who she (implicitly or explicitly) denies to be". The latter function can only be achieved through biometrics since other methods of personal recognition such as passwords, PINs or keys are ineffective.

The first time an individual uses a biometric system is called enrollment. During enrollment, biometric information from an individual is captured and stored. In subsequent uses, biometric information is detected and compared with the information stored at the time of enrollment. Note that it is crucial that storage and retrieval of such systems themselves be secure if the biometric system is to be robust. Biometric data is stored and processed with database servers, encrypted tokens, or physical tokens, while more secure devices will use on-device storage of biometric templates. This type of storage ensures identity authentication without the transference of any sensitive biometric information over the internet to a different server or location. The first block (sensor) is the interface between the real world and the system; it has to acquire all the necessary data. Most of the times it is an image acquisition system, but it can change according to the characteristics desired. The second block performs all the necessary pre-processing: it has to remove artifacts from the sensor, to enhance the input (e.g. removing background noise), to use some kind of normalization, etc. In the third block, necessary features are extracted. This step is an important step as the correct features need to be extracted in an optimal way. A vector of numbers or an image with particular properties is used to create a template. A template is a synthesis of the relevant characteristics extracted from the source. Elements of the biometric measurement that are not used in the comparison algorithm are discarded in the template to reduce the filesize and to protect the identity of the enrollee. However, depending on the scope of the biometric system, original biometric image sources may be retained such as the PIV-cards used in the Federal Information Processing Standard Personal Identity Verification (PIV) of Federal Employees and Contractors (FIPS 201).

During the enrollment phase, the template is simply stored somewhere (on a card or within a database or both). During the matching phase, the obtained template is passed to a matcher that compares it with other existing templates, estimating the distance between them using any algorithm (e.g. Hamming distance). The matching program will analyze the template with the input. This will then be output for a specified use or purpose (e.g. entrance in a restricted area), though it is a fear that the use of biometric data may face mission creep. Selection of biometrics in any practical application depending upon the characteristic measurements and user requirements. In selecting a particular biometric, factors to consider include, performance, social acceptability, ease of circumvention and/or spoofing, robustness, population coverage, size of equipment needed and identity theft deterrence. The selection of a biometric is based on user requirements and considers sensor and device availability, computational time and reliability, cost, sensor size, and power consumption.

Multimodal biometric system

Multimodal biometric systems use multiple sensors or biometrics to overcome the limitations of unimodal biometric systems. For instance iris recognition systems can be compromised by aging irises and electronic fingerprint recognition can be worsened by worn-out or cut fingerprints. While unimodal biometric systems are limited by the integrity of their identifier, it is unlikely that several unimodal systems will suffer from identical limitations. Multimodal biometric systems can obtain sets of information from the same marker (i.e., multiple images of an iris, or scans of the same finger) or information from different biometrics (requiring fingerprint scans and, using voice recognition, a spoken passcode).

Multimodal biometric systems can fuse these unimodal systems sequentially, simultaneously, a combination thereof, or in series, which refer to sequential, parallel, hierarchical and serial integration modes, respectively. Fusion of the biometrics information can occur at different stages of a recognition system. In case of feature level fusion, the data itself or the features extracted from multiple biometrics are fused. Matching-score level fusion consolidates the scores generated by multiple classifiers pertaining to different modalities. Finally, in case of decision level fusion the final results of multiple classifiers are combined via techniques such as majority voting. Feature level fusion is believed to be more effective than the other levels of fusion because the feature set contains richer information about the input biometric data than the matching score or the output decision of a classifier. Therefore, fusion at the feature level is expected to provide better recognition results.

Spoof attacks consist in submitting fake biometric traits to biometric systems, and are a major threat that can curtail their security. Multi-modal biometric systems are commonly believed to be intrinsically more robust to spoof attacks, but recent studies have shown that they can be evaded by spoofing even a single biometric trait.

Performance

The following are used as performance metrics for biometric systems:

