Mapping the human auditory cortex using spectrotemporal receptive fields generated with magnetoencephalography.

We present a novel method to map the functional organization of the human auditory cortex noninvasively using magnetoencephalography (MEG). More specifically, this method estimates via reverse correlation the spectrotemporal receptive fields (STRF) in response to a temporally dense pure tone stimulus, from which important spectrotemporal characteristics of neuronal processing can be extracted and mapped back onto the cortex surface. We show that several neuronal populations can be found examining the spectrotemporal characteristics of their STRFs, and demonstrate how these can be used to generate tonotopic gradient maps. In doing so, we show that the spatial resolution of MEG is sufficient to reliably extract important information about the spatial organization of the auditory cortex, while enabling the analysis of complex temporal dynamics of auditory processing such as best temporal modulation rate and response latency given its excellent temporal resolution. Furthermore, because spectrotemporally dense auditory stimuli can be used with MEG, the time required to acquire the necessary data to generate tonotopic maps is significantly less for MEG than for other neuroimaging tools that acquire BOLD-like signals.

Trade-off in the sound localization abilities of early blind individuals between the horizontal and vertical planes.

There is substantial evidence that sensory deprivation leads to important cross-modal brain reorganization that is paralleled by enhanced perceptual abilities. However, it remains unclear how widespread these enhancements are, and whether they are intercorrelated or arise at the expense of other perceptual abilities. One specific area where such a trade-off might arise is that of spatial hearing, where blind individuals have been shown to possess superior monaural localization abilities in the horizontal plane, but inferior localization abilities in the vertical plane. While both of these tasks likely involve the use of monaural cues due to the absence of any relevant binaural signal, there is currently no proper explanation for this discrepancy, nor has any study investigated both sets of abilities in the same sample of blind individuals. Here, we assess whether the enhancements observed in the horizontal plane are related to the deficits observed in the vertical plane by testing sound localization in both planes in groups of blind and sighted persons. Our results show that the blind individuals who displayed the highest accuracy at localizing sounds monaurally in the horizontal plane are also the ones who exhibited the greater deficit when localizing in the vertical plane. These findings appear to argue against the idea of generalized perceptual enhancements in the early blind, and instead suggest the possibility of a trade-off in the localization proficiency between the two auditory spatial planes, such that learning to use monaural cues for the horizontal plane comes at the expense of using those cues to localize in the vertical plane.

Pairing Cholinergic Enhancement with Perceptual Training Promotes Recovery of Age-Related Changes in Rat Primary Auditory Cortex.

We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.

Early visual deprivation changes cortical anatomical covariance in dorsal-stream structures.

Early blind individuals possess thicker occipital cortex compared to sighted ones. Occipital cortical thickness is also predictive of performance on several auditory discrimination tasks in the blind, which suggests that it can serve as a neuroanatomical marker of auditory behavioural abilities. In light of this atypical relationship between occipital thickness and auditory function, we sought to investigate here the covariation of occipital cortical morphology in occipital areas with that of all other areas across the cortical surface, to assess whether the anatomical covariance with the occipital cortex differs between early blind and sighted individuals. We observed a reduction in anatomical covariance between the right occipital cortex and several areas of the visual dorsal stream in a group of early blind individuals relative to sighted controls. In a separate analysis, we show that the performance of the early blind in a transposed melody discrimination task was strongly predicted by the strength of the cortical covariance between the occipital cortex and intraparietal sulcus, a region for which cortical thickness in the sighted was previously shown to predict performance in the same task. These findings therefore constitute the first evidence linking altered anatomical covariance to early sensory deprivation. Moreover, since covariation of cortical morphology could potentially be related to anatomical connectivity or driven by experience-dependent plasticity, it could consequently help guide future functional connectivity and diffusion tractography studies.

Evidence for both compensatory plastic and disuse atrophy-related neuroanatomical changes in the blind.

