Central visual pathways affected by degenerative retinal disease before and after gene therapy.

Genetic diseases affecting the retina can result in partial or complete loss of visual function. Leber's congenital amaurosis (LCA) is a rare blinding disease, usually inherited in an autosomally recessive manner, with no cure. Retinal gene therapy has been shown to improve vision in LCA patients caused by mutations in the RPE65 gene (LCA2). However, little is known about how activity in central visual pathways is affected by the disease or by subsequent gene therapy. Functional MRI (fMRI) was used to assess retinal signal transmission in cortical and subcortical visual structures before and 1 year after retinal intervention. The fMRI paradigm consisted of 15-s blocks of flickering (8 Hz) black and white checkerboards interleaved with 15 s of blank (black) screen. Visual activation in the brain was assessed using the general linear model, with multiple comparisons corrected using the false discovery rate method. Response to visual stimulation through untreated eyes of LCA2 patients showed heightened fMRI responses in the superior colliculus and diminished activities in the lateral geniculate nucleus (LGN) compared to controls, indicating a shift in the patients' visual processing towards the retinotectal pathway. Following gene therapy, stimuli presented to the treated eye elicited significantly stronger fMRI responses in the LGN and primary visual cortex, indicating some re-engagement of the geniculostriate pathway (GS) pathway. Across patients, the post-treatment LGN fMRI responses correlated significantly with performance on a clinical test measuring light sensitivity. Our results demonstrate that the low vision observed in LCA2 patients involves a shift in visual processing toward the retinotectal pathway, and that gene therapy partially reinstates visual transmission through the GS pathway. This selective boosting of retinal output through the GS pathway and its correlation to improved visual performance, following several years of degenerative retinal disease, is striking. However, while retinal gene therapy and other ocular interventions have given hope to RPE65 patients, it may take years before development of therapies tailored to treat the diseases in other low vision patients are available. Our demonstration of a shift toward the retinotectal pathway in these patients may spur the development of new tools and rehabilitation strategies to help maximize the use of residual visual abilities and augment experience-dependent plasticity.

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM. DESIGN: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial. PARTICIPANTS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS: Patients received uniocular subfoveal injections of low-dose (up to 5 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. MAIN OUTCOME MEASURES: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.

BACKGROUND: Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study. METHODS: In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1.5 × 10(11) vector genomes) in a total volume of 300 µL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11-46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1.71-4.58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. FINDINGS: No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0.0003, white light full-field sensitivity p<0.0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0.7398, white light full-field sensitivity p=0.6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0.49 for all time-points compared with baseline). INTERPRETATION: To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. FUNDING: Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation-Flanders.

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

PURPOSE: Gene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT. DESIGN: Individuals with RPE65 mutations who underwent GT in their worse-seeing eye in a phase 1 clinical trial received a second subretinal injection in their contralateral eye in a follow-on clinical trial. Functional magnetic resonance imaging (MRI) was performed longitudinally to assess brain responses of patients with RPE65 mutations after stimulation of their most recently treated eye before and 1 to 3 years after GT. PARTICIPANTS: Seven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study. METHODS: All participants underwent fMRI using a 3-Tesla MRI system and a 32-channel head coil. Participants' cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI-compatible video system. MAIN OUTCOME MEASURES: The primary parameters being measured in this study were the qualitative and quantitative fMRI cortical activations produced by our population in response to the visual task. RESULTS: Functional MRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least 3 years after GT was observed for all participants. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full-field light sensitivity threshold for white, red, and blue colors; visual field; and pupillary light reflex. CONCLUSIONS: Participants with RPE65 mutations showed intact visual pathways, which became responsive and strengthened after treatment. Functional MRI results independently revealed the efficacy and durability of a 1-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same patients. Results from this study demonstrated that fMRI may play an important role in providing complementary information to patients' ophthalmic clinical evaluation and has usefulness as an outcome measure for future retinal intervention studies.

Effect of socioeconomic status (SES) disparity on neural development in female African-American infants at age 1 month.