• False match rate (FMR, also called FAR = False Accept Rate): the probability that the system incorrectly matches the input pattern to a non-matching template in the database. It measures the percent of invalid inputs that are incorrectly accepted. In case of similarity scale, if the person is an imposter in reality, but the matching score is higher than the threshold, then he is treated as genuine. This increases the FMR, which thus also depends upon the threshold value.
• False non-match rate (FNMR, also called FRR = False Reject Rate): the probability that the system fails to detect a match between the input pattern and a matching template in the database. It measures the percent of valid inputs that are incorrectly rejected.
• Receiver operating characteristic or relative operating characteristic (ROC): The ROC plot is a visual characterization of the trade-off between the FMR and the FNMR. In general, the matching algorithm performs a decision based on a threshold that determines how close to a template the input needs to be for it to be considered a match. If the threshold is reduced, there will be fewer false non-matches but more false accepts. Conversely, a higher threshold will reduce the FMR but increase the FNMR. A common variation is the Detection error trade-off (DET), which is obtained using normal deviation scales on both axes. This more linear graph illuminates the differences for higher performances (rarer errors).
• Equal error rate or crossover error rate (EER or CER): the rate at which both acceptance and rejection errors are equal. The value of the EER can be easily obtained from the ROC curve. The EER is a quick way to compare the accuracy of devices with different ROC curves. In general, the device with the lowest EER is the most accurate.
• Failure to enroll rate (FTE or FER): the rate at which attempts to create a template from an input is unsuccessful. This is most commonly caused by low-quality inputs.
• Failure to capture rate (FTC): Within automatic systems, the probability that the system fails to detect a biometric input when presented correctly.
• Template capacity: the maximum number of sets of data that can be stored in the system.

History

An early cataloguing of fingerprints dates back to 1881 when Juan Vucetich started a collection of fingerprints of criminals in Argentina. Josh Ellenbogen and Nitzan Lebovic argued that Biometrics originated in the identification systems of criminal activity developed by Alphonse Bertillon (1853–1914) and by Francis Galton's theory of fingerprints and physiognomy. According to Lebovic, Galton's work "led to the application of mathematical models to fingerprints, phrenology, and facial characteristics", as part of "absolute identification" and "a key to both inclusion and exclusion" of populations. Accordingly, "the biometric system is the absolute political weapon of our era" and a form of "soft control". The theoretician David Lyon showed that during the past two decades biometric systems have penetrated the civilian market, and blurred the lines between governmental forms of control and private corporate control. Kelly A. Gates identified 9/11 as the turning point for the cultural language of our present: "in the language of cultural studies, the aftermath of 9/11 was a moment of articulation, where objects or events that have no necessary connection come together and a new discourse formation is established: automated facial recognition as a homeland security technology."

Adaptive biometric systems

Adaptive biometric systems aim to auto-update the templates or model to the intra-class variation of the operational data. The two-fold advantages of these systems are solving the problem of limited training data and tracking the temporal variations of the input data through adaptation. Recently, adaptive biometrics have received a significant attention from the research community. This research direction is expected to gain momentum because of their key promulgated advantages. First, with an adaptive biometric system, one no longer needs to collect a large number of biometric samples during the enrollment process. Second, it is no longer necessary to enrol again or retrain the system from scratch in order to cope with the changing environment. This convenience can significantly reduce the cost of maintaining a biometric system. Despite these advantages, there are several open issues involved with these systems. For mis-classification error (false acceptance) by the biometric system, cause adaptation using impostor sample. However, continuous research efforts are directed to resolve the open issues associated to the field of adaptive biometrics. More information about adaptive biometric systems can be found in the critical review by Rattani et al.

Recent advances in emerging biometrics

In recent times, biometrics based on brain (electroencephalogram) and heart (electrocardiogram) signals have emerged. The research group at University of Kent led by Ramaswamy Palaniappan has shown that people have certain distinct brain and heart patterns that are specific for each individual. Another example is finger vein recognition, using pattern-recognition techniques, based on images of human vascular patterns. The advantage of such 'futuristic' technology is that it is more fraud resistant compared to conventional biometrics like fingerprints. However, such technology is generally more cumbersome and still has issues such as lower accuracy and poor reproducibility over time. This new generation of biometrical systems is called biometrics of intent and it aims to scan intent. The technology will analyze physiological features such as eye movement, body temperature, breathing etc. and predict dangerous behaviour or hostile intent before it materializes into action.

On the portability side of biometric products, more and more vendors are embracing significantly miniaturized biometric authentication systems (BAS) thereby driving elaborate cost savings, especially for large-scale deployments.

Operator signatures

An operator signature is a biometric mode where the manner in which a person using a device or complex system is recorded as a verification template. One potential use for this type of biometric signature is to distinguish among remote users of telerobotic surgery systems that utilize public networks for communication.

Proposed requirement for certain public networks

John Michael (Mike) McConnell, a former vice admiral in the United States Navy, a former Director of U.S. National Intelligence, and Senior Vice President of Booz Allen Hamilton promoted the development of a future capability to require biometric authentication to access certain public networks in his keynote speech at the 2009 Biometric Consortium Conference.

