Altered Neuronal Activity Research Articles

Tau pathology induced alteration in neuronal activity disrupt sleep and cerebral metabolic rhythms in the P301S PS19 mouse model of tauopathy

AbstractBackgroundAlzheimer’s disease is defined by the pathological aggregation of amyloid‐beta and hyperphosphorylated tau. AD patients often exhibit other symptoms like metabolic and sleep dysfunction. Currently, it is unclear if impairments are a cause or consequence of Aβ or tau aggregation. Previously, we demonstrated cerebral and peripheral changes in glucose elevate brain lactate levels stimulating wake. Further, previous work showed tau pathology corresponds with decreased sleep. Currently, it’s unclear what mechanisms drive sleep changes or if it relates to metabolic dysfunction. Therefore, we investigated how tau pathology impacts sleep and metabolism in P301S mice.MethodsTo examine peripheral metabolism, glucose tolerance tests were conducted on P301S and wild‐type mice(female). Recordings of indirect calorimetry over 3 days further explored peripheral metabolism. Paired glucose and lactate biosensors in the hippocampi tracked sub‐second fluctuations of brain interstitial fluid (ISF) to observe cerebral metabolic changes. EEG and EMG recorded cortical activity over a 3‐day period and spectral analysis investigated sleep/wake architecture.ResultTau aggregation preserves peripheral glucose tolerance and diurnal rhythms of brain glucose/lactate, normally lost in aged controls, suggesting increased glucose utilization. Similarly, P301S mice show increased respiratory exchange ratio suggesting heightened carbohydrate utilization. Conversely, they exhibit diminished energy expenditure. EEG spectral analysis revealed increased delta, increased theta, and decreased beta with pathology, suggesting disrupted GABA activity and sleep drive. Starting early in pathology, mice display increased wake and decreased NREM/REM. Effects on total sleep depend heavily on decreased REM bout number and duration.ConclusionBlood glucose levels in P301S mice fail to rise in response to glucose injection. Brain glucose/lactate fluctuations are maintained suggesting tau pathology preserves glucose utilization. Conversely, decreased NREM and REM and increased wake were exhibited with tau pathology. EEG spectral analysis indicates decreased beta activity, suggesting diminished GABA activity. Increased theta during NREM suggests increased pressure to transition to REM sleep. Reduced sleep drive is illustrated by increased delta in wake. Together, tau pathology reduces sleep drive and ability to switch between vigilant states despite increased sleep need. These results suggest that tau pathology causes excitatory/inhibitory imbalance and sleep impairment but does not contribute to profound effects on cerebral metabolic rhythms.

CNSC-64. BEYOND THE LOCAL TUMOR MICROENVIRONMENT: CHARACTERIZING CHANGES TO NEURONAL ACTIVITY INDUCED BY PEDIATRIC HIGH-GRADE GLIOMA

Abstract Bidirectional electrochemical signaling between neurons and tumor cells is emerging as a critical regulator of pediatric high-grade glioma (HGG) pathology. Neuron-tumor interactions are known to induce local neuronal hyperactivity. However, recent work tracing the projections of these neuron-tumor networks revealed that HGG neuronal recruitment extends beyond the local tumor microenvironment (TME). These findings suggest that tumor-induced hyperexcitability may spread beyond the local TME and drive brain-wide circuit-level changes. To elucidate how non-tumor innervated brain regions are affected by TME hyperactivity we first characterized neuronal hyperactivity induced by a cortical patient-derived pediatric high-grade cell line in vitro on human iPSC-derived neurons. In vitro calcium imaging experiments demonstrated an increase in the number of calcium fluctuations in glioma co-cultured neurons. In parallel, multi-electrode recordings revealed increased population spiking activity and amplitude in neurons co-cultured with glioma cells. We then xenografted these HGG cells into the prefrontal cortex of mice and performed whole brain-clearing and cFos staining on tumor-bearing vs saline-injected control samples. As cFos is an immediate early gene activated by neuronal activity, we utilized the density of cFos expression as a readout-out of neuronal activation in our atlas-aligned segmented brain section analyses. We expectedly observed increased cFos expression within the ipsilateral primary and secondary motor region, which collectively comprise the local TME. Interestingly, we additionally observed elevated cFos in non-tumor bearing brain regions on both the ipsilateral and contralateral hemispheres, largely in layer 2/3 cortical neurons. These neurons form extensive cortico-cortical projections, and we coincidingly observed increased cFos expression in known cortical projection targets of the prefrontal xenograft location, such as somatosensory, visual, and retrosplenial cortices. Our findings suggest that tumor-induced neuronal hyperactivity extends beyond the local TME in a brain-wide manner and potentially follows established neuronal circuits, rendering these connected regions vulnerable to alterations in neuronal activity.

