High-resolution quantitative and functional MRI indicate lower myelination of thin and thick stripes in human secondary visual cortex.

The characterization of cortical myelination is essential for the study of structure-function relationships in the human brain. However, knowledge about cortical myelination is largely based on post-mortem histology, which generally renders direct comparison to function impossible. The repeating pattern of pale-thin-pale-thick stripes of cytochrome oxidase (CO) activity in the primate secondary visual cortex (V2) is a prominent columnar system, in which histology also indicates different myelination of thin/thick versus pale stripes. We used quantitative magnetic resonance imaging (qMRI) in conjunction with functional magnetic resonance imaging (fMRI) at ultra-high field strength (7 T) to localize and study myelination of stripes in four human participants at sub-millimeter resolution in vivo. Thin and thick stripes were functionally localized by exploiting their sensitivity to color and binocular disparity, respectively. Resulting functional activation maps showed robust stripe patterns in V2 which enabled further comparison of quantitative relaxation parameters between stripe types. Thereby, we found lower longitudinal relaxation rates (R1) of thin and thick stripes compared to surrounding gray matter in the order of 1-2%, indicating higher myelination of pale stripes. No consistent differences were found for effective transverse relaxation rates (R2*). The study demonstrates the feasibility to investigate structure-function relationships in living humans within one cortical area at the level of columnar systems using qMRI.

Quantitative MRI maps of human neocortex explored using cell type-specific gene expression analysis.

Quantitative magnetic resonance imaging (qMRI) allows extraction of reproducible and robust parameter maps. However, the connection to underlying biological substrates remains murky, especially in the complex, densely packed cortex. We investigated associations in human neocortex between qMRI parameters and neocortical cell types by comparing the spatial distribution of the qMRI parameters longitudinal relaxation rate (${R_{1}}$), effective transverse relaxation rate (${R_{2}}^{\ast }$), and magnetization transfer saturation (MTsat) to gene expression from the Allen Human Brain Atlas, then combining this with lists of genes enriched in specific cell types found in the human brain. As qMRI parameters are magnetic field strength-dependent, the analysis was performed on MRI data at 3T and 7T. All qMRI parameters significantly covaried with genes enriched in GABA- and glutamatergic neurons, i.e. they were associated with cytoarchitecture. The qMRI parameters also significantly covaried with the distribution of genes enriched in astrocytes (${R_{2}}^{\ast }$ at 3T, ${R_{1}}$ at 7T), endothelial cells (${R_{1}}$ and MTsat at 3T), microglia (${R_{1}}$ and MTsat at 3T, ${R_{1}}$ at 7T), and oligodendrocytes and oligodendrocyte precursor cells (${R_{1}}$ at 7T). These results advance the potential use of qMRI parameters as biomarkers for specific cell types.

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics.

Ultra-high field MRI across the depth of the cortex has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease like Huntington's disease that show layer-selective vulnerability. Here we compare multi-parametric mapping (MPM) measures across cortical depths for a 7T 500 µm whole brain acquisition to (a) layer-specific cell measures from the von Economo histology atlas, (b) layer-specific gene expression, using the Allen Human Brain atlas and (c) white matter connections using high-fidelity diffusion tractography, at a 1.3 mm isotropic voxel resolution, from a 300mT/m Connectom MRI system. We show that R2*, but not R1, across cortical depths is highly correlated with layer-specific cell number and layer-specific gene expression. R1- and R2*-weighted connectivity strength of cortico-striatal and intra-hemispheric cortical white matter connections was highly correlated with grey matter R1 and R2* across cortical depths. Limitations of the layer-specific relationships demonstrated are at least in part related to the high cross-correlations of von Economo atlas cell counts and layer-specific gene expression across cortical layers. These findings demonstrate the potential and limitations of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease.

Predictive Coding Over the Lifespan: Increased Reliance on Perceptual Priors in Older Adults-A Magnetoencephalography and Dynamic Causal Modeling Study.

Aging is accompanied by unisensory decline. To compensate for this, two complementary strategies are potentially relied upon increasingly: first, older adults integrate more information from different sensory organs. Second, according to the predictive coding (PC) model, we form "templates" (internal models or "priors") of the environment through our experiences. It is through increased life experience that older adults may rely more on these templates compared to younger adults. Multisensory integration and predictive coding would be effective strategies for the perception of near-threshold stimuli, which may however come at the cost of integrating irrelevant information. Both strategies can be studied in multisensory illusions because these require the integration of different sensory information, as well as an internal model of the world that can take precedence over sensory input. Here, we elicited a classic multisensory illusion, the sound-induced flash illusion, in younger (mean: 27 years, N = 25) and older (mean: 67 years, N = 28) adult participants while recording the magnetoencephalogram. Older adults perceived more illusions than younger adults. Older adults had increased pre-stimulus beta-band activity compared to younger adults as predicted by microcircuit theories of predictive coding, which suggest priors and predictions are linked to beta-band activity. Transfer entropy analysis and dynamic causal modeling of pre-stimulus magnetoencephalography data revealed a stronger illusion-related modulation of cross-modal connectivity from auditory to visual cortices in older compared to younger adults. We interpret this as the neural correlate of increased reliance on a cross-modal predictive template in older adults leading to the illusory percept.