A basic premise in the above proposal is that the person that has uniquely authenticated themselves using biometrics with the computer is in fact also the agent performing potentially malicious actions from that computer. However, if control of the computer has been subverted, for example in which the computer is part of a botnet controlled by a hacker, then knowledge of the identity of the user at the terminal does not materially improve network security or aid law enforcement activities.

Recently, another approach to biometric security was developed, this method scans the entire body of prospects to guarantee a better identification of this prospect. This method is not globally accepted because it is very complex and prospects are concerned about their privacy.

Animal biometrics

Rather than tags or tattoos, biometric techniques may be used to identify individual animals: zebra stripes, blood vessel patterns in rodent ears, muzzle prints, bat wing patterns, primate facial recognition and koala spots have all been tried.

Video

Videos have become a pronounced way of identifying information. There are features in videos that look at how intense certain parts of a frame are compared to others which help with identification.

Issues and concerns

Surveillance humanitarianism in times of crisis

Biometrics are employed by many aid programs in times of crisis in order to prevent fraud and ensure that resources are properly available to those in need. Humanitarian efforts are motivated by promoting the welfare of individuals in need, however the use of biometrics as a form of surveillance humanitarianism can create conflict due to varying interests of the groups involved in the particular situation. Disputes over the use of biometrics between aid programs and party officials stalls the distribution of resources to people that need help the most. In July of 2019, the United Nations World Food Program and Houthi Rebels were involved in a large dispute over the use of biometrics to ensure resources are provided to the hundreds of thousands of civilians in Yemen whose lives are threatened. The refusal to cooperate with the interests of the United Nations World Food Program resulted in the suspension of food aid to the Yemen population. The use of biometrics may provide aid programs with valuable information, however its potential solutions may not be best suited for chaotic times of crisis. Conflicts that are caused by deep-rooted political problems, in which the implementation of biometrics may not provide a long-term solution.

Human dignity

Biometrics have been considered also instrumental to the development of state authority (to put it in Foucauldian terms, of discipline and biopower). By turning the human subject into a collection of biometric parameters, biometrics would dehumanize the person, infringe bodily integrity, and, ultimately, offend human dignity.

In a well-known case, Italian philosopher Giorgio Agamben refused to enter the United States in protest at the United States Visitor and Immigrant Status Indicator (US-VISIT) program's requirement for visitors to be fingerprinted and photographed. Agamben argued that gathering of biometric data is a form of bio-political tattooing, akin to the tattooing of Jews during the Holocaust. According to Agamben, biometrics turn the human persona into a bare body. Agamben refers to the two words used by Ancient Greeks for indicating "life", zoe, which is the life common to animals and humans, just life; and bios, which is life in the human context, with meanings and purposes. Agamben envisages the reduction to bare bodies for the whole humanity. For him, a new bio-political relationship between citizens and the state is turning citizens into pure biological life (zoe) depriving them from their humanity (bios); and biometrics would herald this new world.

In Dark Matters: On the Surveillance of Blackness, surveillance scholar Simone Browne formulates a similar critique as Agamben, citing a recent study relating to biometrics R&D that found that the gender classification system being researched "is inclined to classify Africans as males and Mongoloids as females." Consequently, Browne argues that the conception of an objective biometric technology is difficult if such systems are subjectively designed, and are vulnerable to cause errors as described in the study above. The stark expansion of biometric technologies in both the public and private sector magnifies this concern. The increasing commodification of biometrics by the private sector adds to this danger of loss of human value. Indeed, corporations value the biometric characteristics more than the individuals value them. Browne goes on to suggest that modern society should incorporate a "biometric consciousness" that "entails informed public debate around these technologies and their application, and accountability by the state and the private sector, where the ownership of and access to one's own body data and other intellectual property that is generated from one's body data must be understood as a right."

Other scholars have emphasized, however, that the globalized world is confronted with a huge mass of people with weak or absent civil identities. Most developing countries have weak and unreliable documents and the poorer people in these countries do not have even those unreliable documents. Without certified personal identities, there is no certainty of right, no civil liberty. One can claim her rights, including the right to refuse to be identified, only if she is an identifiable subject, if she has a public identity. In such a sense, biometrics could play a pivotal role in supporting and promoting respect for human dignity and fundamental rights.

The biometrics of intent poses further risks. In his paper in Harvard International Review, Prof Nayef Al-Rodhan cautions about the high risks of miscalculations, wrongful accusations and infringements of civil liberties. Critics in the US have also signalled a conflict with the 4th Amendment.