Exploring the cognitive effects of hearing loss in adult rats: Implications for visuospatial attention, social behavior, and prefrontal neural activity

Age-related hearing loss in humans has been associated with cognitive decline, though the underlying mechanisms remain unknown. We investigated the long-term effects of hearing loss on attention, impulse control, social interaction, and neural activity within medial prefrontal cortex (mPFC) subregions.Hearing loss was induced in adult rats via intracochlear neomycin injection (n = 13), with non-operated rats as controls (n = 10). Rats were tested for motor activity (open field), coordination (Rotarod), and social interaction (including ultrasonic vocalization, USV) before surgery and at weeks 1, 2, 4, 8, 16, and 24 post-surgery. From week 8 on, rats were trained in the five-choice serial reaction time task (5-CSRTT) to assess visuospatial attention and impulse control. Finally, oscillatory neuronal activity in mPFC subregions was recorded with multielectrode arrays during anesthesia, followed by immunohistological staining for NeuN+ and Parvalbumin+ cells.Deafened rats were more active than controls, whereas social interaction and USV were temporarily reduced. They also had difficulties to learn the concept of the 5-CSRTT paradigm and made more incorrect responses. Electrophysiology showed decreased power in theta, alpha, and beta frequency, and enhanced high gamma band in the mPFC in deafened rats, which was most pronounced in the cingulate subregion (Cg1). The number of NeuN+ and Parvalbumin+ cells, however, did not differ between groups.The behavioral deficits together with the altered neuronal activity found in the Cg1 subregion of the mPFC in adult deafened rats may be used as an endophenotype to elucidate the mechanisms behind the cognitive decline seen in older patients with hearing loss.

Cognitive impairments and neurobiological changes induced by unilateral vestibular dysfunction in mice

The vestibular system is essential for balance and spatial orientation, and its dysfunction can lead to cognitive deficits. This study investigates the effects of unilateral vestibular dysfunction (UVL) on cognitive function and the underlying neurobiological changes in mice. We established a unilateral labyrinthectomy (UL) model in mice and assessed cognitive function at 28 days post-surgery using a comprehensive battery of behavioral tests. We found significant impairments in spatial reference memory, working memory, and synaptic plasticity in UL mice, which persisted despite compensation for vestibular and postural motor deficits. Immunofluorescence staining revealed enhanced activation of c-Fos in the hippocampal dentate gyrus (DG) at various time points post-UL, suggesting a role of the hippocampus in cognitive deficits following UVL. RNA sequencing of the DG identified differentially expressed genes (DEGs) and altered pathways related to cognitive function, synaptic plasticity, and neuronal activation. Quantitative real-time PCR (qRT-PCR) validated the expression changes of selected genes. Our findings indicate that UVL leads to persistent cognitive impairments in mice, associated with altered neuronal activation and gene expression in the hippocampus. This study offers valuable insights into the neurobiological mechanisms underlying cognitive deficits associated with UVL. Moreover, it underscores the importance of early cognitive screening in patients with vestibular diseases, as this approach is instrumental in comprehensive condition assessment, precise diagnosis, targeted treatment, and effective rehabilitation.