There is increasing interest in both the cumulative and long-term impact of early life adversity on brain structure and function, especially as the brain is both highly vulnerable and highly adaptive during childhood. Relationships between SES and neural development have been shown in children older than age 2 years. Less is known regarding the impact of SES on neural development in children before age 2. This paper examines the effect of SES, indexed by income-to-needs (ITN) and maternal education, on cortical gray, deep gray, and white matter volumes in term, healthy, appropriate for gestational age, African-American, female infants. At 5 weeks postnatal age, unsedated infants underwent MRI (3.0T Siemens Verio scanner, 32-channel head coil). Images were segmented based on a locally constructed template. Utilizing hierarchical linear regression, SES effects on MRI volumes were examined. In this cohort of healthy African-American female infants of varying SES, lower SES was associated with smaller cortical gray and deep gray matter volumes. These SES effects on neural outcome at such a young age build on similar studies of older children, suggesting that the biological embedding of adversity may occur very early in development.

Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation.

We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic 'butterfly'-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term 'diencephalic-mesencephalic junction dysplasia' to characterize this autosomal recessive malformation.

Motion-selective areas V5/MT and MST appear resistant to deterioration in choroideremia.

Choroideremia (CHM) is an X-linked recessive form of hereditary retinal degeneration, which preserves only small islands of central retinal tissue. Previously, we demonstrated the relationship between central vision and structure and population receptive fields (pRF) using functional magnetic resonance imaging (fMRI) in untreated CHM subjects. Here, we replicate and extend this work, providing a more in-depth analysis of the visual responses in a cohort of CHM subjects who participated in a retinal gene therapy clinical trial. fMRI was conducted in six CHM subjects and six age-matched healthy controls (HC's) while they viewed drifting contrast pattern stimuli monocularly. A single ∼3-minute fMRI run was collected for each eye. Participants also underwent ophthalmic evaluations of visual acuity and static automatic perimetry (SAP). Consistent with our previous report, a single âˆ¼ 3 min fMRI run accurately characterized ophthalmic evaluations of visual function in most CHM subjects. In-depth analyses of the cortical distribution of pRF responses revealed that the motion-selective regions V5/MT and MST appear resistant to progressive retinal degenerations in CHM subjects. This effect was restricted to V5/MT and MST and was not present in either primary visual cortex (V1), motion-selective V3A or regions within the ventral visual pathway. Motion-selective areas V5/MT and MST appear to be resistant to the continuous detrimental impact of CHM. Such resilience appears selective to these areas and may be mediated by independent retina-V5/MT anatomical connections that bypass V1. We did not observe any significant impact of gene therapy.

Dynamic structural remodeling of the human visual system prompted by bilateral retinal gene therapy.

The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge on human brain plasticity of the visual systems comes from animal studies. Reinstating vision in a group of patients with low vision through retinal gene therapy creates a unique opportunity to dynamically study the underlying process responsible for brain plasticity. Historically, increases in the axonal myelination of the visual pathway has been the biomarker for brain plasticity. Here, we demonstrate that to reach the long-term effects of myelination increase, the human brain may undergo demyelination as part of a plasticity process. The maximum change in dendritic arborization of the primary visual cortex and the neurite density along the geniculostriate tracks occurred at three months (3MO) post intervention, in line with timing for the peak changes in postnatal synaptogenesis within the visual cortex reported in animal studies. The maximum change at 3MO for both the gray and white matter significantly correlated with patients' clinical responses to light stimulations called full field sensitivity threshold (FST). Our results shed a new light on the underlying process of brain plasticity by challenging the concept of increase myelination being the hallmark of brain plasticity and instead reinforcing the idea of signal speed optimization as a dynamic process for brain plasticity.

Neuroplasticity of the Lateral Geniculate Nucleus in Response to Retinal Gene Therapy in a Group of Patients with RPE65 Mutations.