Superficial white matter imaging: Contrast mechanisms and whole-brain in vivo mapping.

Superficial white matter (SWM) contains the most cortico-cortical white matter connections in the human brain encompassing the short U-shaped association fibers. Despite its importance for brain connectivity, very little is known about SWM in humans, mainly due to the lack of noninvasive imaging methods. Here, we lay the groundwork for systematic in vivo SWM mapping using ultrahigh resolution 7 T magnetic resonance imaging. Using biophysical modeling informed by quantitative ion beam microscopy on postmortem brain tissue, we demonstrate that MR contrast in SWM is driven by iron and can be linked to the microscopic iron distribution. Higher SWM iron concentrations were observed in U-fiber-rich frontal, temporal, and parietal areas, potentially reflecting high fiber density or late myelination in these areas. Our SWM mapping approach provides the foundation for systematic studies of interindividual differences, plasticity, and pathologies of this crucial structure for cortico-cortical connectivity in humans.

Impairment in predictive processes during auditory mismatch negativity in ScZ: Evidence from event-related fields.

Patients with schizophrenia (ScZ) show pronounced dysfunctions in auditory perception but the underlying mechanisms as well as the localization of the deficit remain unclear. To examine these questions, the current study examined whether alterations in the neuromagnetic mismatch negativity (MMNm) in ScZ-patients could involve an impairment in sensory predictions in local sensory and higher auditory areas. Using a whole-head MEG-approach, we investigated the MMNm as well as P300m and N100m amplitudes during a hierarchical auditory novelty paradigm in 16 medicated ScZ-patients and 16 controls. In addition, responses to omitted sounds were investigated, allowing for a critical test of the predictive coding hypothesis. Source-localization was performed to identify the generators of the MMNm, omission responses as well as the P300m. Clinical symptoms were examined with the positive and negative syndrome scale. Event-related fields (ERFs) to standard sounds were intact in ScZ-patients. However, the ScZ-group showed a reduction in the amplitude of the MMNm during both local (within trials) and global (across trials) conditions as well as an absent P300m at the global level. Importantly, responses to sound omissions were reduced in ScZ-patients which overlapped both in latency and generators with the MMNm sources. Thus, our data suggest that auditory dysfunctions in ScZ involve impaired predictive processes that involve deficits in both automatic and conscious detection of auditory regularities. Hum Brain Mapp 38:5082-5093, 2017. © 2017 Wiley Periodicals, Inc.

The Faces of Predictive Coding.

Recent neurophysiological accounts of predictive coding hypothesized that a mismatch of prediction and sensory evidence-a prediction error (PE)-should be signaled by increased gamma-band activity (GBA) in the cortical area where prediction and evidence are compared. This hypothesis contrasts with alternative accounts where violated predictions should lead to reduced neural responses. We tested these hypotheses by violating predictions about face orientation and illumination direction in a Mooney face-detection task, while recording magnetoencephalographic responses in a large sample of 48 human subjects. The investigated predictions, acquired via lifelong experience, are known to be processed at different time points and brain regions during face recognition.Behavioral responses confirmed the induction of PEs by our task. Beamformer source analysis revealed an early PE signal for unexpected orientation in visual brain areas followed by a PE signal for unexpected illumination in areas involved in 3D shape from shading and spatial working memory. Both PE signals were reflected by increases in high-frequency (68-140 Hz) GBA. In high-frequency GBA we also observed a late interaction effect in visual brain areas, probably corresponding to a high-level PE signal. In addition, increased high-frequency GBA for expected illumination was observed in brain areas involved in attention to internal representations. Our results strongly support the hypothesis that increased GBA signals PEs. Additionally, GBA may represent attentional effects.

Structure predicts function: combining non-invasive electrophysiology with in-vivo histology.

We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the current density over individuals and thus is of functional relevance. Equivalent current dipole locations and moments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi-parameter maps (MPMs) acquired at 800µm isotropic resolution. Myelin estimates across cortical areas correlated positively with dipole magnitude. This correlation was spatially specific: regions of interest in the auditory cortex provided significantly better models than those covering whole hemispheres. Based on the MPM data we identified the auditory cortical area TE1.2 as the most likely origin of the pitch ERFs measured by MEG. We can now proceed to exploit the higher spatial resolution of quantitative MPMs to identify the cortical origin of M/EEG signals, inform M/EEG source reconstruction and explore structure-function relationships at a fine structural level in the living human brain.

Source-reconstruction of event-related fields reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode schizophrenia patients during Mooney face processing.

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.