Statistical method accounts for microscopic electric field distortions around neurons when simulating activation thresholds.

Notwithstanding advances in computational models of neuromodulation, there are mismatches between simulated and experimental activation thresholds. Transcranial Magnetic Stimulation (TMS) of the primary motor cortex generates motor evoked potentials (MEPs). At the threshold of MEP generation, whole-head models predict macroscopic (at millimeter scale) electric fields (50-70 V/m) which are considerably below conventionally simulated cortical neuron thresholds (200-300 V/m). We hypothesize that this apparent contradiction is in part a consequence of electrical field warping by brain microstructure. Classical neuronal models ignore the physical presence of neighboring neurons and microstructure and assume that the macroscopic field directly acts on the neurons. In previous work, we performed advanced numerical calculations considering realistic microscopic compartments (e.g., cells, blood vessels), resulting in locally inhomogeneous (micrometer scale) electric field and altered neuronal activation thresholds. Here we combine detailed neural threshold simulations under homogeneous field assumptions with microscopic field calculations, leveraging a novel statistical approach. We show that, provided brain-region specific microstructure metrics, a single statistically derived scaling factor between microscopic and macroscopic electric fields can be applied in predicting neuronal thresholds. For the cortical sample considered, the statistical methods match TMS experimental thresholds. Our approach can be broadly applied to neuromodulation models, where fully coupled microstructure scale simulations may not be practical.

TDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats.

The effects of transcranial direct current stimulation (tDCS) are typically attributed to the polarization of cortical neurons by the weak electric fields it generates in the cortex. However, emerging evidence indicates that certain tDCS effects may be mediated through the co-stimulation of peripheral or cranial nerves, particularly the trigeminal nerve (TN), which projects to critical brainstem nuclei that regulate the release of various neurotransmitters throughout the central nervous system. Despite this, the specific pathways involved remain inadequately characterized. In this study, we examined the effects of acute transcutaneous TN direct current stimulation (TN-DCS) on tonic (i.e. mean spike rate and spike rate over time) and phasic (number of bursts, spike rate per burst, burst duration, and inter-burst interval) activities while simultaneously recording single-neuron activity across three brainstem nuclei in rats: the locus coeruleus (LC), dorsal raphe nucleus (DRN), and median raphe nucleus (MnRN). We found that TN-DCS significantly modulated tonic activity in the LC, with notable interactions between stimulation amplitude, polarity, and time epoch affecting mean spike rates. Similar effects were observed in the DRN regarding tonic activity. Further, phasic activity in the LC was influenced by TN-DCS, with changes in burst number, duration, and inter-burst intervals linked to stimulation parameters. Conversely, MnRN tonic activity following TN-DCS remained unchanged. Importantly, xylocaine administration to block TN abolished the effects on tonic activities in both the LC and DRN. These results suggest that tDCS effects may partially arise from indirect modulation of the TN, leading to altered neuronal activity in DRN and LC. Besides, the differential changes in tonic and phasic LC activities underscore their complementary roles in mediating TN-DCS effects on higher cortical regions. This research bears significant translational implications, providing mechanistic insights that could enhance the efficacy of tDCS applications and deepen our understanding of its neurophysiological effects.

Electrophysiological and Behavioral Markers of Hyperdopaminergia in DAT-KO Rats.

