Toward AI-driven neuroepigenetic imaging biomarker for alcohol use disorder: A proof-of-concept study.

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

Investigating cerebral neurovascular responses to hyperglycemia in a rat model of type 2 diabetes using multimodal assessment techniques.

To study neurovascular function in type 2 diabetes mellitus (T2DM), we established a high-fat diet/streptozotocin (HFD/STZ) rat model. Electrocorticography-laser speckle contrast imaging (ECoG-LSCI) revealed that the somatosensory-evoked potential (SSEP) amplitude and blood perfusion volume were significantly lower in the HFD/STZ group. Cortical spreading depression (CSD) velocity was used as a measure of neurovascular function, and the results showed that the blood flow velocity and the number of CSD events were significantly lower in the HFD/STZ group. In addition, to compare changes during acute hyperglycemia and hyperglycemia, we used intraperitoneal injection (IPI) of glucose to induce transient hyperglycemia. The results showed that CSD velocity and blood flow were significantly reduced in the IPI group. The significant neurovascular changes observed in the brains of rats in the HFD/STZ group suggest that changes in neuronal apoptosis may play a role in altered glucose homeostasis in T2DM.

Low intensity transcranial ultrasound stimulation induces hemodynamic responses through neurovascular coupling.

Collective studies have demonstrated that transcranial ultrasound stimulation (TUS) can elicit activation in hemodynamics, implying its potential in treating cerebral or peripheral vessel-related malfunction. The theory for hemodynamic response to TUS is neurovascular coupling (NVC) following the ultrasound-induced cellular (de)polarization. However, it was not conclusive due to the co-existence of the pathway of direct ultrasound-vessel interactions. This study thus aims to investigate and provide direct evidence for NVC pathway in a rodent model of TUS by inhibiting neural activity with sodium valproate (VPA), a GABAergic agent. Twenty Sprague-Dawley rats were randomly assigned to VPA and Saline groups. Microelectrode and optical imaging were utilized to record local field potential and relative cerebral blood flow (rCBF) during baseline, before, and after TUS periods. We found the attenuated neural activity was associated with reduced rCBF responses. These results provided direct evidence for the presence of NVC pathway in hemodynamic modulation by TUS.

New AAV9 engineered variants with enhanced neurotropism and reduced liver off-targeting in mice and marmosets.

Although adeno-associated virus 9 (AAV9) has been highly exploited as delivery platform for gene-based therapies, its efficacy is hampered by low efficiency in crossing the adult blood-brain barrier (BBB) and pronounced targeting to the liver upon intravenous delivery. We generated a new galactose binding-deficient AAV9 peptide display library and selected two new AAV9 engineered capsids with enhanced targeting in mouse and marmoset brains after intravenous delivery. Interestingly, the loss of galactose binding greatly reduced undesired targeting to peripheral organs, particularly the liver, while not compromising transduction of the brain vasculature. However, the galactose binding was necessary to efficiently infect non-endothelial brain cells. Thus, the combinatorial actions of the galactose-binding domain and the incorporated displayed peptide are crucial to enhance BBB crossing along with brain cell transduction. This study describes two novel capsids with high brain endothelial infectivity and extremely low liver targeting based on manipulating the AAV9 galactose-binding domain.

Optogenetic behavioral studies in depression research: A systematic review.

Optogenetics has made substantial contributions to our understanding of the mechanistic underpinnings of depression. This systematic review employs quantitative analysis to investigate the impact of optogenetic stimulation in mice and rats on behavioral alterations in social interaction, sucrose consumption, and mobility. The review analyses optogenetic behavioral studies using standardized behavioral tests to detect behavioral changes induced via optogenetic stimulation in stressed or stress-naive mice and rats. Behavioral changes were evaluated as either positive, negative, or not effective. The analysis comprises the outcomes of 248 behavioral tests of 168 studies described in 37 articles, including negative and null results. Test outcomes were compared for each behavior, depending on the animal cohort, applied type of stimulation and the stimulated neuronal circuit and cell type. The presented synthesis contributes toward a comprehensive picture of optogenetic behavioral research in the context of depression.

Localizing 3D motion through the fingertips: Following in the footsteps of elephants.

Each sense serves a different specific function in spatial perception, and they all form a joint multisensory spatial representation. For instance, hearing enables localization in the entire 3D external space, while touch traditionally only allows localization of objects on the body (i.e., within the peripersonal space alone). We use an in-house touch-motion algorithm (TMA) to evaluate individuals' capability to understand externalized 3D information through touch, a skill that was not acquired during an individual's development or in evolution. Four experiments demonstrate quick learning and high accuracy in localization of motion using vibrotactile inputs on fingertips and successful audio-tactile integration in background noise. Subjective responses in some participants imply spatial experiences through visualization and perception of tactile "moving" sources beyond reach. We discuss our findings with respect to developing new skills in an adult brain, including combining a newly acquired "sense" with an existing one and computation-based brain organization.

