bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, August 3rd, 2024
| Time |
Event |
| 12:32a |
Inhibitory mechanisms in the prefrontal-cortex differentially mediate Putamen activity during valence-based learning
Learning from appetitive and aversive stimuli is important for survival. It involves interactions between the prefrontal cortex and subcortical structures, with inhibition playing a crucial role. However, direct evidence for this in humans is limited. Here, we overcome the difficulty of measuring inhibition in the human brain and find that GABA, the main inhibitory neurotransmitter, affects how the dACC interacts with subcortical structures during appetitive and aversive learning differently. We used 7T magnetic resonance spectroscopy (MRS) to track GABA levels in the dACC alongside whole-brain fMRI scans while participants engaged in appetitive and aversive learning tasks. During appetitive learning, dACC GABA levels were negatively correlated with learning performance and BOLD activity measured from the dACC and the Putamen. While under aversive learning, dACC GABA concentration negatively correlated with the functional connectivity between the dACC and the Putamen. Our results show that inhibition in the dACC mediates appetitive and aversive learning in humans through distinct mechanisms. | | 12:32a |
Reducing maladaptive behavior in neuropsychiatric disorders using network modification
Neuropsychiatric disorders are caused by many factors and produce a wide range of symptomatic maladaptive behaviors in patients. Despite this great variance in causes and resulting behavior, we believe the maladaptive behaviors that characterize neuropsychiatric disorders are most proximally determined by networks of neurons and that this forms a common conceptual link between these disorders. Operating from this premise, it follows that treating neuropsychiatric disorders to reduce maladaptive behavior can be accomplished by modifying the patients network of neurons. In this proof-of-concept computational psychiatry study, we tested this approach in a simple neural network model that produces aversion-resistant alcohol drinking - a key maladaptive behavior associated with alcohol use disorder. We demonstrated that it was possible to predict personalized network modifications that substantially reduced maladaptive behavior without inducing side effects. Furthermore, we found that it was possible to predict effective treatments with limited knowledge of the model and that information about neural activity during certain types of trials was more helpful in predicting treatment than information about model parameters. We hypothesize that this is a general feature of developing effective treatment strategies for networks of neurons. This computational study lays the groundwork for future studies utilizing more biologically realistic network models in conjunction with in vivo data. | | 12:32a |
Normative Growth Modeling of Cortical Thickness Identify Neuroanatomical Variability and Distinct Subtypes in Brainstem Tumor Patients
BackgroundBrainstem tumors can cause structural brain changes, but the resulting heterogeneity within wholebrain structure is not well-studied. This study examines cortical thickness to identify patterns of structural alterations and explore underlying biological subtypes and their associations with clinical factors.
Materials and MethodsThis study involved 124 pediatric brainstem tumor patients, aged 4-18 years. Cortical thickness was measured using CAT12 segmentation of 3D T1-weighted structural MRI. A normative model was established using data from 849 healthy children. Deviations in cortical thickness were estimated, and patients were classified into two subtypes using spectral clustering. Clinical statistical analyses were conducted with SPSS 26.0.
ResultsThe normative model revealed significant heterogeneity in cortical thickness deviations, which correlated with tumor size and growth patterns. Focal tumors primarily caused negative deviations (t = 3.14, p = 0.02). There was a significant positive correlation between extreme positive deviations and tumor volume (r = 0.214, p = 0.010), and between extreme negative deviations and progression-free survival (r = 0.39, p = 0.008). Two subtypes were identified: Subtype 1, consisting of diffuse tumors with extreme positive deviations, and Subtype 2, consisting of focal tumors with extreme negative deviations. Subtype and tumor growth pattern significantly influenced duration (p < 0.01). The Kaplan-Meier survival curves for Subtype 1 and Subtype 2 demonstrated a significant difference in survival probabilities over time (p = 0.03).
ConclusionOverall, this study identifies two major patterns of cortical thickness changes in brainstem tumor patients, enhancing our understanding of their relationship with cortical morphology. The findings suggest that cortical thickness alterations could serve as valuable biomarkers for predicting progression-free survival, which is crucial for clinical assessment and personalized treatment strategies. This research provides new insights into the physiological mechanisms by which brainstem tumors affect brain structure, supporting more precise clinical interventions and efficacy monitoring in the future. | | 12:32a |
Augmenting complex and dynamic performance through mindfulness-based cognitive training: an investigation of on-task EEG dynamics.