Background/Objectives: Dopamine dysfunction (DA) is a hallmark of many neurological disorders. In this case, the mechanism of changes in dopamine transmission on behavior remains unclear. This study is a look into the intricate link between disrupted DA signaling, neuronal activity patterns, and behavioral abnormalities in a hyperdopaminergic animal model. Methods: To study the relationship between altered DA levels, neuronal activity, and behavioral deficits, local field potentials (LFPs) were recorded during four different behaviors in dopamine transporter knockout rats (DAT-KO). At the same time, local field potentials were recorded in the striatum and prefrontal cortex. Correlates of LFP and accompanying behavioral patterns in genetically modified (DAT-KO) and control animals were studied. Results: DAT-KO rats exhibited desynchronization between LFPs of the striatum and prefrontal cortex, particularly during exploratory behavior. A suppressive effect of high dopamine levels on the striatum was also observed. Wild-type rats showed greater variability in LFP patterns across certain behaviors, while DAT-KO rats showed more uniform patterns. Conclusions: The decisive role of the synchrony of STR and PFC neurons in the organization of motor acts has been revealed. The greater variability of control animals in certain forms of behavior probably suggests greater adaptability. More uniform patterns in DAT-KO rats, indicating a loss of striatal flexibility when adapting to specific motor tasks. It is likely that hyperdopaminergy in the DAT-KO rat reduces the efficiency of information processing due to less synchronized activity during active behavior.

Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a Mecp2 mouse model for Rett syndrome.

Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca2+-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca2+ signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca2+ signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca2+ signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.

Whole-brain model replicates sleep-like slow-wave dynamics generated by stroke lesions

Focal brain injuries, such as stroke, cause local structural damage as well as alteration of neuronal activity in distant brain regions. Experimental evidence suggests that one of these changes is the appearance of sleep-like slow waves in the otherwise awake individual. This pattern is prominent in areas surrounding the damaged region and can extend to connected brain regions in a way consistent with the individual's specific long-range connectivity patterns. In this paper we present a generative whole-brain model based on (f)MRI data that, in combination with the disconnection mask associated with a given patient, explains the effects of the sleep-like slow waves originated in the vicinity of the lesion area on the distant brain activity. Our model reveals new aspects of their interaction, being able to reproduce functional connectivity patterns of stroke patients and offering a detailed, causal understanding of how stroke-related effects, in particular slow waves, spread throughout the brain. The presented findings demonstrate that the model effectively captures the links between stroke occurrences, sleep-like slow waves, and their subsequent spread across the human brain.

Investigating the effect of pregabalin on neuronal development using ultrashort self-assembling peptides: Assessing 3D neuronal cultures with high throughput robotic 3D bioprinting

Pregabalin is a widely prescribed drug for various neurological disorders, yet its effects on embryonic cortical neuron development when given to pregnant women remain inadequately explored. In this study, we employed advanced three-dimensional (3D) culturing and in-house developed high-throughput robotic 3D bioprinting technologies to evaluate their potential in neuropharmacology applications, using pregabalin as a model compound. Using a robotic 3D bioprinter and tetrameric IIZK peptide hydrogel as bioink, we created constructs with pregabalin-treated and untreated primary mouse embryonic cortical neurons. This setup allowed us to study the drug’s effects on cell viability, expression of neuronal markers, and neuron development. Our comparative analysis between 2D and 3D peptide-based cell culture models revealed that at a therapeutic concentration of 10 μM, pregabalin does not affect neuronal viability or the morphogenesis of cortical neurons. However, it significantly alters adenosine triphosphate (ATP) release, suggesting potential disruptions in mitochondrial function. Moreover, gene expression analysis of key genes involved in the development of the forebrain and the differentiation and maturation of neurons revealed significant alterations, including the downregulation of Dlx2, Nhlh2, Otp, and Gad67. These findings, together with observed alterations in neuronal activity and oscillations, emphasize the complex impact of pregabalin on neuronal development and function. They highlight the necessity for comprehensive clinical evaluations of its use during pregnancy. Furthermore, our research demonstrates the feasibility and value of integrating 3D cultures with high-throughput 3D bioprinting in neuropharmacology, opening new avenues for investigating drug effects on neuronal development and function, and contributing to safer clinical practices.