Introduction: Previous works on experience-dependent brain plasticity have been limited to the cortical structures, overlooking subcortical visual structures such as the lateral geniculate nucleus (LGN). Animal studies have shown substantial experience dependent plasticity and using fMRI, human studies have demonstrated similar properties in patients with cataract surgery. However, in neither animal nor human studies LGN has not been directly assessed, mainly due to its small size, tissue heterogeneity, low contrast/noise ratio, and low spatial resolution. Methods: Utilizing a new algorithm that markedly improves the LGN visibility, LGN was evaluated in a group of low vision patients before and after retinal intervention to reinstate vision and normal sighted matched controls. Results: Between and within groups comparisons showed that patients had significantly smaller left (p< 0.0001) and right (p < 0.00002) LGN volumes at baseline as compared to the one-year follow-up volumes. The same baseline and one year comparison in controls was not significant. Significant positive correlations were observed between the incremental volume increase after gene therapy of the left LGN and the incremental increase in the right (r = 0.71, p < 0.02) and left (r = 0.72, p = 0.018) visual fields. Incremental volume increase of the right LGN also showed a similar positive slope but did not reach significance. Discussion: These results show that despite significantly less volume at baseline, retinal gene therapy promotes robust expansion and increase in LGN volume. Reinstating vision may have facilitated the establishment of new connections between the retina and the LGN and/or unmasking of the dormant connections. The exact trajectory of the structural changes taking place in LGN is unclear but our data shows that even after years of low vision, the LGN in RPE65 patients has the potential for plasticity and expansion to a nearly normal volume one year after gene therapy administration.

Resolving axon fiber crossings at clinical b-values: an evaluation study.

PURPOSE: Diffusion tensor magnetic resonance imaging is widely used to study the structure of the fiber pathways of brain white matter. However, the diffusion tensor cannot capture complex intravoxel fiber architecture such as fiber crossings of bifurcations. Consequently, a number of methods have been proposed to recover intravoxel fiber bundle orientations from high angular resolution diffusion imaging scans, optimized to resolve fiber crossings. It is important to improve the brain tractography by applying these multifiber methods to diffusion tensor protocols with a clinical b- value (low), which are optimized on computing tensor scalar statistics. In order to characterize the variance among different methods, consequently to be able to select the most appropriate one for a particular application, it is desirable to compare them under identical experimental conditions. METHODS: In this work, the authors study how QBall, spherical deconvolution, persistent angular structure, stick and ball, diffusion basis functions, and analytical QBall methods perform under clinically-realistic scanning conditions, where the b-value is typically lower (around 1000 s∕mm(2)), and the number of diffusion encoding orientations is fewer (30-60) than in dedicated high angular resolution diffusion imaging scans. To characterize the performance of the methods, they consider the accuracy of the estimated number of fibers, the relative contribution of each fiber population to the total magnetic resonance signal, and the recovered orientation error for each fiber bundle. To this aim, they use four different sources of data: synthetic data from Gaussian mixture model, cylinder restricted model, and in vivo data from two different acquisition schemes. RESULTS: Results of their experiments indicate that: (a) it is feasible to apply only a subset of these methods to clinical data sets and (b) it allows one to characterize the performance of each method. In particular, two methods are not feasible to the kind of magnetic resonance diffusion data they test. By the characterization of their systematic behavior, among other conclusions, they report the method which better performs for the estimation of the number of diffusion peaks per voxel, also the method which better estimates the diffusion orientation. CONCLUSIONS: The framework they propose for comparison allows one to effectively characterize and compare the performance of the most frequently used multifiber algorithms under realistic medical settings and realistic signal-to-noise ratio environments. The framework is based on several crossings with a non-orientational bias and different signal models. The results they present are relevant for medical doctors and researchers, interested in the use of the multifiber solution for tractography.

Improving the Quantification of the Lateral Geniculate Nucleus in Magnetic Resonance Imaging Using a Novel 3D-Edge Enhancement Technique.