Attention to cardiac sensations enhances the heartbeat-evoked potential during exhalation.

Respiration and cardiac activity intricately interact through complex physiological mechanisms. The heartbeat-evoked potential (HEP) is an EEG fluctuation reflecting the cortical processing of cardiac signals. We recently found higher HEP amplitude during exhalation than inhalation during a task involving attention to cardiac sensations. This may have been due to reduced cardiac perception during inhalation and heightened perception during exhalation through attentional mechanisms. To investigate relationships between HEP, attention, and respiration, we introduced an experimental setup that included tasks related to cardiac and respiratory interoceptive and exteroceptive attention. Results revealed HEP amplitude increases during the interoceptive tasks over fronto-central electrodes. When respiratory phases were taken into account, HEP increases were primarily driven by heartbeats recorded during exhalation, specifically during the cardiac interoceptive task, while inhalation had minimal impact. These findings emphasize the role of respiration in cardiac interoceptive attention and could have implications for respiratory interventions to fine-tune cardiac interoception.

Understanding the cognitive and neuroimaging bases underlying the detrimental impact of sleep deprivation on reciprocity.

Although the impact of sleep loss on social behaviors has been widely observed in recent years, the mechanisms underpinning these impacts remain unclear. In this study, we explored the detrimental effects of sleep deprivation on reciprocity behavior as well as its underlying psychological and neuroimaging mechanisms by combining sleep manipulation, an interpersonal interactive game, computational modeling and neuroimaging. Our results suggested that after sleep deprivation, individuals showed reduced reciprocity behavior, mainly due to their reduced weights on communal concern when making social decisions. At neural level, we demonstrated that sleep deprivation's effects were observed in the precuneus (hyperactivity) and temporoparietal junction, dorsal lateral prefrontal cortex (DLPFC) (both hypoactivity), and reduced reciprocity was also accounted for by increased precuneus-thalamus connectivity and DLPFC-thalamus connectivity. Our findings contributed to the understanding of the psychological and neuroimaging bases underlying the deleterious impact of sleep deprivation on social behaviors.

Neurovascular coupling in the attention during visual working memory processes.

Focusing attention in visual working memory (vWM) depends on the ability to filter distractors and expand the scope of targets. Although many properties of attention processes in vWM have been well documented, it remains unclear how the mechanisms of neurovascular coupling (NVC) function during attention processes in vWM. Here, we show simultaneous multimodal data that reveal the similar temporal and spatial features of attention processes during vWM. These similarities lead to common NVC outcomes across individuals. When filtering out distractors, the electroencephalography (EEG)-informed NVC displayed broader engagement across the frontoparietal network. A negative correlation may exist between behavioral metrics and EEG-informed NVC strength related to attention control. On a dynamic basis, NVC features exhibited higher discriminatory power in predicting behavior than other features alone. These results underscore how multimodal approaches can advance our understanding of the role of attention in vWM, and how NVC fluctuations are associated with actual behavior.

Dynamics of brain-muscle networks reveal effects of age and somatosensory function on gait.

Walking is a complex motor activity that requires coordinated interactions between the sensory and motor systems. We used mobile EEG and EMG to investigate the brain-muscle networks involved in gait control during overground walking in young people, older people, and individuals with Parkinson's disease. Dynamic interactions between the sensorimotor cortices and eight leg muscles within a gait cycle were assessed using multivariate analysis. We identified three distinct brain-muscle networks during a gait cycle. These networks include a bilateral network, a left-lateralized network activated during the left swing phase, and a right-lateralized network active during the right swing. The trajectories of these networks are contracted in older adults, indicating a reduction in neuromuscular connectivity with age. Individuals with the impaired tactile sensitivity of the foot showed a selective enhancement of the bilateral network, possibly reflecting a compensation strategy to maintain gait stability. These findings provide a parsimonious description of interindividual differences in neuromuscular connectivity during gait.

Investigation of vagal sensory neurons in mice using optical vagal stimulation and tracheal neuroanatomy.

