Pons-to-Cerebellum Hypoconnectivity Along the Psychosis Spectrum and Associations With Sensory Prediction and Hallucinations in Schizophrenia.

BACKGROUND: Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking. METHODS: We examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity. RESULTS: Compared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia. CONCLUSIONS: Deficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum.

Perceptual learning with dichoptic attention tasks improves attentional modulation in V1 and IPS and reduces interocular suppression in human amblyopia.

Long-term and chronic visual suppression to the non-preferred eye in early childhood is a key factor in developing amblyopia, as well as a critical barrier to treat amblyopia. To explore the relationship between selective visual attention and amblyopic suppression and its role in the success of amblyopic training, we used EEG source-imaging to show that training human adults with strabismic and anisometropic amblyopia with dichoptic attention tasks improved attentional modulation of neural populations in the primary visual cortex (V1) and intraparietal sulcus (IPS). We also used psychophysics to show that training reduced interocular suppression along with visual acuity and stereoacuity improvements. Importantly, our results revealed that the reduction of interocular suppression by training was significantly correlated with the improvement of selective visual attention in both training-related and -unrelated tasks in the amblyopic eye, relative to the fellow eye. These findings suggest a relation between interocular suppression and selective visual attention bias between eyes in amblyopic vision, and that dichoptic training with high-attention demand tasks in the amblyopic eye might be an effective way to treat amblyopia.

Motion Processing Deficits in Children With Cerebral Visual Impairment and Good Visual Acuity.

Purpose: We sought to characterize neural motion processing deficits in children with cerebral visual impairment (CVI) who have good visual acuity using an objective, quantifiable method (steady-state visual evoked potentials [SSVEPs]). Methods: We recorded SSVEPs in response to three types of visual motion - absolute motion and more complex relative and rotary motion, comparing them to form-related vernier and contour responses. We studied a group of 31 children with CVI diagnosed via detailed clinical examinations and 28 age-matched healthy controls. Results: Using measurements made at the appropriate response harmonics of the stimulation frequency, we found significant deficits in cerebral processing of relative and rotary motion but not of absolute motion in children with CVI compared with healthy controls. Vernier acuity, in keeping with good recognition acuity in both groups, was not different, nor were contour-related form responses. Conclusions: Deficits for complex motion but relative sparing of elementary motion and form-related signals suggests preferential damage to extra-striate visual motion areas in children with CVI. The fact that these preferential losses occur in the absence of significant acuity loss indicates that they are not secondary to reduced visual acuity, but rather are an independent vulnerability in CVI. These results corroborate parental and caregivers' reports of difficulties with tasks that involve motion perception in children with CVI.

Mental Visualization in the Cerebellum: Rapid Non-motor Learning at Sub-Lobular and Causal Network Levels.

It is generally understood that the main role of the cerebellum is in movement planning and coordination, but neuroimaging has led to striking findings of its involvement in many aspects of cognitive processing. Mental visualization is such a cognitive process, extensively involved in learning and memory, artistic and inventive creativity, etc. Here, our aim was to conduct a multidimensional study of cerebellar involvement in the non-motor cognitive tasks. First, we used fMRI to investigate whether the cognitive task of visualization from an immediate memory of complex spatial structures (line drawings) engages the cerebellum, and identified a cerebellar network of both strongly activated and suppressed regions. Second, the task-specificity of these regions was examined by comparative analysis with the task of perceptual exploration and memorization of the drawings to be later visualized from memory. BOLD response patterns over the iterations of each task differed significantly; unexpectedly, the suppression grew markedly stronger in visualization. Third, to gain insights in the organization of these regions into cerebellar networks, we determined the directed inter-regional causal influences using Granger Causal Connectivity analysis. Additionally, the causal interactions of the cerebellar networks with a large-scale cortical network, the Default Mode Network (DMN), were studied. Fourth, we investigated rapid cognitive learning in the cerebellum at the level of short-term BOLD response evolution within each region of interest, and at the higher level of network reorganization. Our paradigm of interleaved sequences of iteration between two tasks combined with some innovative analyses were instrumental in addressing these questions. In particular, rapid forms of non-motor learning that strongly drive cerebellar plasticity through mental visualization were uncovered and characterized at both sub-lobular and network levels. Collectively, these findings provide novel and expansive insights into high-order cognitive functions in the cerebellum, and its macroscale functional neuroanatomy. They represent a basis for a framework of rapid cerebellar reorganization driven by non-motor learning, with implications for the enhancement of cognitive abilities such as learning and memory.