The lateral geniculate nucleus (LGN) is a small, inhomogeneous structure that relays major sensory inputs from the retina to the visual cortex. LGN morphology has been intensively studied due to various retinal diseases, as well as in the context of normal brain development. However, many of the methods used for LGN structural evaluations have not adequately addressed the challenges presented by the suboptimal routine MRI imaging of this structure. Here, we propose a novel method of edge enhancement that allows for high reliability and accuracy with regard to LGN morphometry, using routine 3D-MRI imaging protocols. This new algorithm is based on modeling a small brain structure as a polyhedron with its faces, edges, and vertices fitted with one plane, the intersection of two planes, and the intersection of three planes, respectively. This algorithm dramatically increases the contrast-to-noise ratio between the LGN and its surrounding structures as well as doubling the original spatial resolution. To show the algorithm efficacy, two raters (MA and ML) measured LGN volumes bilaterally in 19 subjects using the edge-enhanced LGN extracted areas from the 3D-T1 weighted images. The averages of the left and right LGN volumes from the two raters were 175 ± 8 and 174 ± 9 mm3, respectively. The intra-class correlations between raters were 0.74 for the left and 0.81 for the right LGN volumes. The high contrast edge-enhanced LGN images presented here, from a 7-min routine 3T-MRI acquisition, is qualitatively comparable to previously reported LGN images that were acquired using a proton density sequence with 30-40 averages and 1.5-h of acquisition time. The proposed edge-enhancement algorithm is not limited only to the LGN, but can significantly improve the contrast-to-noise ratio of any small deep-seated gray matter brain structure that is prone to high-levels of noise and partial volume effects, and can also increase their morphometric accuracy and reliability. An immensely useful feature of the proposed algorithm is that it can be used retrospectively on noisy and low contrast 3D brain images previously acquired as part of any routine clinical MRI visit.

Compensatory Cross-Modal Plasticity Persists After Sight Restoration.

Sensory deprivation prompts extensive structural and functional reorganizations of the cortex resulting in the occupation of space for the lost sense by the intact sensory systems. This process, known as cross-modal plasticity, has been widely studied in individuals with vision or hearing loss. However, little is known on the neuroplastic changes in restoring the deprived sense. Some reports consider the cross-modal functionality maladaptive to the return of the original sense, and others view this as a critical process in maintaining the neurons of the deprived sense active and operational. These controversial views have been challenged in both auditory and vision restoration reports for decades. Recently with the approval of Luxturna as the first retinal gene therapy (GT) drug to reverse blindness, there is a renewed interest for the crucial role of cross-modal plasticity on sight restoration. Employing a battery of task and resting state functional magnetic resonance imaging (rsfMRI), in comparison to a group of sighted controls, we tracked the functional changes in response to auditory and visual stimuli and at rest, in a group of patients with biallelic mutations in the RPE65 gene ("RPE65 patients") before and 3 years after GT. While the sighted controls did not present any evidence for auditory cross-modal plasticity, robust responses to the auditory stimuli were found in occipital cortex of the RPE65 patients overlapping visual responses and significantly elevated 3 years after GT. The rsfMRI results showed significant connectivity between the auditory and visual areas for both groups albeit attenuated in patients at baseline but enhanced 3 years after GT. Taken together, these findings demonstrate that (1) RPE65 patients present with an auditory cross-modal component; (2) visual and non-visual responses of the visual cortex are considerably enhanced after vision restoration; and (3) auditory cross-modal functions did not adversely affect the success of vision restitution. We hypothesize that following GT, to meet the demand for the newly established retinal signals, remaining or dormant visual neurons are revived or unmasked for greater participation. These neurons or a subset of these neurons respond to both the visual and non-visual demands and further strengthen connectivity between the auditory and visual cortices.

Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use.

BACKGROUND: There is growing evidence that adolescence is a key period for neuronal maturation. Despite the high prevalence of marijuana use among adolescents and young adults in the United States and internationally, very little is known about its impact on the developing brain. Based on neuroimaging literature on normal brain developmental during adolescence, we hypothesized that individuals with heavy cannabis use (HCU) would have brain structure abnormalities in similar brain regions that undergo development during late adolescence, particularly the fronto-temporal connection. METHOD: Fourteen young adult males in residential treatment for cannabis dependence and 14 age-matched healthy male control subjects were recruited. Patients had a history of HCU throughout adolescence; 5 had concurrent alcohol abuse. Subjects underwent structural and diffusion tensor magnetic resonance imaging. White matter integrity was compared between subject groups using voxelwise and fiber tractography analysis. RESULTS: Voxelwise and tractography analyses revealed that adolescents with HCU had reduced fractional anisotropy, increased radial diffusivity, and increased trace in the homologous areas known to be involved in ongoing development during late adolescence, particularly in the fronto-temporal connection via arcuate fasciculus. CONCLUSIONS: Our results support the hypothesis that heavy cannabis use during adolescence may affect the trajectory of normal brain maturation. Due to concurrent alcohol consumption in five HCU subjects, conclusions from this study should be considered preliminary, as the DTI findings reported here may be reflective of the combination of alcohol and marijuana use. Further research in larger samples, longitudinal in nature, and controlling for alcohol consumption is needed to better understand the pathophysiology of the effect of cannabis on the developing brain.

Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia.

The objective of this study was to investigate the clinical and neuropsychological correlates of white matter abnormalities in patients with schizophrenia studied early in the course of illness. A total of 33 (21 male/12 female) patients with recent onset schizophrenia and 30 (18 male/12 female) healthy volunteers completed structural and diffusion tensor imaging exams. Patients also received clinical and neuropsychological assessments. Fractional anisotropy (FA) maps were compared between groups in the white matter using a voxelwise analysis following intersubject registration to Talairach space and correlated with functional indices. Compared to healthy volunteers, patients demonstrated significantly (p<0.001, cluster size >or=100) lower FA within temporal lobe white matter regions corresponding approximately to the right and left uncinate fasciculus, left inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. There were no areas of significantly higher FA in patients compared to healthy volunteers. Lower FA in the bilateral uncinate fasciculus correlated significantly with greater severity of negative symptoms (alogia and affective flattening), and worse verbal learning/memory functioning. In addition, higher FA in the inferior fronto-occipital fasciculus correlated significantly with greater severity of delusions and hallucinations. White matter abnormalities are evident in patients with schizophrenia early in the course of illness, appearing most robust in left temporal regions. These abnormalities have clinical and neuropsychological correlates, which may be useful in further characterizing structure-function relations in schizophrenia and constraining neurobiological models of the disorder.

Gray matter structural alterations in obsessive-compulsive disorder: relationship to neuropsychological functions.

Numerous magnetic resonance (MR) studies have examined gray matter structural alterations in patients with obsessive-compulsive disorder (OCD). Few, however, have used automated, highly reliable techniques such as voxel-based morphometry (VBM) to examine the entire brain in contrast to selected regions of interest. Moreover, few studies have examined the functional correlates of gray matter abnormalities in OCD. We used VBM to evaluate regional gray matter differences between 21 OCD patients and 21 age- and sex-matched healthy volunteers. All patients had comprehensive neuropsychological assessments. MR images were normalized to a customized template and segmented using optimized VBM. OCD patients had significantly more gray matter in the left thalamus compared with healthy volunteers. OCD patients without major depression had significantly more gray matter in the thalamus (bilaterally) and left orbitofrontal cortex as well as an unpredicted region of more right dorsolateral prefrontal gray matter, which remained significant after correction for multiple comparisons, compared with healthy volunteers. In the subgroup of patients without depression, greater right hemisphere thalamic and dorsolateral prefrontal gray matter correlated significantly with worse motor functioning and processing speed, respectively. In this subgroup there was also a tendency for more gray matter in the left orbitofrontal cortex and right dorsolateral prefrontal cortex to be associated with greater symptom severity. Our findings provide additional support for the involvement of cortical-striatal-thalamic circuits in the pathophysiology of OCD and preliminary evidence that a defect involving the dorsolateral prefrontal cortex may also be implicated. Moreover, our data suggest that gray matter structural alterations in OCD have neuropsychological correlates, which may be useful in further characterizing structure-function relations in this disorder.

Comparing Clinical Perimetry and Population Receptive Field Measures in Patients with Choroideremia.