Privacy and discrimination

It is possible that data obtained during biometric enrollment may be used in ways for which the enrolled individual has not consented. For example, most biometric features could disclose physiological and/or pathological medical conditions (e.g., some fingerprint patterns are related to chromosomal diseases, iris patterns could reveal genetic sex, hand vein patterns could reveal vascular diseases, most behavioral biometrics could reveal neurological diseases, etc.). Moreover, second generation biometrics, notably behavioral and electro-physiologic biometrics (e.g., based on electrocardiography, electroencephalography, electromyography), could be also used for emotion detection.

There are three categories of privacy concerns:

1. Unintended functional scope: The authentication goes further than authentication, such as finding a tumor.
2. Unintended application scope: The authentication process correctly identifies the subject when the subject did not wish to be identified.
3. Covert identification: The subject is identified without seeking identification or authentication, i.e. a subject's face is identified in a crowd.

Danger to owners of secured items

When thieves cannot get access to secure properties, there is a chance that the thieves will stalk and assault the property owner to gain access. If the item is secured with a biometric device, the damage to the owner could be irreversible, and potentially cost more than the secured property. For example, in 2005, Malaysian car thieves cut off the finger of a Mercedes-Benz S-Class owner when attempting to steal the car.

Presentation attacks

In the context of biometric systems, presentation attacks may also be called "spoofing attacks".

As per the recent ISO/IEC 30107 standard, presentation attacks are defined as "presentation to the biometric capture subsystem with the goal of interfering with the operation of the biometric system". These attacks can be either impersonation or obfuscation attacks. Impersonation attacks try to gain access by pretending to be someone else. Obfuscation attacks may, for example, try to evade face detection and face recognition systems.

Recently several methods have been proposed to counteract presentation attacks. Today's sophisticated biometric systems use "liveness" elements to detect spoofs (a.k.a. fake images), and some fingerprint scanners have pulse detectors. Automated detection of a presentation attack is called a "presentation attack detection" (PAD).

Cancelable biometrics

One advantage of passwords over biometrics is that they can be re-issued. If a token or a password is lost or stolen, it can be cancelled and replaced by a newer version. This is not naturally available in biometrics. If someone's face is compromised from a database, they cannot cancel or reissue it. If the electronic biometric identifier is stolen, it is nearly impossible to change a biometric feature. This renders the person's biometric feature questionable for future use in authentication, such as the case with the hacking of security-clearance-related background information from the Office of Personnel Management (OPM) in the United States.

Cancelable biometrics is a way in which to incorporate protection and the replacement features into biometrics to create a more secure system. It was first proposed by Ratha et al. 

"Cancelable biometrics refers to the intentional and systematically repeatable distortion of biometric features in order to protect sensitive user-specific data. If a cancelable feature is compromised, the distortion characteristics are changed, and the same biometrics is mapped to a new template, which is used subsequently. Cancelable biometrics is one of the major categories for biometric template protection purpose besides biometric cryptosystem." In biometric cryptosystem, "the error-correcting coding techniques are employed to handle intraclass variations." This ensures a high level of security but has limitations such as specific input format of only small intraclass variations.

Several methods for generating new exclusive biometrics have been proposed. The first fingerprint-based cancelable biometric system was designed and developed by Tulyakov et al. Essentially, cancelable biometrics perform a distortion of the biometric image or features before matching. The variability in the distortion parameters provides the cancelable nature of the scheme. Some of the proposed techniques operate using their own recognition engines, such as Teoh et al. and Savvides et al., whereas other methods, such as Dabbah et al., take the advantage of the advancement of the well-established biometric research for their recognition front-end to conduct recognition. Although this increases the restrictions on the protection system, it makes the cancellable templates more accessible for available biometric technologies

Soft biometrics

Soft biometrics traits are physical, behavioral or adhered human characteristics that have been derived from the way human beings normally distinguish their peers (e.g. height, gender, hair color). They are used to complement the identity information provided by the primary biometric identifiers. Although soft biometric characteristics lack the distinctiveness and permanence to recognize an individual uniquely and reliably, and can be easily faked, they provide some evidence about the users identity that could be beneficial. In other words, despite the fact they are unable to individualize a subject, they are effective in distinguishing between people. Combinations of personal attributes like gender, race, eye color, height and other visible identification marks can be used to improve the performance of traditional biometric systems. Most soft biometrics can be easily collected and are actually collected during enrollment. Two main ethical issues are raised by soft biometrics. First, some of soft biometric traits are strongly cultural based; e.g., skin colors for determining ethnicity risk to support racist approaches, biometric sex recognition at the best recognizes gender from tertiary sexual characters, being unable to determine genetic and chromosomal sexes; soft biometrics for aging recognition are often deeply influenced by ageist stereotypes, etc. Second, soft biometrics have strong potential for categorizing and profiling people, so risking of supporting processes of stigmatization and exclusion.