Excitatory Contribution to Binocular Interactions in Human Visual Cortex Is Reduced in Strabismic Amblyopia.

Binocular summation in strabismic amblyopia is typically reported as being absent or greatly reduced in behavioral studies and is thought to be because of a preferential loss of excitatory interactions between the eyes. Here, we studied how excitatory and suppressive interactions contribute to binocular contrast interactions along the visual cortical hierarchy of humans with strabismic and anisometropic amblyopia in both sexes, using source-imaged steady-state visual evoked potentials (SSVEP) over a wide range of relative contrast between the two eyes. Dichoptic parallel grating stimuli modulated at unique temporal frequencies in each eye allowed us to quantify spectral response components associated with monocular inputs (self-terms) and the response components because of interaction of the inputs of the two eyes [intermodulation (IM) terms]. Although anisometropic amblyopes revealed a similar pattern of responses to normal-vision observers, strabismic amblyopes exhibited substantially reduced IM responses across cortical regions of interest (V1, V3a, hV4, hMT+ and lateral occipital cortex), indicating reduced interocular interactions in visual cortex. A contrast gain control model that simultaneously fits self- and IM-term responses within each cortical area revealed different patterns of binocular interactions between individuals with normal and disrupted binocularity. Our model fits show that in strabismic amblyopia, the excitatory contribution to binocular interactions is significantly reduced in both V1 and extra-striate cortex, whereas suppressive contributions remain intact. Our results provide robust electrophysiological evidence supporting the view that disruption of binocular interactions in strabismus or amblyopia is because of preferential loss of excitatory interactions between the eyes.SIGNIFICANCE STATEMENT We studied how excitatory and suppressive interactions contribute to binocular contrast interactions along the visual cortical hierarchy of humans with normal and amblyopic vision, using source-imaged SSVEP and frequency-domain analysis of dichoptic stimuli over a wide range of relative contrast between the two eyes. A dichoptic contrast gain control model was used to characterize these interactions in amblyopia and provided a quantitative comparison to normal vision. Our model fits revealed different patterns of binocular interactions between normal and amblyopic vision. Strabismic amblyopia significantly reduced excitatory contributions to binocular interactions, whereas suppressive contributions remained intact. Our results provide robust evidence supporting the view that the preferential loss of excitatory interactions disrupts binocular interactions in strabismic amblyopia.

Contrast Normalization Accounts for Binocular Interactions in Human Striate and Extra-striate Visual Cortex.

During binocular viewing, visual inputs from the two eyes interact at the level of visual cortex. Here we studied binocular interactions in human visual cortex, including both sexes, using source-imaged steady-state visual evoked potentials over a wide range of relative contrast between two eyes. The ROIs included areas V1, V3a, hV4, hMT+, and lateral occipital cortex. Dichoptic parallel grating stimuli in each eye modulated at distinct temporal frequencies allowed us to quantify spectral components associated with the individual stimuli from monocular inputs (self-terms) and responses due to interaction between the inputs from the two eyes (intermodulation [IM] terms). Data with self-terms revealed an interocular suppression effect, in which the responses to the stimulus in one eye were reduced when a stimulus was presented simultaneously to the other eye. The suppression magnitude varied depending on visual area, and the relative contrast between the two eyes. Suppression was strongest in V1 and V3a (50% reduction) and was least in lateral occipital cortex (20% reduction). Data with IM terms revealed another form of binocular interaction, compared with self-terms. IM response was strongest at V1 and was least in hV4. Fits of a family of divisive gain control models to both self- and IM-term responses within each cortical area indicated that both forms of binocular interaction shared a common gain control nonlinearity. However, our model fits revealed different patterns of binocular interaction along the cortical hierarchy, particularly in terms of excitatory and suppressive contributions.SIGNIFICANCE STATEMENT Using source-imaged steady-state visual evoked potentials and frequency-domain analysis of dichoptic stimuli, we measured two forms of binocular interactions: one is associated with the individual stimuli that represent interocular suppression from each eye, and the other is a direct measure of interocular interaction between inputs from the two eyes. We demonstrated that both forms of binocular interactions share a common gain control mechanism in striate and extra-striate cortex. Furthermore, our model fits revealed different patterns of binocular interaction along the visual cortical hierarchy, particularly in terms of excitatory and suppressive contributions.