Purpose: Choroideremia (CHM) is an X-linked recessive form of hereditary retinal degeneration, which, at advanced stages, leaves only small central islands of preserved retinal tissue. Unlike many other retinal diseases, the spared tissue in CHM supports excellent central vision and stable fixation. Such spared topography in CHM presents an ideal platform to explore the relationship between preserved central retinal structure and the retinotopic organization of visual cortex by using functional magnetic resonance imaging (fMRI). Methods: fMRI was conducted in four participants with CHM and four healthy control participants while they viewed drifting contrast pattern stimuli monocularly. A single ∼3-minute fMRI run was collected for each eye separately. fMRI data were analyzed using the population receptive field (pRF) modeling approach. Participants also underwent ophthalmic evaluations of visual acuity and static automatic perimetry. Results: The spatial distribution and strength of pRF estimates correlated positively and significantly with clinical outcome measures in most participants with CHM. Importantly, the positive relationship between clinical and pRF measurements increased with increasing disease progression. A less consistent relationship was observed for control participants. Conclusions: Although reflecting only a small sample size, clinical evaluations of visual function in participants with CHM were well characterized by the spatial distribution and strength of pRF estimates by using a single ∼3-minute fMRI experiment. fMRI data analyzed with pRF modeling may be an efficient and objective outcome measure to complement current ophthalmic evaluations. Specifically, pRF modeling may be a feasible approach for evaluating the impact of interventions to restore visual function.

Cortisol levels in relation to hippocampal sub-regions in subjects with first episode schizophrenia.

The etiology of hippocampal volumetric reductions in schizophrenia is largely unknown. In addition to genetic factors, environmental factors might also play a role. High levels of glucocorticoids are known to affect hippocampal volume in disorders such as Cushing's syndrome, but the relationship between cortisol and hippocampal volumes has not been studied in schizophrenia. We obtained diurnal salivary cortisol levels and MRI images to explore the link between cortisol levels and regional hippocampal volumes in healthy controls (N=29) and subjects with first episode schizophrenia (N=16) at the time of first admission. T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Using ANOVA, cumulative daily cortisol exposure calculated as area under the curve for each subject revealed significantly higher cortisol levels in the patient group [F(1,43)=4.4 p=0.04]. However, there were no statistically significant associations between the cortisol measures and regional hippocampal volumes in the subjects, except a trend level link between anterior hippocampal volume and cortisol in the positive direction, in parallel to previous findings in healthy adolescents. Our findings do not suggest a robust association between cortisol levels and hippocampal volumes in a first episode schizophrenia sample. Larger scale studies are needed to conclude a link between the two measures, yet it is possible that the negative association that was previously shown in other disorders may not apply to schizophrenia.

CSF sub-compartments in relation to plasma osmolality in healthy controls and in patients with first episode schizophrenia.

Preliminary evidence suggests that plasma Na(+) level/osmolality may have effects on brain morphology; thus we investigated the link between plasma osmolality and ventricle size in healthy controls and patients with first episode schizophrenia. A total of 16 patients and 28 healthy controls were examined with magnetic resonance imaging (MRI) and gave blood samples. High-resolution 3D SPGR images were obtained on a 1.5 Tesla scanner. Scalp-edited MRI volumes were used for estimates of intracranial gray, white matter and CSF. Regional changes in CSF concentration and ventricular morphology were measured. The groups did not differ in plasma osmolality, but patients had higher plasma Na(+). There were no differences in ventricle size. Controlling for plasma osmolality did not change the results. A mixed model procedure indicated a significant group effect and a significant osmolality by group interaction in ventricle measures. Healthy control group showed a significant relationship between osmolality and ventricle measures; this relationship was absent in the patients. Significant correlations between osmolality and lateral ventricle surface deformations were observed along the superior horn of the lateral ventricles in the healthy controls. These results suggest that plasma osmolality is related to ventricle size in healthy volunteers and that this physiological link is impaired in patients with first episode schizophrenia.

Increased stress and smaller anterior hippocampal volume.

Animal studies indicate that stress negatively impacts hippocampal structure; little is known, however, regarding the relationship between stress and hippocampal morphology in healthy humans. Twenty-one healthy adults underwent structural magnetic resonance imaging examinations and completed the Derogatis Stress Profile. Greater psychological stress at the time of the scan correlated significantly and more strongly with anterior than posterior hippocampal volume. These findings suggest that psychological stress may be associated with structural alterations in the anterior hippocampal formation and that this relationship may differ along the rostrocaudal axis of the hippocampus. Our results may also have implications for neuropsychiatric disorders that have implicated stress and hippocampal abnormalities in their pathogenesis.