In rats and guinea pigs, sensory innervation of the airways is derived largely from the vagus nerve, with the extrapulmonary airways innervated by Wnt1+ jugular neurons and the intrapulmonary airways and lungs by Phox2b+ nodose neurons; however, our knowledge of airway innervation in mice is limited. We used genetically targeted expression of enhanced yellow fluorescent protein-channelrhodopsin-2 (EYFP-ChR2) in Wnt1+ or Phox2b+ tissues to characterize jugular and nodose-mediated physiological responses and airway innervation in mice. With optical stimulation, Phox2b+ vagal fibers modulated cardiorespiratory function in a frequency-dependent manner while right Wnt1+ vagal fibers induced a small increase in respiratory rate. Mouse tracheae contained sparse Phox2b-EYFP fibers but dense networks of Wnt1-EYFP fibers. Retrograde tracing from the airways showed limited tracheal innervation by the jugular sensory neurons, distinct from other species. These differences in physiology and vagal sensory distribution have important implications when using mice for studying airway neurobiology.

Small effects of electric field on motor cortical excitability following anodal tDCS.

The dose-response characteristics of transcranial direct current stimulation (tDCS) remain uncertain but may be related to variability in brain electric fields due to individual anatomical factors. Here, we investigated whether the electric fields influence the responses to motor cortical tDCS. In a randomized cross-over design, 21 participants underwent 10 min of anodal tDCS with 0.5, 1.0, 1.5, or 2.0 mA or sham. Compared to sham, all active conditions increased the size of motor evoked potentials (MEP) normalized to the pre-tDCS baseline, irrespective of anterior or posterior magnetic test stimuli. The electric field calculated in the motor cortex of each participant had a nonlinear effect on the normalized MEP size, but its effects were small compared to those of other participant-specific factors. The findings support the efficacy of anodal tDCS in enhancing the MEP size but do not demonstrate any benefits of personalized electric field modeling in explaining tDCS response variability.

The GDNF-gel/HA-Mg conduit promotes the repair of peripheral nerve defects by regulating PPAR-γ/RhoA/ROCK signaling pathway.

Magnesium (Mg)-based conduits have gained more attention in repairing peripheral nerve defects. However, they are limited due to poor corrosion resistance and rapid degradation rate. To tackle this issue, glial cell line-derived neurotrophic factor (GDNF)- Gelatin methacryloyl (Gel)/hydroxylapatite (HA)-Mg nerve conduit was developed and implanted in sciatic nerve defect model in Sprague-Dawley (SD) rats. The sciatic functional index measurement showed that the GDNF-Gel/HA-Mg nerve conduit effectively promoted the recovery of sciatic nerve function. The pathological examination results showed that there were more regenerated nerve tissues in GDNF-Gel/HA-Mg group, with a higher number of regenerating axons, and the thickness of the myelin sheath was significantly larger than that of control group (NC group). Immunofluorescence results revealed that the GDNF-Gel/HA-Mg conduit significantly promoted the expression of genes associated with nerve repair. RNA-seq and molecular test results indicated that GDNF-Gel/HA-Mg might be involved in the repair of peripheral nerve defects by regulating PPAR-γ/RhoA/ROCK signaling pathway. Biological sciences; Neuroscience; Molecular neuroscience; Techniques in neuroscience.

Encoded and updated spatial working memories share a common representational format in alpha activity.

Working memory (WM) flexibly updates information to adapt to the dynamic environment. Here, we used alpha-band activity in the EEG to reconstruct the content of dynamic WM updates and compared this representational format to static WM content. An inverted encoding model using alpha activity precisely tracked both the initially encoded position and the updated position following an auditory cue signaling mental updating. The timing of the update, as tracked in the EEG, correlated with reaction times and saccade latency. Finally, cross-training analyses revealed a robust generalization of alpha-band reconstruction of WM contents before and after updating. These findings demonstrate that alpha activity tracks the dynamic updates to spatial WM and that the format of this activity is preserved across the encoded and updated representations. Thus, our results highlight a new approach for measuring updates to WM and show common representational formats during dynamic mental updating and static storage.

Modeling the precise interaction of glioblastoma with human brain region-specific organoids.

Glioblastoma is a highly aggressive malignant tumor of the central nervous system, but the interaction between glioblastoma and different types of neurons remains unclear. Here, we established a co-culture model in vitro using 3D printed molds with microchannels, in which glioblastoma organoids (GB), dorsal forebrain organoids (DO, mainly composed of excitatory neurons), and ventral forebrain organoids (VO, mainly composed of inhibitory neurons) were assembled. Our results indicate that DO has a greater impact on altered gene expression profiles of GB, resulting in increased invasive potential. GB cells preferentially invaded DO along axons, whereas this phenomenon was not observed in VO. Furthermore, GB cells selectively inhibited neurite outgrowth in DOs and reduced the expression of the vesicular GABA transporter (VGAT), leading to neuronal hyperexcitability. By revealing how glioblastoma interacts with brain cells, our study provides a more comprehensive understanding of this disease.