International sharing of biometric data

Many countries, including the United States, are planning to share biometric data with other nations.

In testimony before the US House Appropriations Committee, Subcommittee on Homeland Security on "biometric identification" in 2009, Kathleen Kraninger and Robert A Mocny commented on international cooperation and collaboration with respect to biometric data, as follows:

To ensure we can shut down terrorist networks before they ever get to the United States, we must also take the lead in driving international biometric standards. By developing compatible systems, we will be able to securely share terrorist information internationally to bolster our defenses. Just as we are improving the way we collaborate within the U.S. Government to identify and weed out terrorists and other dangerous people, we have the same obligation to work with our partners abroad to prevent terrorists from making any move undetected. Biometrics provide a new way to bring terrorists' true identities to light, stripping them of their greatest advantage—remaining unknown.

According to an article written in 2009 by S. Magnuson in the National Defense Magazine entitled "Defense Department Under Pressure to Share Biometric Data" the United States has bilateral agreements with other nations aimed at sharing biometric data. To quote that article:

Miller [a consultant to the Office of Homeland Defense and America's security affairs] said the United States has bilateral agreements to share biometric data with about 25 countries. Every time a foreign leader has visited Washington during the last few years, the State Department has made sure they sign such an agreement.

Likelihood of full governmental disclosure

Certain members of the civilian community are worried about how biometric data is used but full disclosure may not be forthcoming. In particular, the Unclassified Report of the United States' Defense Science Board Task Force on Defense Biometrics states that it is wise to protect, and sometimes even to disguise, the true and total extent of national capabilities in areas related directly to the conduct of security-related activities. This also potentially applies to Biometrics. It goes on to say that this is a classic feature of intelligence and military operations. In short, the goal is to preserve the security of 'sources and methods'.

Countries applying biometrics

Countries using biometrics include Australia, Brazil, Canada, Cyprus, Greece, China, Gambia, Germany, India, Iraq, Ireland, Israel, Italy, Malaysia, Netherlands, New Zealand, Nigeria, Norway, Pakistan, South Africa, Saudi Arabia, Tanzania, Ukraine, United Arab Emirates, United Kingdom, United States and Venezuela.

Among low to middle income countries, roughly 1.2 billion people have already received identification through a biometric identification program.

There are also numerous countries applying biometrics for voter registration and similar electoral purposes. According to the International IDEA's ICTs in Elections Database, some of the countries using (2017) Biometric Voter Registration (BVR) are Armenia, Angola, Bangladesh, Bhutan, Bolivia, Brazil, Burkina Faso, Cambodia, Cameroon, Chad, Colombia, Comoros, Congo (Democratic Republic of), Costa Rica, Ivory Coast, Dominican Republic, Fiji, Gambia, Ghana, Guatemala, India, Iraq, Kenya, Lesotho, Liberia, Malawi, Mali, Mauritania, Mexico, Morocco, Mozambique, Namibia, Nepal, Nicaragua, Nigeria, Panama, Peru, The Philippines, Senegal, Sierra Leone, Solomon Islands, Somaliland, Swaziland, Tanzania, Uganda, Uruguay, Venezuela, Yemen, Zambia, and Zimbabwe.

India's national ID program

India's national ID program called Aadhaar is the largest biometric database in the world. It is a biometrics-based digital identity assigned for a person's lifetime, verifiable online instantly in the public domain, at any time, from anywhere, in a paperless way. It is designed to enable government agencies to deliver a retail public service, securely based on biometric data (fingerprint, iris scan and face photo), along with demographic data (name, age, gender, address, parent/spouse name, mobile phone number) of a person. The data is transmitted in encrypted form over the internet for authentication, aiming to free it from the limitations of physical presence of a person at a given place.

About 550 million residents have been enrolled and assigned 480 million Aadhaar national identification numbers as of 7 November 2013. It aims to cover the entire population of 1.2 billion in a few years. However, it is being challenged by critics over privacy concerns and possible transformation of the state into a surveillance state, or into a Banana republic.§ The project was also met with mistrust regarding the safety of the social protection infrastructures. To tackle the fear amongst the people, India's supreme court put a new ruling into action that stated that privacy from then on was seen as a fundamental right. On 24 August 2017 this new law was established.