The behavioural and neurofunctional consequences of blindness are becoming increasingly well established, and it has become evident that the amount of reorganization is directly linked to the behavioural adaptations observed in the blind. However investigations of potential neuroanatomical changes resulting from blindness have yielded conflicting results as to the nature of the observed changes, because apparent loss of occipital tissue is difficult to reconcile with observed functional recruitment. To address this issue we used two complementary brain measures of neuroanatomy, voxel-based morphometry and magnetization transfer imaging, with the latter providing insight into myelin concentration through the magnetization transfer ratio. Both early and late blind, as well as sighted control subjects participated in the study and were tested on a series of auditory and tactile tasks to provide behavioural data that we could relate to neuroanatomy. The behavioural findings show that the early blind outperform the sighted in four of five tasks, whereas the late blind do so for only one. Moreover, correlations between the auditory and tactile performance of early blind individuals seem to indicate that they might benefit from some general-purpose compensatory plasticity mechanisms, as opposed to modality-specific ones. Neuroanatomical findings reveal three key findings: (i) occipital regions in the early blind have higher magnetization transfer ratio and grey matter concentration than in the sighted; (ii) behavioural performance of the blind is strongly predicted by magnetization transfer ratio and grey matter concentration in different occipital regions; and (iii) lower grey matter and white matter concentration was also found in other occipital areas in the early blind compared to the sighted. We thus show a clear dissociation between anatomical changes that are direct result of sensory deprivation and consequent atrophy, and those related to compensatory reorganization and behavioural adaptations. Moreover, the magnetization transfer ratio results also suggest that one mechanism for this reorganization may be related to increased myelination of intracortical neurons, or perhaps of fibres conveying information to and from remote locations.

Impact of blindness onset on the functional organization and the connectivity of the occipital cortex.

Contrasting the impact of congenital versus late-onset acquired blindness provides a unique model to probe how experience at different developmental periods shapes the functional organization of the occipital cortex. We used functional magnetic resonance imaging to characterize brain activations of congenitally blind, late-onset blind and two groups of sighted control individuals while they processed either the pitch or the spatial attributes of sounds. Whereas both blind groups recruited occipital regions for sound processing, activity in bilateral cuneus was only apparent in the congenitally blind, highlighting the existence of region-specific critical periods for crossmodal plasticity. Most importantly, the preferential activation of the right dorsal stream (middle occipital gyrus and cuneus) for the spatial processing of sounds was only observed in the congenitally blind. This demonstrates that vision has to be lost during an early sensitive period in order to transfer its functional specialization for space processing toward a non-visual modality. We then used a combination of dynamic causal modelling with Bayesian model selection to demonstrate that auditory-driven activity in primary visual cortex is better explained by direct connections with primary auditory cortex in the congenitally blind whereas it relies more on feedback inputs from parietal regions in the late-onset blind group. Taken together, these results demonstrate the crucial role of the developmental period of visual deprivation in (re)shaping the functional architecture and the connectivity of the occipital cortex. Such findings are clinically important now that a growing number of medical interventions may restore vision after a period of visual deprivation.

Functional specialization for auditory-spatial processing in the occipital cortex of congenitally blind humans.

The study of the congenitally blind (CB) represents a unique opportunity to explore experience-dependant plasticity in a sensory region deprived of its natural inputs since birth. Although several studies have shown occipital regions of CB to be involved in nonvisual processing, whether the functional organization of the visual cortex observed in sighted individuals (SI) is maintained in the rewired occipital regions of the blind has only been recently investigated. In the present functional MRI study, we compared the brain activity of CB and SI processing either the spatial or the pitch properties of sounds carrying information in both domains (i.e., the same sounds were used in both tasks), using an adaptive procedure specifically designed to adjust for performance level. In addition to showing a substantial recruitment of the occipital cortex for sound processing in CB, we also demonstrate that auditory-spatial processing mainly recruits the right cuneus and the right middle occipital gyrus, two regions of the dorsal occipital stream known to be involved in visuospatial/motion processing in SI. Moreover, functional connectivity analyses revealed that these reorganized occipital regions are part of an extensive brain network including regions known to underlie audiovisual spatial abilities (i.e., intraparietal sulcus, superior frontal gyrus). We conclude that some regions of the right dorsal occipital stream do not require visual experience to develop a specialization for the processing of spatial information and to be functionally integrated in a preexisting brain network dedicated to this ability.

Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.