Neuronal functional connectivity is impaired in a layer dependent manner near chronically implanted intracortical microelectrodes in C57BL6 wildtype mice

Objective. This study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near chronically implanted microelectrodes. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how the FBR affects the functional stability of neural circuits near implanted brain–computer interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders. Approach. This study utilized single-shank, 16-channel,100 µm site-spacing Michigan-style microelectrodes (3 mm length, 703 µm2 site area) that span all cortical layers and the hippocampal CA1 region. Sex balanced C57BL6 wildtype mice (11–13 weeks old) received perpendicularly implanted microelectrode in left primary visual cortex. Electrophysiological recordings were performed during both spontaneous activity and visual sensory stimulation. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of local field potential (LFP) and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation. Main results. The study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations. Significance. This study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our study’s understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

Emerging role of the lateral habenula in conditioned inhibition and depression.

Associating a neutral conditioned stimulus (CS) with the absence of a biologically significant unconditioned stimulus (US) confers conditioned inhibitory properties upon the CS, referred to as conditioned inhibition. Conditioned inhibition and conditioned excitation, an association of a CS with the presence of the US, are fundamental components of associative learning. While the neural substrates of conditioned excitation are well established, those of conditioned inhibition remain poorly understood. Recent research has shed light on the lateral habenula (LHb) engagement in conditioned inhibition, along with the midbrain dopaminergic neurons. This article reviews behavioral tasks conducted to assess conditioned inhibition and how experimental LHb manipulations affect performance in these tasks. These results underscore the critical role of the LHb in conditioned inhibition. Intriguingly, stress increases LHb reactivity and impairs performances in tasks consisting of a component of conditioned inhibition in animals. Dysfunction of the LHb is observed in patients with depression. The ability of an organism to perform conditioned inhibition is closely linked to altered neuronal activity in the LHb, which has implications for mental disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Gray matter gamma-hydroxy-butyric acid and glutamate reflect beta-amyloid burden at old age.

Gray matter-specific metabolic imaging with high-resolution atlas-based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß-amyloid burden, in an APOE4-dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD.

Impaired long-range excitatory time scale predicts abnormal neural oscillations and cognitive deficits in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex

BackgroundIn children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. MethodsHearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). ResultsIn the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p < 0.05). Deafened rats showed significantly more play fighting during development (p < 0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p > 0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p < 0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p < 0.05). ConclusionsHearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

Impaired neuronal activity as a potential factor contributing to the underdeveloped cerebrovasculature in a young Parkinson’s disease mouse model

Misfolding of α-synuclein (α-Syn) in the brain causes cellular dysfunction, leading to cell death in a group of neurons, and consequently causes the progression of Parkinson’s disease (PD). Although many studies have demonstrated the pathological connections between vascular dysfunction and neurodegenerative diseases, it remains unclear how neuronal accumulation of α-Syn affects the structural and functional aspects of the cerebrovasculature to accelerate early disease progression. Here, we demonstrated the effect of aberrant α-Syn expression on the brain vasculature using a PD mouse model expressing a familial mutant form of human α-Syn selectively in neuronal cells. We showed that young PD mice have an underdeveloped cerebrovasculature without significant α-Syn accumulation in the vasculature. During the early phase of PD, toxic α-Syn was selectively increased in neuronal cells, while endothelial cell proliferation was decreased in the absence of vascular cell death or neuroinflammation. Instead, we observed altered neuronal activation and minor changes in the activity-dependent gene expression in brain endothelial cells (ECs) in young PD mice. These findings demonstrated that neuronal expression of mutant α-Syn in the early stage of PD induces abnormal neuronal activity and contributes to vascular patterning defects, which could be associated with a reduced angiogenic potential of ECs.

Brain Dynamics Complexity as a Signature of Cognitive Decline in Parkinson's Disease.