Prosopagnosia

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Prosopagnosia 

 

Prosopagnosia
Other names	Face blindness
The fusiform face area, the part of the brain associated with facial recognition
Pronunciation	/ˌprɒsəpæɡˈnoʊzɪə/
Specialty	Neurology

Prosopagnosia (from Greek prósōpon, meaning "face", and agnōsía, meaning "non-knowledge"), also called face blindness, is a cognitive disorder of face perception in which the ability to recognize familiar faces, including one's own face (self-recognition), is impaired, while other aspects of visual processing (e.g., object discrimination) and intellectual functioning (e.g., decision-making) remain intact. The term originally referred to a condition following acute brain damage (acquired prosopagnosia), but a congenital or developmental form of the disorder also exists, with a prevalence rate of 2.5%. The specific brain area usually associated with prosopagnosia is the fusiform gyrus, which activates specifically in response to faces. The functionality of the fusiform gyrus allows most people to recognize faces in more detail than they do similarly complex inanimate objects. For those with prosopagnosia, the new method for recognizing faces depends on the less sensitive object-recognition system. The right hemisphere fusiform gyrus is more often involved in familiar face recognition than the left. It remains unclear whether the fusiform gyrus is only specific for the recognition of human faces or if it is also involved in highly trained visual stimuli.

Acquired prosopagnosia results from occipito-temporal lobe damage and is most often found in adults. This is further subdivided into apperceptive and associative prosopagnosia. In congenital prosopagnosia, the individual never adequately develops the ability to recognize faces.

Though there have been several attempts at remediation, no therapies have demonstrated lasting real-world improvements across a group of prosopagnosics. Prosopagnosics often learn to use "piecemeal" or "feature-by-feature" recognition strategies. This may involve secondary clues such as clothing, gait, hair color, skin color, body shape, and voice. Because the face seems to function as an important identifying feature in memory, it can also be difficult for people with this condition to keep track of information about people, and socialize normally with others. Prosopagnosia has also been associated with other disorders that are associated with nearby brain areas: left hemianopsia (loss of vision from left side of space, associated with damage to the right occipital lobe), achromatopsia (a deficit in color perception often associated with unilateral or bilateral lesions in the temporo-occipital junction) and topographical disorientation (a loss of environmental familiarity and difficulties in using landmarks, associated with lesions in the posterior part of the parahippocampal gyrus and anterior part of the lingual gyrus of the right hemisphere). It is from the Greek: prosopon = "face" and agnosia = "not knowing".

The opposite of prosopagnosia is the skill of superior face recognition ability. People with this ability are called "super recognizers".

Types

Apperceptive

Apperceptive prosopagnosia has typically been used to describe cases of acquired prosopagnosia with some of the earliest processes in the face perception system. The brain areas thought to play a critical role in apperceptive prosopagnosia are right occipital temporal regions. People with this disorder cannot make any sense of faces and are unable to make same–different judgments when they are presented with pictures of different faces. They are unable to recognize both familiar and unfamiliar faces. In addition, apperceptive sub-types of prosopagnosia struggle recognizing facial emotion. However, they may be able to recognize people based on non-face clues such as their clothing, hairstyle, skin color, or voice. Apperceptive prosopagnosia is believed to be associated with impaired fusiform gyrus. It is interesting that experiments on the formation of new face detectors in adults on face-like stimuli (learning to distinguish the faces of cats) indicate that such new detectors are formed not in the fusiform, but in the lingual gyrus.

Associative

Associative prosopagnosia has typically been used to describe cases of acquired prosopagnosia with spared perceptual processes but impaired links between early face perception processes and the semantic information we hold about people in our memories. Right anterior temporal regions may also play a critical role in associative prosopagnosia. People with this form of the disorder may be able to tell whether photos of people's faces are the same or different and derive the age and sex from a face (suggesting they can make sense of some face information) but may not be able to subsequently identify the person or provide any information about them such as their name, occupation, or when they were last encountered. Associative prosopagnosia is thought to be due to impaired functioning of the parahippocampal gyrus.

Developmental

Developmental prosopagnosia (DP), also called congenital prosopagnosia (CP), is a face-recognition deficit that is lifelong, manifesting in early childhood, and that cannot be attributed to acquired brain damage. A number of studies have found functional deficits in DP both on the basis of EEG measures and fMRI. It has been suggested that a genetic factor is responsible for the condition. The term "hereditary prosopagnosia" was introduced if DP affected more than one family member, essentially accenting the possible genetic contribution of this condition. To examine this possible genetic factor, 689 randomly selected students were administered a survey in which seventeen developmental prosopagnosics were quantifiably identified. Family members of fourteen of the DP individuals were interviewed to determine prosopagnosia-like characteristics, and in all fourteen families, at least one other affected family member was found.

In 2005, a study led by Ingo Kennerknecht showed support for the proposed congenital disorder form of prosopagnosia. This study provides epidemiological evidence that congenital prosopagnosia is a frequently occurring cognitive disorder that often runs in families. The analysis of pedigree trees formed within the study also indicates that the segregation pattern of hereditary prosopagnosia (HPA) is fully compatible with autosomal dominant inheritance. This mode of inheritance explains why HPA is so common among certain families (Kennerknecht et al. 2006).

