Biology subjects

Schmitz, T. W.

Publications and source records attributed to Schmitz, T. W..

11 recordsLinked to original sources

bioRxiv2025

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

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bioRxiv2025

Hippocampal grey matter changes across scales in Alzheimer's Disease

Alzheimers disease (AD) is a progressive and debilitating neurodegenerative disease of the central nervous system, characterized by deterioration in cognitive function including extensive memory impairment. The hippocampus, a medial temporal lobe region, is a key orchestrator in the encoding and retrieval of memory and is believed to be one of the first regions to deteriorate in AD. In this work we examined hippocampal macrostructure (specifically gyrification and thickness) and microstructure in Alzheimers disease (AD) and mild cognitive impairment (MCI) relative to healthy aged controls in the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. We first utilized an iterative training paradigm to adapt an existing deep learning approach for capturing hippocampal topology to elderly individuals as well as individuals with potential hippocampal degeneration. Using this new model, we found notable decreases in both thickness and gyrification in AD and MCI across both the subfields and anterior-posterior axis. Using the diffusion tensor representation derived from diffusion MRI data, we found significant increases in the mean diffusivity across the extent of the hippocampus in AD and MCI, which may be related to a number of changes such as loss of neuronal cells, decreased fiber density, demyelination, and increased presence of CSF. Examining the primary direction of diffusion relative to canonical hippocampal axes, we found distinct diffusion orientation shifts in AD and MCI throughout the anterior-posterior extent of the subiculum and CA1. Specifically, we found a decrease in diffusion oriented tangentially, and an increase in diffusion oriented along the long-axis. This could potentially be related to the known degeneration of the perforant path, which is greatly affected in AD and is a largely tangential oriented pathway. The AD-related changes in diffusion orientations were found to not have significant spatial overlap with AD-related changes in mean diffusivity, suggesting that they may be capturing distinct spatially-localized disease processes. Finally, we showed that the macro- and microstructure of the hippocampus in AD changed less across age relative to MCI and controls. As well, the age-related hippocampal macrostructure changes in MCI appeared indistinguishable from healthy aging.

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bioRxiv2025

Multiplexed BOLD oscillations reveal the interplay of normalization and attention

Monkey electrophysiology has linked attention to divisive normalization, yet noninvasive evidence in humans remains limited. We use frequency-tagged fMRI to isolate visual cortical populations that simultaneously encode multiple competing inputs. We show that responses of these sites are suppressed during inattention and enhanced during attention - consistent with the normalization model, which predicts that attention selectively disinhibits competing inputs - offering a noninvasive translational bridge to study fine-grained computations underlying attentional selection.

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bioRxiv2025

Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Synaptic dysfunction is a hallmark of Alzheimers disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses were associated with cognitive resilience over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (MAPT) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.

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bioRxiv2025

Attentional enhancement and suppression of stimulus-synchronized BOLD oscillations

Visual cortical neurons synchronize their firing rates to periodic visual stimuli. EEG is commonly used to study directed attention by frequency-tagging brain responses to multiple stimuli oscillating at different frequencies, but is limited by its coarse spatial resolution. Here we leverage frequency-tagging fMRI (ft-fMRI) to study the influence of directed attention on the fine-grained spatiotemporal dynamics of competing stimulus-driven visual cortical oscillations. Our analysis reveals that distinct populations of visual cortical neurons exhibit in-phase (enhancing) or anti-phase (suppressive) synchronization with the oscillating stimuli. Directed attention homogeneously increases the amplitude of anti-phase BOLD oscillations across the visual hierarchy, consistent with a distributed suppressive field. In contrast, attentional modulation of in-phase BOLD oscillations increases hierarchically from V1 to hV4. The strength of anti-phase, but not in-phase, modulation predicted psychophysical correlates of attentional performance. Our results strongly corroborate the biased competition model of attention and unveil a novel BOLD correlate of attentional suppression.

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bioRxiv2024

Frequency-tagged fMRI: A platform for fine-grained spatiotemporal analysis of cortical function

Frequency tagging with functional MRI (ft-fMRI) enables precise mapping of neural dynamics by synchronizing oscillatory stimuli to stimulus-driven blood-oxygen-level-dependent (BOLD) responses. We developed and validated a dual-frequency tagging protocol to dissociate fundamental, multiplexed, and nonlinear intermodulation frequency responses across the human visual cortex at high spatial resolution. Using 3T and 7T fMRI, we reliably detected frequency-tagged BOLD responses at the level of individual vertices, revealing fine-grained cortical topographies and robust temporal synchronization to driving frequencies. Multiplexed responses, encoding multiple frequencies simultaneously, and nonlinear intermodulation components, were spatially dissociable and exhibited reproducible dynamics within and across experimental sessions. These findings establish ft-fMRI as a powerful tool for investigating fine-grained cortical computations, previously inaccessible to traditional fMRI. By bridging the spatiotemporal resolution gap between electrophysiology and fMRI, ft-fMRI provides a versatile platform for studying perception, attention, and multisensory integration in health and disease.