Differential Experience-Dependent Plasticity of Form and Motion Mechanisms in Anisometropic Amblyopia.

Purpose: We measure neural responses associated with form and motion processing in children with anisometropia before and after treatment with spectacles and occlusion. Methods: In this prospective, case-control treatment study, 10 children with anisometropia and amblyopia and 16 age-matched visually normal children participated. Steady-state visual evoked potentials (VEP) were recorded from electrodes over the occipital cortex. The visual stimulus comprised a horizontal bar grating into which Vernier offsets were introduced and withdrawn periodically at 3.75 Hz. The VEP amplitude at 3.75 Hz (first harmonic [1F]) and 7.5 Hz (second harmonic [2F]) were recorded to index the sensitivity of form/position-sensitive versus motion/transient-sensitive neural populations, respectively. Response amplitude at 1F and 2F were recorded over a series of 10 logarithmically spaced offset sizes before and after treatment. Main outcome measures are VEP amplitude versus displacement functions, interocular response amplitude differences. Results: After relaxing into spectacles (minimally-treated state), form/position-sensitive responses in the dominant/less ametropic eye of the children with anisometropia were larger and responses in the more ametropic eye were smaller than those of controls. Motion-transient responses were equal to those of controls in the less ametropic eye, but were smaller than controls in the more ametropic eye. After treatment, responses did not differ from those of controls. Conclusions: Form and motion responses are differentially susceptible to neural deprivation via optical blur. Form responses are more plastic than motion responses in minimally-treated children with anisometropic amblyopia. Most treatment effects occurred above threshold range, suggesting some treatment effects are not detected clinically.

Learning face perception without vision: Rebound learning effect and hemispheric differences in congenital vs late-onset blindness.

To address the longstanding questions of whether the blind-from-birth have an innate face-schema, what plasticity mechanisms underlie non-visual face learning, and whether there are interhemispheric face processing differences in face processing in the blind, we used a unique non-visual drawing-based training in congenitally blind (CB), late-blind (LB) and blindfolded-sighted (BF) groups of adults. This Cognitive-Kinesthetic Drawing approach previously developed by Likova (e.g., 2010, 2012, 2013) enabled us to rapidly train and study training-driven neuroplasticity in both the blind and sighted groups. The five-day two-hour training taught participants to haptically explore, recognize, memorize raised-line images, and draw them free-hand from memory, in detail, including the fine facial characteristics of the face stimuli. Such drawings represent an externalization of the formed memory. Functional MRI was run before and after the training. Tactile-face perception activated the occipito-temporal cortex in all groups. However, the training led to a strong, predominantly left-hemispheric reorganization in the two blind groups, in contrast to right-hemispheric in blindfolded-sighted, i.e., the post-training response-change was stronger in the left hemisphere in the blind, but in the right in the blindfolded. This is the first study to discover interhemispheric differences in non-visual face processing. Remarkably, for face perception this learning-based change was positive in the CB and BF groups, but negative in the LB-group. Both the lateralization and inversed-sign learning effects were specific to face perception, but absent for the control nonface categories of small objects and houses. The unexpected inversed-sign training effect in CB vs LB suggests different stages of brain plasticity in the ventral pathway specific to the face category. Importantly, the fact that only after a very few days of our training, the totally-blind-from-birth CB manifested a very good (haptic) face perception, and even developed strong empathy to the explored faces, implies a preexisting face schema that can be "unmasked" and "tuned up" by a proper learning procedure. The Likova Cognitive-Kinesthetic Training is a powerful tool for driving brain plasticity, and providing deeper insights into non-visual learning, including emergence of perceptual categories. A rebound learning model and a neuro-Bayesian economy principle are proposed to explain the multidimensional learning effects. The results provide new insights into the Nature-vs-Nurture interplay in rapid brain plasticity and neurorehabilitation.

The Cortical Network for Braille Writing in the Blind.

