Sensitive Period for a Multimodal Response in Human Visual Motion Area

The middle temporal complex (MT/MST) is a brain region specialized for the perception of motion in the visual modality [ [1], [2], [3] and [4]]. However, this specialization is modified by visual experience: after long-standing blindness, MT/MST responds to sound [5]. Recent evidence also suggests that the auditory response of MT/MST is selective for motion [ [6] and [7]]. The developmental time course of this plasticity is not known. To test for a sensitive period in MT/MST development, we used fMRI to compare MT/MST function in congenitally blind, late-blind, and sighted adults. MT/MST responded to sound in congenitally blind adults, but not in late-blind or sighted adults, and not in an individual who lost his vision between ages of 2 and 3 years. All blind adults had reduced functional connectivity between MT/MST and other visual regions. Functional connectivity was increased between MT/MST and lateral prefrontal areas in congenitally blind relative to sighted and late-blind adults. These data suggest that early blindness affects the function of feedback projections from prefrontal cortex to MT/MST. We conclude that there is a sensitive period for visual specialization in MT/MST. During typical development, early visual experience either maintains or creates a vision-dominated response. Once established, this response profile is not altered by long-standing blindness.David and Lucille Packard FoundationNational Center for Research Resources: Harvard-Thorndike General Clinical Research Center at Beth Israel Deaconess Medical Center (NCRR MO1 RR01032)Harvard Clinical and Translational Science Center (UL1 RR025758)National Institutes of Health (U.S.) (grant K24 RR018875)National Institutes of Health (U.S.) (grant RO1-EY12091

Data-Driven Classification of Spectral Profiles Reveals Brain Region-Specific Plasticity in Blindness

Congenital blindness has been shown to result in behavioral adaptation and neuronal reorganization, but the underlying neuronal mechanisms are largely unknown. Brain rhythms are characteristic for anatomically defined brain regions and provide a putative mechanistic link to cognitive processes. In a novel approach, using magnetoencephalography resting state data of congenitally blind and sighted humans, deprivation-related changes in spectral profiles were mapped to the cortex using clustering and classification procedures. Altered spectral profiles in visual areas suggest changes in visual alpha-gamma band inhibitory-excitatory circuits. Remarkably, spectral profiles were also altered in auditory and right frontal areas showing increased power in theta-to-beta frequency bands in blind compared with sighted individuals, possibly related to adaptive auditory and higher cognitive processing. Moreover, occipital alpha correlated with microstructural white matter properties extending bilaterally across posterior parts of the brain. We provide evidence that visual deprivation selectively modulates spectral profiles, possibly reflecting structural and functional adaptation

Resting state functional connectivity in early blind humans

Task-based neuroimaging studies in early blind humans (EB) have demonstrated heightened visual cortex responses to non-visual paradigms. Several prior functional connectivity studies in EB have shown altered connections consistent with these task-based results. But these studies generally did not consider behavioral adaptations to lifelong blindness typically observed in EB. Enhanced cognitive abilities shown in EB include greater serial recall and attention to memory. Here, we address the question of the extent to which brain intrinsic activity in EB reflects such adaptations. We performed a resting-state functional magnetic resonance imaging study contrasting 14 EB with 14 age/gender matched normally sighted controls (NS). A principal finding was markedly greater functional connectivity in EB between visual cortex and regions typically associated with memory and cognitive control of attention. In contrast, correlations between visual cortex and non-deprived sensory cortices were significantly lower in EB. Thus, the available data, including that obtained in prior task-based and resting state fMRI studies, as well as the present results, indicate that visual cortex in EB becomes more heavily incorporated into functional systems instantiating episodic recall and attention to non-visual events. Moreover, EB appear to show a reduction in interactions between visual and non-deprived sensory cortices, possibly reflecting suppression of inter-sensory distracting activity

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

Thalamocortical Connectivity and Microstructural Changes in Congenital and Late Blindness