Cause

Prosopagnosia can be caused by lesions in various parts of the inferior occipital areas (occipital face area), fusiform gyrus (fusiform face area), and the anterior temporal cortex. Positron emission tomography (PET) and fMRI scans have shown that, in individuals without prosopagnosia, these areas are activated specifically in response to face stimuli. The inferior occipital areas are mainly involved in the early stages of face perception and the anterior temporal structures integrate specific information about the face, voice, and name of a familiar person.

Acquired prosopagnosia can develop as the result of several neurologically damaging causes. Vascular causes of prosopagnosia include posterior cerebral artery infarcts (PCAIs) and hemorrhages in the infero-medial part of the temporo-occipital area. These can be either bilateral or unilateral, but if they are unilateral, they are almost always in the right hemisphere. Recent studies have confirmed that right hemisphere damage to the specific temporo-occipital areas mentioned above is sufficient to induce prosopagnosia. MRI scans of patients with prosopagnosia showed lesions isolated to the right hemisphere, while fMRI scans showed that the left hemisphere was functioning normally. Unilateral left temporo-occipital lesions result in object agnosia, but spare face recognition processes, although a few cases have been documented where left unilateral damage resulted in prosopagnosia. It has been suggested that these face recognition impairments caused by left hemisphere damage are due to a semantic defect blocking retrieval processes that are involved in obtaining person-specific semantic information from the visual modality.

Other less common etiologies include carbon monoxide poisoning, temporal lobectomy, encephalitis, neoplasm, right temporal lobe atrophy, injury, Parkinson's disease, and Alzheimer's disease.

Diagnosis

There are few neuropsychological assessments that can definitively diagnose prosopagnosia. One commonly used test is the famous faces tests, where individuals are asked to recognize the faces of famous persons. However, this test is difficult to standardize. The Benton Facial Recognition Test (BFRT) is another test used by neuropsychologists to assess face recognition skills. Individuals are presented with a target face above six test faces and are asked to identify which test face matches the target face. The images are cropped to eliminate hair and clothes, as many people with prosopagnosia use hair and clothing cues to recognize faces. Both male and female faces are used during the test. For the first six items only one test face matches the target face; during the next seven items, three of the test faces match the target faces and the poses are different. The reliability of the BFRT was questioned when a study conducted by Duchaine and Nakayama showed that the average score for 11 self-reported prosopagnosics was within the normal range.

The test may be useful for identifying patients with apperceptive prosopagnosia, since this is mainly a matching test and they are unable to recognize both familiar and unfamiliar faces. They would be unable to pass the test. It would not be useful in diagnosing patients with associative prosopagnosia since they are able to match faces.

The Cambridge Face Memory Test (CFMT) was developed by Duchaine and Nakayama to better diagnose people with prosopagnosia. This test initially presents individuals with three images each of six different target faces. They are then presented with many three-image series, which contain one image of a target face and two distracters. Duchaine and Nakayama showed that the CFMT is more accurate and efficient than previous tests in diagnosing patients with prosopagnosia. Their study compared the two tests and 75% of patients were diagnosed by the CFMT, while only 25% of patients were diagnosed by the BFRT. However, similar to the BFRT, patients are being asked to essentially match unfamiliar faces, as they are seen only briefly at the start of the test. The test is not currently widely used and will need further testing before it can be considered reliable.

The 20-item Prosopagnosia Index (PI20) is a freely available and validated self-report questionnaire that can be used alongside computer-based face recognition tests to help identify individuals with prosopagnosia. It has been validated using objective measures of face perception ability including famous face recognition tests and the Cambridge Face Memory Test. Less than 1.5% of the general population score above 65 on the PI20 and less than 65% on the CFMT.

Prognosis

Management strategies for acquired prosopagnosia, such as a person who has difficulty recognizing people's faces after a stroke, generally have a low rate of success. Acquired prosopagnosia sometimes spontaneously resolves on its own.

History

Selective inabilities to recognize faces were documented as early as the 19th century, and included case studies by Hughlings Jackson and Charcot. However, it was not named until the term prosopagnosia was first used in 1947 by Joachim Bodamer [de], a German neurologist. He described three cases, including a 24-year-old man who suffered a bullet wound to the head and lost his ability to recognize his friends, family, and even his own face. However, he was able to recognize and identify them through other sensory modalities such as auditory, tactile, and even other visual stimuli patterns (such as gait and other physical mannerisms). Bodamer gave his paper the title Die Prosop-Agnosie, derived from Classical Greek πρόσωπον (prósōpon) meaning "face" and αγνωσία (agnōsía) meaning "non-knowledge". In October 1996, Bill Choisser began popularizing the term face blindness for this condition; the earliest-known use of the term is in an 1899 medical paper.