A pilot study on a patient with refractory headache: Personalized deep brain stimulation through stereoelectroencephalography.

The integration of stereoelectroencephalography with therapeutic deep brain stimulation (DBS) holds immense promise as a viable approach for precise treatment of refractory disorders, yet it has not been explored in the domain of headache or pain management. Here, we implanted 14 electrodes in a patient with refractory migraine and integrated clinical assessment and electrophysiological data to investigate personalized targets for refractory headache treatment. Using statistical analyses and cross-validated machine-learning models, we identified high-frequency oscillations in the right nucleus accumbens as a critical headache-related biomarker. Through a systematic bipolar stimulation approach and blinded sham-controlled survey, combined with real-time electrophysiological data, we successfully identified the left dorsal anterior cingulate cortex as the optimal target for the best potential treatment. In this pilot study, the concept of the herein-proposed data-driven approach to optimizing precise and personalized treatment strategies for DBS may create a new frontier in the field of refractory headache and even pain disorders.

Enhanced attention-related alertness following right anterior insular cortex neurofeedback training.

The anterior insular cortex, a central node of the salience network, plays a critical role in cognitive control and attention. Here, we investigated the feasibility of enhancing attention using real-time fMRI neurofeedback training that targets the right anterior insular cortex (rAIC). 56 healthy adults underwent two neurofeedback training sessions. The experimental group received feedback from neural responses in the rAIC, while control groups received sham feedback from the primary visual cortex or no feedback. Cognitive functioning was evaluated before, immediately after, and three months post-training. Our results showed that only the rAIC neurofeedback group successfully increased activity in the rAIC. Furthermore, this group showed enhanced attention-related alertness up to three months after the training. Our findings provide evidence for the potential of rAIC neurofeedback as a viable approach for enhancing attention-related alertness, which could pave the way for non-invasive therapeutic strategies to address conditions characterized by attention deficits.

Connecting the dots in the zona incerta: A study of neural assemblies and motifs of inter-area coordination in mice.

The zona incerta (ZI), a subthalamic area connected to numerous brain regions, has raised clinical interest because its stimulation alleviates the motor symptoms of Parkinson's disease. To explore its coordinative nature, we studied the assembly formation in a dataset of neural recordings in mice and quantified the degree of functional coordination of ZI with other 24 brain areas. We found that the ZI is a highly integrative area. The analysis in terms of "loop-like" motifs, directional assemblies composed of three neurons spanning two areas, has revealed reciprocal functional interactions with reentrant signals that, in most cases, start and end with the activation of ZI units. In support of its proposed integrative role, we found that almost one-third of the ZI's neurons formed assemblies with more than half of the other recorded areas and that loop-like assemblies may stand out as hyper-integrative motifs compared to other types of activation patterns.

Prediction error drives associative learning and conditioned behavior in a spiking model of Drosophila larva.

Predicting reinforcement from sensory cues is beneficial for goal-directed behavior. In insect brains, underlying associations between cues and reinforcement, encoded by dopaminergic neurons, are formed in the mushroom body. We propose a spiking model of the Drosophila larva mushroom body. It includes a feedback motif conveying learned reinforcement expectation to dopaminergic neurons, which can compute prediction error as the difference between expected and present reinforcement. We demonstrate that this can serve as a driving force in learning. When combined with synaptic homeostasis, our model accounts for theoretically derived features of acquisition and loss of associations that depend on the intensity of the reinforcement and its temporal proximity to the cue. From modeling olfactory learning over the time course of behavioral experiments and simulating the locomotion of individual larvae toward or away from odor sources in a virtual environment, we conclude that learning driven by prediction errors can explain larval behavior.

Monitoring Alzheimer's disease via ultraweak photon emission.

In an innovative experiment, we detected ultraweak photon emission (UPE) from the hippocampus of male rat brains and found significant correlations between Alzheimer's disease (AD), memory decline, oxidative stress, and UPE intensity. These findings may open up novel methods for screening, detecting, diagnosing, and classifying neurodegenerative diseases, particularly AD. The study suggests that UPE from the brain's neural tissue can serve as a valuable indicator. It also proposes the development of a minimally invasive brain-computer interface (BCI) photonic chip for monitoring and diagnosing AD, offering high spatiotemporal resolution of brain activity. The study used a rodent model of sporadic AD, demonstrating that STZ-induced sAD resulted in increased hippocampal UPE, which was associated with oxidative stress. Treatment with donepezil reduced UPE and improved oxidative stress. These findings support the potential utility of UPE as a screening and diagnostic tool for AD and other neurodegenerative diseases.