Studying the oculomotor system provides a unique window to assess brain health and function in various clinical populations. Although the use of detailed oculomotor parameters in clinical research has been limited due to the scalability of the required equipment, the development of novel tablet-based technologies has created opportunities for fast, easy, cost-effective, and reliable eye tracking. Oculomotor measures captured via a mobile tablet-based technology have previously been shown to reliably discriminate between Parkinson's Disease (PD) patients and healthy controls. Here we further investigate the use of oculomotor measures from tablet-based eye-tracking to inform on various cognitive abilities and disease severity in PD patients. When combined using partial least square regression, the extracted oculomotor parameters can explain up to 71% of the variance in cognitive test scores (e.g. Trail Making Test). Moreover, using a receiver operating characteristics (ROC) analysis we show that eye-tracking parameters can be used in a support vector classifier to discriminate between individuals with mild PD from those with moderate PD (based on UPDRS cut-off scores) with an accuracy of 90%. Taken together, our findings highlight the potential usefulness of mobile tablet-based technology to rapidly scale eye-tracking use and usefulness in both research and clinical settings by informing on disease stage and cognitive outcomes.

Assessment of the caudate nucleus and its relation to route learning in both congenital and late blind individuals.

BACKGROUND: In the absence of visual input, the question arises as to how complex spatial abilities develop and how the brain adapts to the absence of this modality. As such, the aim of the current study was to investigate the relationship between visual status and an important brain structure with a well established role in spatial cognition and navigation, the caudate nucleus. We conducted a volumetric analysis of the caudate nucleus in congenitally and late blind individuals, as well as in matched sighted control subjects. RESULTS: No differences in the volume of the structure were found either between congenitally blind (CB) and matched sighted controls or between late blind (LB) and matched sighted controls. Moreover, contrary to what was expected, no significant correlation was found between caudate volume and performance in a spatial navigation task. Finally, consistent with previously published reports, the volume of the caudate nucleus was found to be negatively correlated with age in the sighted; however such correlations were not significant in the blind groups. CONCLUSION: Although there were no group differences, the absence of an age-volume correlation in the blind suggests that visual deprivation may still have an effect on the developmental changes that occur in the caudate nucleus.

Occipital cortical thickness predicts performance on pitch and musical tasks in blind individuals.

The behavioral and neurofunctional consequences of blindness often include performance enhancements and recruitment of occipital regions for nonvisual tasks. How the neuroanatomical changes resulting from this sensory loss relate to these functional changes is, however, less clear. Previous studies using cortical thickness (CT) measures have shown thicker occipital cortex in early-blind (EB) individuals compared with sighted controls. We hypothesized that this finding reflects the crossmodal plasticity often observed in blind individuals and thus could reflect behavioral adaptations. To address this issue, CT measures in blind (early and late) and sighted subjects were obtained along with several auditory behavioral measures in an attempt to relate behavioral and neuroanatomical changes. Group contrasts confirmed previous results in showing thicker occipital cortex in the EB. Regression analyses between CT measures across the whole brain of all blind individuals with the behavioral scores from 2 tasks in which EB subjects were superior (pitch and melody discrimination) showed that CT of occipital areas was directly related to behavioral enhancements. These findings constitute a compelling demonstration that anatomical changes in occipital areas are directly related to heightened behavioral abilities in the blind and hence support the idea that these anatomical features reflect adaptive compensatory plasticity.

A novel tablet-based software for the acquisition and analysis of gaze and eye movement parameters: a preliminary validation study in Parkinson's disease.

The idea that eye movements can reflect certain aspects of brain function and inform on the presence of neurodegeneration is not a new one. Indeed, a growing body of research has shown that several neurodegenerative disorders, such as Alzheimer's and Parkinson's Disease, present characteristic eye movement anomalies and that specific gaze and eye movement parameters correlate with disease severity. The use of detailed eye movement recordings in research and clinical settings, however, has been limited due to the expensive nature and limited scalability of the required equipment. Here we test a novel technology that can track and measure eye movement parameters using the embedded camera of a mobile tablet. We show that using this technology can replicate several well-known findings regarding oculomotor anomalies in Parkinson's disease (PD), and furthermore show that several parameters significantly correlate with disease severity as assessed with the MDS-UPDRS motor subscale. A logistic regression classifier was able to accurately distinguish PD patients from healthy controls on the basis of six eye movement parameters with a sensitivity of 0.93 and specificity of 0.86. This tablet-based tool has the potential to accelerate eye movement research via affordable and scalable eye-tracking and aid with the identification of disease status and monitoring of disease progression in clinical settings.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

Short-term crossmodal plasticity of the auditory steady-state response in blindfolded sighted individuals.