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bioRxiv2024

Task-specific topographical maps of neural activity in the primate lateral prefrontal cortex

Neurons in the primate lateral prefrontal cortex (LPFC) flexibly adapt their activity to support a wide range of cognitive tasks. Whether and how the topography of LPFC neural activity changes as a function of task is unclear. In the present study, we address this issue by characterizing the functional topography of LPFC neural activity in awake behaving macaques performing three distinct cognitive tasks. We recorded from chronically implanted multi-electrode arrays and show that the topography of LPFC activity is stable within a task, but adaptive across tasks. The topography of neural activity exhibits a spatial scale compatible with prior anatomical tracing work on a!erent LPFC inputs. Our findings show that LPFC maps of neural population activity are stable for a specific task, providing robust neural codes that support task specialization. Moreover, the variability in functional topographies across tasks indicates activity landscapes can adapt, providing flexibility to LPFC neural codes.

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bioRxiv2023

Focal acetylcholinergic modulation of the human midcingulo-insular network during attention: Meta-analytic neuroimaging and behavioral evidence

The basal forebrain cholinergic neurons provide acetylcholine to the cortex via large projections. Recent molecular imaging work in humans indicates that the cortical cholinergic innervation is not uniformly distributed, but rather may disproportionately innervate cortical areas relevant to supervisory attention. In this study, we therefore reexamined the spatial relationship between acetylcholinergic modulation and attention in the human cortex using meta-analytic strategies targeting both pharmacological and nonpharmacological neuroimaging studies. We found that pharmaco-modulation of acetylcholine evoked both increased activity in the anterior cingulate and decreased activity in the opercular and insular cortex. In large independent meta-analyses of non-pharmacological neuroimaging research, we demonstrate that during attentional engagement these cortical areas exhibit (1) task-related co-activation with the basal forebrain, (2) task-related co-activation with one another, and (3) spatial overlap with dense cholinergic innervations originating from the BF, as estimated by multimodal PET and MR imaging. Finally, we provide meta-analytic evidence that pharmaco-modulation of acetylcholine also induces a speeding of responses to targets with no apparent tradeoff in accuracy. In sum, we demonstrate in humans that acetylcholinergic modulation of midcingulo-insular hubs of the ventral attention/salience network via basal forebrain afferents may coordinate selection of task relevant information, thereby facilitating cognition and behavior.

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bioRxiv2023

Multimodal gradients of human basal forebrain connectivity

The cholinergic innervation of the cortex originates almost entirely from populations of neurons in the basal forebrain (BF). Structurally, the ascending BF cholinergic projections are highly branched, with individual cells targeting multiple different cortical regions. However, it is not known whether the structural organization of basal forebrain projections reflects their functional integration with the cortex. We therefore used high-resolution 7T diffusion and resting state functional MRI in humans to examine multimodal gradients of BF cholinergic connectivity with the cortex. Moving from anteromedial to posterolateral BF, we observed reduced tethering between structural and functional connectivity gradients, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). The cortical expression of this structure-function gradient revealed progressively weaker tethering moving from unimodal to transmodal cortex, with the lowest tethering in midcingulo-insular cortex. We used human [18F] fluoroethoxy-benzovesamicol (FEOBV) PET to demonstrate that cortical areas with higher concentrations of cholinergic innervation tend to exhibit lower tethering between BF structural and functional connectivity, suggesting a pattern of increasingly diffuse axonal arborization. Anterograde viral tracing of cholinergic projections and [18F] FEOBV PET in mice confirmed a gradient of axonal arborization across individual BF cholinergic neurons. Like humans, cholinergic neurons with the highest arborization project to cingulo-insular areas of the mouse isocortex. Altogether, our findings reveal that BF cholinergic neurons vary in their branch complexity, with certain subpopulations exhibiting greater modularity and others greater diffusivity in the functional integration of their cortical targets.

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bioRxiv2021

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

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bioRxiv2020

Dynamic targeting enables domain-general inhibitory control over action and thought by the prefrontal cortex.

Successful self-control requires the ability to stop unwanted actions or thoughts. Stopping is regarded as a central function of inhibitory control, a mechanism enabling the suppression of diverse mental content, and strongly associated with the prefrontal cortex. A domain-general inhibitory control capacity, however, would require the region or regions implementing it to dynamically shift top-down inhibitory connectivity to diverse target regions in the brain. Here we show that stopping unwanted thoughts and stopping unwanted actions engage common regions in the right anterior dorsolateral and right ventrolateral prefrontal cortex, and that both areas exhibit this dynamic targeting capacity. Within each region, pattern classifiers trained to distinguish stopping actions from making actions also could identify when people were suppressing their thoughts (and vice versa) and could predict which people successfully forgot thoughts after inhibition. Effective connectivity analysis revealed that both regions contributed to action and thought stopping, by dynamically shifting inhibitory connectivity to motor area M1 or to the hippocampus, depending on the goal, suppressing task-specific activity in those regions. These findings support the existence of a domain-general inhibitory control mechanism that contributes to self-control and establish dynamic inhibitory targeting as a key mechanism enabling these abilities.

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