Higuchi's fractal dimension (FD) captures brain dynamics complexity and may be a promising method to analyze resting-state functional magnetic resonance imaging (fMRI) data and detect the neuronal interaction complexity underlying Parkinson's disease (PD) cognitive decline. The aim was to compare FD with a more established index of spontaneous neural activity, the fractional amplitude of low-frequency fluctuations (fALFF), and identify through machine learning (ML) models which method could best distinguish across PD-cognitive states, ranging from normal cognition (PD-NC), mild cognitive impairment (PD-MCI) to dementia (PDD). Finally, the aim was to explore correlations between fALFF and FD with clinical and cognitive PD features. Among 118 PD patients age-, sex-, and education matched with 35 healthy controls, 52 were classified with PD-NC, 46 with PD-MCI, and 20 with PDD based on an extensive cognitive and clinical evaluation. fALFF and FD metrics were computed on rs-fMRI data and used to train ML models. FD outperformed fALFF metrics in differentiating between PD-cognitive states, reaching an overall accuracy of 78% (vs. 62%). PD showed increased neuronal dynamics complexity within the sensorimotor network, central executive network (CEN), and default mode network (DMN), paralleled by a reduction in spontaneous neuronal activity within the CEN and DMN, whose increased complexity was strongly linked to the presence of dementia. Further, we found that some DMN critical hubs correlated with worse cognitive performance and disease severity. Our study indicates that PD-cognitive decline is characterized by an altered spontaneous neuronal activity and increased temporal complexity, involving the CEN and DMN, possibly reflecting an increased segregation of these networks. Therefore, we propose FD as a prognostic biomarker of PD-cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Importance of functional outcome measures when evaluating the efficacy of tau immunotherapies

AbstractBackgroundTau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. Using in vivo two‐photon calcium imaging, we have observed altered neuronal calcium activity in behaving JNPL3 tauopathy mice at both early and advanced stage of tauopathy. We have also shown that two mouse monoclonal antibodies, targeting phosphorylated tau‐Ser396/Ser404, partially restored these neuronal deficits (Wu Q et al Neurobiol Dis 2021, Ji C et al Alzheimers Dement AAIC 2022). Recently, we reported that novel single domain antibodies (sdAbs) and their divalent derivatives conjugated to Fc fragment showed varied efficacy to reduce tau pathology in culture, and to clear tau in brain interstitial fluid by in vivo microdialysis. Whether these sdAbs restore tauopathy‐induced neuronal deficits warrants further evaluation.MethodSomatic calcium activity in the motor cortex of homozygous 6‐month‐old JNPL3 mice was imaged by two‐photon microscopy when animals were either quiet or running. Two doses (100 µg each) of a tau IgG1‐(sdAb)2 or a control IgG1 were administered intravenously four days apart after the first imaging session. Somatic calcium activity was assessed again four days later, and compared to profile before treatment. Tau pathology was then analyzed in the mouse brain lysates by immunoblotting.ResultAbnormal cortical calcium activity was observed in resting and running JNPL3 mice at 6 months of age. Acute treatment with the tau IgG1‐(sdAb)2 did not normalize the frequency, amplitude or total activity of calcium transients in motor cortical neurons. Littermate mice treated with control IgG1 showed worsening of the tauopathy‐induced calcium dysfunction in the resting condition, and no improvement in the running condition. Interestingly, tau IgG1‐(sdAb)2 treatment decreased soluble phosphorylated tau in the treated mice, although it did not improve neuronal function. Additional analyses are ongoing, including of antibody target engagement.ConclusionThese findings confirmed neuronal calcium dysregulation in young JNPL3 mice. The failure of this particular acute tau antibody treatment to restore neuronal function is in contrast to our prior findings on two other tau antibodies targeting a different epitope, although all reduced soluble phospho‐tau. Therefore, these results highlight the importance of including a functional readout during preclinical development of tau antibodies.