This study investigated the effect of short-term visual deprivation on auditory steady-state response (ASSR) to amplitude-modulated tones. Magnetoencephalography data were acquired while subjects performed an auditory detection task under both monaural and dichotic presentation conditions. Analyses were performed on the spectral power, mean amplitudes and dipole positions of the ASSR at the onset of blindfolding, as well as after 2, 4 and 6 h of visual deprivation. Results show a modulation of the spectral power of the ASSR at the frequencies that were present in the stimulus after 6 h of sensory deprivation, and this was especially true for the dichotic condition. Moreover, participants showed two spectral peaks in the occipital cortex at the end of the visual deprivation period, a phenomenon normally observed in the auditory cortex. Our results shed light not only on the timeline associated with short-term crossmodal recruitment of input-deprived sensory cortices but also demonstrate that the visual cortex can display auditory cortex-like functioning in response to the ASSR. Importantly, our results also highlight the importance of taking into consideration individual differences when investigating crossmodal plastic phenomena. Indeed, the occipital spectral peaks were only observed in half the subjects following short-term deprivation.

Brain structure changes visualized in early- and late-onset blind subjects.

We examined 3D patterns of volume differences in the brain associated with blindness, in subjects grouped according to early and late onset. Using tensor-based morphometry, we mapped volume reductions and gains in 16 early-onset (EB) and 16 late-onset (LB) blind adults (onset <5 and >14 years old, respectively) relative to 16 matched sighted controls. Each subject's structural MRI was fluidly registered to a common template. Anatomical differences between groups were mapped based on statistical analysis of the resulting deformation fields revealing profound deficits in primary and secondary visual cortices for both blind groups. Regions outside the occipital lobe showed significant hypertrophy, suggesting widespread compensatory adaptations. EBs but not LBs showed deficits in the splenium and the isthmus. Gains in the non-occipital white matter were more widespread in the EBs. These differences may reflect regional alterations in late neurodevelopmental processes, such as myelination, that continue into adulthood.

3D mapping of brain differences in native signing congenitally and prelingually deaf subjects.

In the prelingual and congenital deaf, functional reorganization is known to occur throughout brain regions normally associated with hearing. However, the anatomical correlates of these changes are not yet well understood. Here, we perform the first tensor-based morphometric analysis of voxel-wise volumetric differences in native signing prelingual and congenitally deaf subjects when compared with hearing controls. We obtained T1-weighted scans for 14 native signing prelingual and congenitally deaf subjects and 16 age- and gender-matched controls. We used linear and fluid registration to align each image to a common template. Using the voxel-wise determinant of the Jacobian of the fluid deformation, significant volume increases, of up to 20%, were found in frontal lobe white matter regions including Broca's area, and adjacent regions involved in motor control and language production. A similar analysis was performed on hand-traced corpora callosa. A strong trend for group differences was found in the area of the splenium considered to carry fibers connecting the temporal (and occipital) lobes. These anatomical differences may reflect experience-mediated developmental differences in myelination and cortical maturation associated with prolonged monomodal sensory deprivation.

Neuropsychology: pitch discrimination in the early blind.

Do blind people develop superior abilities in auditory perception to compensate for their lack of vision? They are known to be better than sighted people at orientating themselves by sound, but it is not clear whether this enhanced awareness extends to other auditory domains, such as listening to music or to voices. Here we show that blind people are better than sighted controls at judging the direction of pitch change between sounds, even when the speed of change is ten times faster than that perceived by the controls--but only if they became blind at an early age. The younger the onset of blindness, the better is the performance, which is in line with cerebral plasticity being optimal during the early years.