There is ample evidence that the occipital cortex of congenitally blind individuals processes nonvisual information. It remains a debate whether the cross-modal activation of the occipital cortex is mediated through the modulation of preexisting corticocortical projections or the reorganisation of thalamocortical connectivity. Current knowledge on this topic largely stems from anatomical studies in animal models. The aim of this study was to test whether purported changes in thalamocortical connectivity in blindness can be revealed by tractography based on diffusion-weighted magnetic resonance imaging. To assess the thalamocortical network, we used a clustering method based on the thalamic white matter projections towards predefined cortical regions. Five thalamic clusters were obtained in each group representing their cortical projections. Although we did not find differences in the thalamocortical network between congenitally blind individuals, late blind individuals, and normal sighted controls, diffusion tensor imaging (DTI) indices revealed significant microstructural changes within thalamic clusters of both blind groups. Furthermore, we find a significant decrease in fractional anisotropy (FA) in occipital and temporal thalamocortical projections in both blind groups that were not captured at the network level. This suggests that plastic microstructural changes have taken place, but not in a degree to be reflected in the tractography-based thalamocortical network

Ongoing Spontaneous Activity Controls Access to Consciousness: A Neuronal Model for Inattentional Blindness

Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden “ignition” of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of “inattentional blindness,” in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness

Molecular Mechanisms Responsible for Functional Cortical Plasticity During Development and after Focal Ischemic Brain Injury

The cerebral cortex is organized into functional representations, or maps, defined by increased activity during specific tasks. In addition, the brain exhibits robust spontaneous activity with spatiotemporal organization that defines the brain’s functional architecture (termed functional connectivity). Task-evoked representations and functional connectivity demonstrate experience-dependent plasticity, and this plasticity may be important in neurological development and disease. An important case of this is in focal ischemic injury, which results in destruction of the involved representations and disruption of functional connectivity relationships. Behavioral recovery correlates with representation remapping and functional connectivity normalization, suggesting functional organization is critical for recovery and a potentially valuable therapeutic target. However, the cellular and molecular mechanisms that drive this systems-level plasticity are unknown, making it difficult to approach therapeutic modulation of functional brain organization. Using cortical neuroimaging in mice, this dissertation explores the role of specific genes in sensory deprivation induced functional brain map plasticity during development and after focal ischemic injury. In the three contained chapters, I demonstrate the following: 1) Arc, an excitatory neuron synaptic-plasticity gene, is required for representation remapping and behavioral recovery after focal cortical ischemia. Further, perilesional sensory deprivation can direct remapping and improve behavioral recovery. 2) Early visual experience modulates functional connectivity within and outside of the visual cortex through an Arc-dependent mechanism. 3) Electrically coupled inhibitory interneuron networks limit spontaneous activity syncrhony between distant cortical regions. This work starts to define the molecular basis for plasticity in functional brain organization and may help develop approaches for therapeutic modulation of functional brain organization

Epigenetics and cell death: DNA hypermethylation in programmed retinal cell death.

BackgroundVertebrate genomes undergo epigenetic reprogramming during development and disease. Emerging evidence suggests that DNA methylation plays a key role in cell fate determination in the retina. Despite extensive studies of the programmed cell death that occurs during retinal development and degeneration, little is known about how DNA methylation might regulate neuronal cell death in the retina.MethodsThe developing chicken retina and the rd1 and rhodopsin-GFP mouse models of retinal degeneration were used to investigate programmed cell death during retinal development and degeneration. Changes in DNA methylation were determined by immunohistochemistry using antibodies against 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC).ResultsPunctate patterns of hypermethylation paralleled patterns of caspase3-dependent apoptotic cell death previously reported to occur during development in the chicken retina. Degenerating rd1 mouse retinas, at time points corresponding to the peak of rod cell death, showed elevated signals for 5mC and 5hmC in photoreceptors throughout the retina, with the most intense staining observed in the peripheral retina. Hypermethylation of photoreceptors in rd1 mice was associated with TUNEL and PAR staining and appeared to be cCaspase3-independent. After peak rod degeneration, during the period of cone death, occasional hypermethylation was observed in the outer nuclear layer.ConclusionThe finding that cell-specific increases of 5mC and 5hmC immunostaining are associated with the death of retinal neurons during both development and degeneration suggests that changes in DNA methylation may play a role in modulating gene expression during the process of retinal degeneration. During retinal development, hypermethylation of retinal neurons associates with classical caspase-dependent apoptosis as well as caspase-3 independent cell death, while hypermethylation in the rd1 mouse photoreceptors is primarily associated with caspase-3 independent programmed cell death. These findings suggest a previously unrecognized role for epigenetic mechanisms in the onset and/or progression of programed cell death in the retina