Fundamental forms of high-order cognition, such as reading and writing, are usually studied in the context of one modality - vision. People without sight, however, use the kinesthetic-based Braille writing, and haptic-based Braille reading. We asked whether the cognitive and motor control mechanisms underlying writing and reading are modality-specific or supramodal. While a number of previous functional Magnetic Resonance Imaging (fMRI) studies have investigated the brain network for Braille reading in the blind, such studies on Braille writing are lacking. Consequently, no comparative network analysis of Braille writing vs. reading exists. Here, we report the first study of Braille writing, and a comparison of the brain organization for Braille writing vs Braille reading. FMRI was conducted in a Siemens 3T Trio scanner. Our custom MRI-compatible drawing/writing lectern was further modified to provide for Braille reading and writing. Each of five paragraphs of novel Braille text describing objects, faces and navigation sequences was read, then reproduced twice by Braille writing from memory, then read a second time. During Braille reading, the haptic-sensing of the Braille letters strongly activated not only the early visual area V1 and V2, but some highly specialized areas, such as the classical visual grapheme area and the Exner motor grapheme area. Braille-writing-from-memory, engaged a significantly more extensive network in dorsal motor, somatosensory/kinesthetic, dorsal parietal and prefrontal cortex. However, in contrast to the largely extended V1 activation in drawing-from-memory in the blind after training (Likova, 2012), Braille writing from memory generated focal activation restricted to the most foveal part of V1, presumably reflecting topographically the focal demands of such a "pin-pricking" task.

Analysis of Neural-BOLD Coupling Through Four Models of the Neural Metabolic Demand.

The coupling of the neuronal energetics to the blood-oxygen-level-dependent (BOLD) response is still incompletely understood. To address this issue, we compared the fits of four plausible models of neurometabolic coupling dynamics to available data for simultaneous recordings of the local field potential and the local BOLD response recorded from monkey primary visual cortex over a wide range of stimulus durations. The four models of the metabolic demand driving the BOLD response were: direct coupling with the overall LFP; rectified coupling to the LFP; coupling with a slow adaptive component of the implied neural population response; and coupling with the non-adaptive intracellular input signal defined by the stimulus time course. Taking all stimulus durations into account, the results imply that the BOLD response is most closely coupled with metabolic demand derived from the intracellular input waveform, without significant influence from the adaptive transients and nonlinearities exhibited by the LFP waveform.

Deficits in the Activation of Human Oculomotor Nuclei in Chronic Traumatic Brain Injury.

Binocular eye movements form a finely tuned system that requires accurate coordination of the oculomotor dynamics of the brainstem control nuclei when tracking the fine binocular disparities required for 3D vision. They are particularly susceptible to disruption by brain injury and other neural dysfunctions. Here, we report functional magnetic resonance imaging activation of the brainstem oculomotor control nuclei by binocular saccadic and vergence eye movements, and significant reductions in their response amplitudes in mild or diffuse traumatic brain injury (dTBI). Bilateral signals were recorded from a non-TBI control group (n = 11) in the oculomotor control system of the superior colliculi, the oculomotor nuclei, the abducens nuclei, and in the supra-oculomotor area (SOA), which mediate vergence eye movements. Signals from these nuclei were significantly reduced overall in a dTBI group (n = 12) and in particular for the SOA for vergence movements, which also showed significant decreases in velocity for both the convergence and divergence directions.

Consequences of traumatic brain injury for human vergence dynamics.

PURPOSE: Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters. METHODS: Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions. RESULTS: The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters. CONCLUSION: The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI.

Analysis of human vergence dynamics.

Disparity vergence is commonly viewed as being controlled by at least two mechanisms, an open-loop vergence-specific burst mechanism analogous to the ballistic drive of saccades, and a closed-loop feedback mechanism controlled by the disparity error. We show that human vergence dynamics for disparity jumps of a large textured field have a typical time course consistent with predominant control by the open-loop vergence-specific burst mechanism, although various subgroups of the population show radically different vergence behaviors. Some individuals show markedly slow divergence responses, others slow convergence responses, others slow responses in both vergence directions, implying that the two vergence directions have separate control mechanisms. The faster time courses usually had time-symmetric velocity waveforms implying open-loop burst control, while the slow response waveforms were usually time-asymmetric implying closed-loop feedback control. A further type of behavior seen in a distinct subpopulation was a compound anomalous divergence response consisting of an initial convergence movement followed by a large corrective divergence movement with time courses implying closed-loop feedback control. This analysis of the variety of human vergence responses thus contributes substantially to the understanding of the oculomotor control mechanisms underlying the generation of vergence movements [corrected].