Critical periods of brain development.

Brain plasticity is maximal at specific time windows during early development known as critical periods (CPs), during which sensory experience is necessary to establish optimal cortical representations of the surrounding environment. After CP closure, a range of functional and structural elements prevent passive experience from eliciting significant plastic changes in the brain. The transition from a plastic to a more fixed state is advantageous as it allows for the sequential consolidation and retention of new and more complex perceptual, motor, and cognitive functions. However, the formation of stable neural representations may pose limitations on future revisions to the circuitry. If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representations in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life. This chapter begins with a brief introduction to experience-dependent plasticity throughout the lifespan (Section Introduction). Next, we define what constitutes a CP (Section What Are Critical Periods?) and review some of the key CPs in the visual and auditory systems (Section Key Critical Periods of Sensory Systems). We then discuss the mechanisms whereby cortical plasticity is regulated both locally and through neuromodulatory systems (Section How Are Critical Periods Regulated?). Finally, we highlight studies showing that CPs can be extended beyond their normal epochs, closed prematurely, or reopened during adult life by merely altering sensory inputs (Section Timing of Critical Periods: Can CP Plasticity Be Extended, Limited, or Reactivated?).

Pattern of hippocampal shape and volume differences in blind subjects.

Numerous studies in animals and humans have shown that the hippocampus (HP) is involved in spatial navigation and memory. Blind subjects, in particular, must memorize extensive information to compensate for their lack of immediate updating of spatial information. Increased demands on spatial cognition and memory may be associated with functional and structural HP plasticity. Here we examined local size and shape differences in the HP of blind and sighted individuals. A 3D parametric mesh surface was generated to represent right and left HPs in each individual, based on manual segmentations of 3D volumetric T1-weighted MR images of 22 blind subjects and 28 matched controls. Using a new surface mapping algorithm described in (Shi, Y., Thompson, P.M., de Zubicaray, G.I., Rose, S.E., Tu, Z., Dinov, I., Toga, A.W., Direct mapping of hippocampal surfaces with intrinsic shape context, NeuroImage, Available online May 24, (In Press).), we created an average hippocampal surface for the controls, and computed its normal distance to each individual surface. Statistical maps were created to visualize systematic anatomical differences between groups, and randomization tests were performed to correct for multiple comparisons. In both scaled and unscaled data, the anterior right HP was significantly larger, and the posterior right HP significantly smaller in blind individuals. No significant differences were found for left HP. These differences may reflect adaptive responses to sensory deprivation, and/or increased functional demands on memory systems. They offer a neuroanatomical substrate for future correlations with measures of navigation performance or functional activations related to variations in cognitive strategies.

Cross-modal plasticity for the spatial processing of sounds in visually deprived subjects.

Until only a few decades ago, researchers still considered sensory cortices to be fixed or "hardwired," with specific cortical regions solely dedicated to the processing of selective sensory inputs. But recent evidences have shown that the brain can rewire itself, showing an impressive range of cross-modal plasticity. Visual deprivation is one of the rare human models that allow us to explore the role of experience-dependent plasticity of a sensory cortex deprived of its natural inputs. The objective of this paper is to describe recent results regarding the spatial processing of sounds in blind subjects. These studies suggest that blind individuals may demonstrate exceptional abilities in auditory spatial processing and that such enhanced performances may be intrinsically linked to the recruitment of occipital areas deprived of their normal visual inputs. Such results highlight the brain's remarkable ability to rewire its components to compensate for the challenging neurological condition that is visual deprivation. Moreover, we shall discuss that such cross-modal recruitment may, to some extent, follow organizational principles similar to the functional topography of the region observed in the sighted. Even if such recruitment is especially present in individuals having lost their sight in early infancy, occipital regions also show impressive plastic properties when vision is lost at a later age. This observation will be related to recent results demonstrating that occipital regions play a more important role than previously expected in the spatial processing of sounds, even in sighted subjects. Putative physiological mechanisms underlying such cross-modal recruitment will then be discussed. All these results have important implications for understanding the role of visual experience in shaping the development of occipital regions and may guide the implementation of rehabilitative methods such as sensory substitution or neural implants.