A demonstration of cone function plasticity after gene therapy in achromatopsia.

Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.

Development of the spatial contrast sensitivity function (CSF) during childhood: Analysis of previous findings and new psychophysical data.

Although the contrast sensitivity function (CSF) changes markedly during infancy, there is no consensus regarding whether, how, and why it continues to develop in later childhood. Here, we analyzed previously published data (N = 1928 CSFs), and present new psychophysical findings from 98 children (4.7-14.8 years) and 50 adults (18.1-29.7 years), in order to answer the following questions: (1) Does the CSF change during childhood? (2) How large is the developmental effect size? (3) Are any changes uniform across the CSF, or frequency-specific? and (4) Can some or all of the changes be explained by "non-visual" (i.e. procedural/cognitive) factors, such as boredom or inattentiveness? The new data were collected using a four-alternative forced-choice (4AFC) Gabor-detection task, with two different psychophysical procedures (Weighted Staircase; QUEST+), and suprathreshold (false-negative) catch trials to quantify lapse rates. It is shown that from ages 4 to 18 years, the CSF improves (at an exponentially decaying rate) by approximately 0.3 log10 units (a doubling of contrast sensitivity [CS]), with 90% of this change complete by 12 years of age. The size of the effect was small relative to individual variability, with age alone explaining less than one sixth of variability (16%), and most children performing as well as some adults (i.e. falling within the 90% population limits for adults). Development was frequency-specific, with changes occurring primarily around or below the CSF peak (≤ 4 cpd). At least half - and potentially all - of the changes observed could be explained by non-visual factors (e.g. lapses in concentration), although possible biological mechanisms are discussed.

Psychophysics with children: Evaluating the use of maximum likelihood estimators in children aged 4-15 years (QUEST+).

Maximum Likelihood (ML) estimators such as QUEST+ allow complex psychophysical measurements to be made more quickly and precisely than traditional staircase techniques. They could therefore be useful for quantifying sensory function in populations with limited attention spans, such as children. To test this, the present study empirically evaluated the performance of an ML estimator (QUEST+) versus a traditional Up-Down Weighted Staircase in children and adults. Seventy-one children (4.7-14.7 years) and 43 adults (18.1-29.6 years) completed a typical psychophysical procedure: Contrast Sensitivity Function (CSF) determination. Some participants were tested twice with the same method (QUEST+ or Staircase), allowing test-retest repeatability to be quantified. Others were tested once each with either method (QUEST+ and Staircase), allowing accuracy to be quantified. The results showed that QUEST+ was more efficient: In both children and adults, approximately half the number of ML trials were required to attain comparable levels of accuracy and reliability as a traditional Staircase paradigm, and plausible CSF estimates could be made in even the youngest children. The ML procedure was also as robust as the Staircase to lapses in concentration, and its performance did not depend on prespecifying correct model priors. The results show that ML estimators could greatly improve our ability to study sensory processes and detect impairments in children, although important practical considerations for-and-against their use are discussed.

fMRI and gene therapy in adults with CNGB3 mutation.

Achromatopsia is an inherited retinal disease that affects 1 in 30,000-50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.