Vascular risk factors and fMRI activation in a prodromal dementia population

AbstractBackgroundVascular risk factors (VRF) are associated with an increased risk of developing dementia (1). Functional magnetic resonance imaging (fMRI) demonstrates the ability to detect early changes in neuronal activation before cognitive changes are clinically measurable (2). We investigate whether the number of VRF in cognitively healthy persons with a minimum of two VRF present was associated with a change in neuronal activation in the brain measured with task‐based fMRI.Methods56 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR), elderly persons completed an fMRI examination with task‐based fMRI and N‐Back paradigm to access Working Memory (WM). Vascular risk factors included in the study were stable coronary artery disease or cerebrovascular disease according to MRI criteria, hypercholesterolemia, hypertension, diabetes mellitus and overweight (3).We analyzed the fMRI data at a single time point using the FMRIB Software Library (FSL v6.0; Analysis Group, Oxford, UK).ResultsThe mean age was 68.4 (± 5.4) years. The number of VRF present were VRF2 (n = 21), VRF3 (n = 25) and VRF4 (n = 10). The median MMSE were: VRF2: 29 (IQR 29 ‐ 30), VRF3: 30 (IQR 28.8 ‐ 30) and VRF4: 29.5 (IQR 28.3 ‐ 30). A low number of VRF (VRF2) revealed higher neuronal activation than the groups with a higher number of VRF (VRF3 and VRF4). The regional activated clusters in the VRF2 group showed activation in the superior parietal lobule, visual cortex, premotor cortex, Broca’s area and anterior intra‐parietal sulcus.ConclusionOur results show that a lower neuronal activation measured with fMRI is associated with a higher number of VRF. We suggest further studies to assess whether altered neuronal activation measured by fMRI in cognitively healthy elderly persons with VRFs can be associated with a higher risk of developing cognitive decline and dementia.1. O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698‐706.2. Chen J, Glover G. Functional Magnetic Resonance Imaging Methods. Neuropsychology Review. 2015;25(3):289‐313.3. Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.

Vascular risk factors and fMRI activation in a prodromal dementia population

AbstractBackgroundVascular risk factors (VRF) are associated with an increased risk of developing dementia (1). Functional magnetic resonance imaging (fMRI) demonstrates the ability to detect early changes in neuronal activation before cognitive changes are clinically measurable (2). We investigate whether the number of VRF in cognitively healthy persons with a minimum of two VRF present was associated with a change in neuronal activation in the brain measured with task‐based fMRI.Method56 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR), elderly persons completed an fMRI examination with task‐based fMRI and N‐Back paradigm to access Working Memory (WM). Vascular risk factors included in the study were stable coronary artery disease or cerebrovascular disease according to MRI criteria, hypercholesterolemia, hypertension, diabetes mellitus and overweight (3). We analyzed the fMRI data at a single time point using the FMRIB Software Library (FSL v6.0; Analysis Group, Oxford, UK).ResultThe mean age was 68.4 (± 5.4) years. The number of VRF present were VRF2 (n = 21), VRF3 (n = 25) and VRF4 (n = 10). The median MMSE were: VRF2: 29 (IQR 29 ‐ 30), VRF3: 30 (IQR 28.8 ‐ 30) and VRF4: 29.5 (IQR 28.3 ‐ 30). A low number of VRF (VRF2) revealed higher neuronal activation than the groups with a higher number of VRF (VRF3 and VRF4). The regional activated clusters in the VRF2 group showed activation in the superior parietal lobule, visual cortex, premotor cortex, Broca’s area and anterior intra‐parietal sulcus.ConclusionOur results show that a lower neuronal activation measured with fMRI is associated with a higher number of VRF. We suggest further studies to assess whether altered neuronal activation measured by fMRI in cognitively healthy elderly persons with VRFs can be associated with a higher risk of developing cognitive decline and dementia. • O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698‐706. • Chen J, Glover G. Functional Magnetic Resonance Imaging Methods. Neuropsychology Review. 2015;25(3):289‐313. • Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.