Search

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 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.Neuropsychopharmacology (2008) 33, 976–984; doi:10.1038/sj.npp.1301480; published online 20 June 2007 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Los autores compararon las alteraciones volumétricas de la formación hipocampal anterior en pacientes que experimentaban un primer episodio de esquizofrenia con individuos sanos de control. Método: A partir de imágenes coronales adyacentes, de 1,5 mm, obtenidas por resonancia magnética se dividió la formación hipocampal en un segmento anterior y otro posterior, y se separó la formación hipocampal anterior de la amígdala. Se calcularon los volúmenes de la formación hipocampal anterior y posterior y de la amígdala en 46 pacientes (31 varones y 15 mujeres) que experimentaban un primer episodio de esquizofrenia y en 34 individuos sanos de control (21 varones y 13 mujeres). En el momento de realizar la tomografía, 24 pacientes nunca se habían tratado con fármacos antipsicóticos. Resultados: Los pacientes mostraron un volumen total de la formación hipocampal anterior (derecha e izquierda) significativamente menor que los individuos sanos de control, mientras que los volúmenes de la formación hipocampal posterior y de la amígdala no difirieron. Se obtuvieron resultados similares cuando los análisis se limitaron al subgrupo de pacientes que no se habían tratado con antipsicóticos. Condusiones: Estos resultados indican que las anomalías volumétricas del complejo hipocampo-amígdala podrían ser específicas de la formación hipocampal anterior en los pacientes que experimentan un primer episodio de esquizofrenia, en consonancia con las hipótesis que postuIan que las alteraciones de la conectividad frontolímbica intervienen en la fisiopatología del trastorno. [ABSTRACT FROM PUBLISHER]

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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 ∼ 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Albert Maguire reports grants from Spark Therapeutics during the conduct of the study. Jean Bennett reports that Spark Therapeutics licensed intellectual property from UPenn and she and Albert Maguire are co-authors of this IP, “Method of treating or retarding the development of blindness, US Patent Application No. 8,147,823, publication 20140377224, (April 3, 2012) licensed to UPenn, Cornell, U Florida. However, they waived any potential financial interest long before this patent was approved (and prior to the conduct of the study). The authors report no other potential conflicts of interest in relation to this work., (© 2022 Ashtari et al.)

Background and Purpose: The main clinical indication for functional MR imaging (fMRI) has been to preoperatively map the cortex. Motor paradigms to activate the cortex are simple and robust; however, language tasks show greater variability and difficulty. The aim of this study was to develop a language task with an adequate control task to engage the areas of the posterior temporal lobe responsible for sentence comprehension., Methods: We performed a cloze paradigm requiring silent reading of a visually presented sentence-completion task based on semantic meaning versus a letter-scanning epoch requiring the completion of nonlinguistic strings or a rest period. Before this task was clinically used in two patients epilepsy and cavernous angioma, its feasibility and accuracy were tested in 14 healthy right-handed participants., Results: Results showed significant activation of the posterior temporal cortex, including a broad area across the posterior left temporal cortex extending into the inferior parietal lobule. When the sentence completion-minus-letter string task was compared with the sentence completion-minus-rest task, increased activation was present in the posterior temporal lobe., Conclusion: Decreased significant activation during the sentence completion-minus-rest contrast may be attributed to increased noise from intersubject variability in the rest period. Our results suggest that this task elucidates areas important to reading comprehension in the posterior and inferior temporal regions that verbal fluency and auditory discrimination tasks do not. Data from two cases are summarized to exemplify the input of this task for neurosurgery.