A case of a prosopagnosia is "Dr P." in Oliver Sacks' 1985 book The Man Who Mistook His Wife for a Hat, though this is more properly considered to be one of a more general visual agnosia. Although Dr P. could not recognize his wife from her face, he was able to recognize her by her voice. His recognition of pictures of his family and friends appeared to be based on highly specific features, such as his brother's square jaw and big teeth. Oliver Sacks himself suffered from prosopagnosia, but did not know it for much of his life.

The study of prosopagnosia has been crucial in the development of theories of face perception. Because prosopagnosia is not a unitary disorder (i.e., different people may show different types and levels of impairment), it has been argued that face perception involves a number of stages, each of which can cause qualitative differences in impairment that different persons with prosopagnosia may exhibit.

This sort of evidence has been crucial in supporting the theory that there may be a specific face perception system in the brain. Most researchers agree that the facial perception process is holistic rather than featural, as it is for perception of most objects. A holistic perception of the face does not involve any explicit representation of local features (i.e., eyes, nose, mouth, etc.), but rather considers the face as a whole. Because the prototypical face has a specific spatial layout (eyes are always located above nose, and nose located above mouth), it is beneficial to use a holistic approach to recognize individual/specific faces from a group of similar layouts. This holistic processing of the face is exactly what is damaged in prosopagnosics. They are able to recognize the specific spatial layout and characteristics of facial features, but they are unable to process them as one entire face. This is counterintuitive to many people, as not everyone believes faces are "special" or perceived in a different way from other objects in the rest of the world. Though evidence suggests that other visual objects are processed in a holistic manner (e.g., dogs in dog experts), the size of these effects are smaller and are less consistently demonstrated than with faces. In a study conducted by Diamond and Carey, they showed this to be true by performing tests on dog-show judges. They showed pictures of dogs to the judges and to a control group and they then inverted those same pictures and showed them again. The dog-show judges had greater difficulty in recognizing the dogs once inverted compared to the control group; the inversion effect, the increased difficulty in recognizing a picture once inverted, was shown to be in effect. It was previously believed that the inversion effect was associated only with faces, but this study shows that it may apply to any category of expertise.

It has also been argued that prosopagnosia may be a general impairment in understanding how individual perceptual components make up the structure or gestalt of an object. Psychologist Martha Farah has been particularly associated with this view.

Children

Developmental prosopagnosia can be a difficult thing for a child to both understand and cope with. Many adults with developmental prosopagnosia report that for a long time they had no idea that they had a deficit in face processing, unaware that others could distinguish people solely on facial differences.

Prosopagnosia in children may be overlooked; they may just appear to be very shy or slightly odd due to their inability to recognize faces. They may also have a hard time making friends, as they may not recognize their classmates. They often make friends with children who have very clear, distinguishing features.

Children with prosopagnosia may also have difficulties following the plots of television shows and movies, as they have trouble recognizing the different characters. They tend to gravitate towards cartoons, in which characters have simple but well-defined characteristics, and tend to wear the same clothes, may be strikingly different colours or even different species. Prosopagnosiac children even have a hard time telling family members apart, or recognizing people out of context (e.g., the teacher in a grocery store). Some have difficulty recognising themselves in group photographs.

Additionally, children with prosopagnosia can have a difficult time at school, as many school professionals are not well versed in prosopagnosia, if they are aware of the disorder at all.

Notable people with prosopagnosia

• Robert Gascoyne-Cecil, 3rd Marquess of Salisbury (1830–1903)
• Oliver Sacks (1933–2015), British neurologist
• Jane Goodall (born 1934), English primatologist
• Chuck Close (born 1949), American painter
• Duncan Bannatyne (born 1949), Scottish entrepreneur
• Steve Wozniak (born 1950), American computer engineer and co-founder of Apple Inc.

• John Hickenlooper (born 1952), former Governor of Colorado
• Jim Woodring (born 1952), American cartoonist
• Stephen Fry (born 1957), English actor
• Mary Ann Sieghart (born 1961), English journalist and radio presenter
• Margaret Kerry (born 1929), American actress and reference model for Tinker Bell
• Markos Moulitsas (born 1971), American blogger and former member of the military
• Victoria, Crown Princess of Sweden (born 1977)
• Karl Kruszelnicki, Australian science communicator