Mindfulness-based cognitive training exhibits great propensity for improving cognitive performance across a range of contexts. However, the neurophysiological basis of these cognitive enhancements has remained relatively unclear. Previous studies have widely examined EEG during mindfulness practice - or made comparisons with long-term meditators and controls - but have failed to capture how EEG dynamics in subsequent cognitive testing scenarios might be altered as a function of mindfulness-based interventions. The current study therefore aimed to assess a variety of EEG dynamics (oscillatory, aperiodic, and event-related) during engagement in a dynamic and complex cognitive task, following a mindfulness-based cognitive training regime. Participants (n = 40, age range = 18 - 38) attended the lab on two separate occasions (pre- and post-a web-based one-week mindfulness intervention), where EEG was recorded during engagement in the Target Motion Analyst (TMA) task. Previous analysis of the same participants demonstrated that greater adherence to the mindfulness-based cognitive training was associated with improved performance on the TMA task (Dziego, Bornkessel-Schlesewsky, Schlesewsky et al., 2024). Here, we capitalise on these previous findings to assess whether adherence is paralleled by measurable differences in on-task EEG dynamics. Linear mixed-effects modelling demonstrated that, while main effects were observed across session, adherence to cognitive training was not directly associated with alpha power, theta power or 1/f parameters. Challenges also arose when computing event-related potentials (ERPs), illustrating the difficulties of using this technique in more complex testing environments. While these results are challenging to place within the context of previous EEG studies on meditation and cognitive performance, our findings highlight the complexities in understanding the cognitive benefits of mindfulness-based training interventions through EEG dynamics observed during subsequent cognitive testing. | | 1:48a |
The Body Mirroring Thought: The Relationship Between Thought Transitions and Fluctuations in Autonomic Nervous Activity Mediated by Interoception
Our thought states change unconsciously. This study verified that the transference of thought states varies with fluctuations in autonomic nervous activity, and that this effect is modulated by interoceptive accuracy. The participants completed the heartbeat counting task (HCT) and vigilance task (VT). We assessed the participants interoceptive accuracy based on their performance on the HCT. The VT is a simple attention task, and during this task, we asked the participants to report the content and contemplation of their thoughts. Consequently, participants with accurate interoception were more likely to remain in a highly contemplative thought state when sympathetic activity was activated. In contrast, the dominance of parasympathetic activity facilitated transitions to different thought states or experiences of less contemplative thought states in them. The results suggest that even subtle changes in bodily responses at rest can affect thought transitions in people with accurate interoception. | | 1:48a |
Unraveling the Neural Landscape of Mental Disorders using Double Functional Independent Primitives (dFIPs)
Mental illnesses extract a high personal and societal cost, and thus explorations of the links between mental illness and functional connectivity in the brain are critical. Investigating major mental illnesses, believed to arise from disruptions in sophisticated neural connections, allows us to comprehend how these neural network disruptions may be linked to altered cognition, emotional regulation, and social interactions. Although neuroimaging has opened new avenues to explore neural alterations linked to mental illnesses, the field still requires precise and sensitive methodologies to inspect these neural substrates of various psychological disorders. In this study, we employ a hierarchical methodology to derive double functionally independent primitives (dFIPs) from resting state functional magnetic resonance neuroimaging data (rs-fMRI). These dFIPs encapsulate canonical overlapping patterns of functional network connectivity (FNC) within the brain. Our investigation focuses on the examination of how combinations of these dFIPs relate to different mental disorder diagnoses. The central aim is to unravel the complex patterns of FNC that correspond to the diverse manifestations of mental illnesses. To achieve this objective, we used a large brain imaging dataset from multiple sites, comprising 5805 total individuals diagnosed with schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), and controls. The key revelations of our study unveil distinct patterns associated with each mental disorder through the combination of dFIPs. Notably, certain individual dFIPs exhibit disorder-specific characteristics, while others demonstrate commonalities across disorders. This approach offers a novel, data-driven synthesis of intricate neuroimaging data, thereby illuminating the functional changes intertwined with various mental illnesses. Our results show distinct signatures associated with psychiatric disorders, revealing unique connectivity patterns such as heightened cerebellar connectivity in SCZ and sensory domain hyperconnectivity in ASD, both contrasted with reduced cerebellar-subcortical connectivity. Utilizing the dFIP concept, we pinpoint specific functional connections that differentiate healthy controls from individuals with mental illness, underscoring its utility in identifying neurobiological markers. In summary, our findings delineate how dFIPs serve as unique fingerprints for different mental disorders. | | 8:31a |
Word-selective EEG/MEG responses in the English language obtained with Fast Periodic Visual Stimulation (FPVS)
Fast periodic visual stimulation (FPVS) allows the recording of objective brain responses of human word discrimination (i.e., reproducible word-category-selective responses) with a high signal-to-noise ratio. This approach has been successfully employed over the last decade in a number of scalp electroencephalography (EEG) studies. Three important advances were achieved in this study: (1) robust measures of written word-selective responses with this approach have not been reported in English; (2) responses have only been reported in EEG but not with MEG, and (3) without source localization. Thus, we presented English words periodically (2 Hz) among different types of letter strings (10Hz; consonant strings, non-words, pseudowords) whilst recording simultaneous EEG and MEG in 25 participants who performed a simple non-linguistic color detection task. Data were analyzed in sensor and in source space (L2-minimum-norm estimation, MNE). With only 4 minutes of stimulation we observed a robust word discrimination response in each condition including, importantly, even when words were embedded in word-like pseudowords. This response was larger in nonwords and largest in consonant strings. We observed left-lateralized responses in all conditions in the majority of our participants. Cluster-based permutation tests revealed that these responses were left-lateralized in sensor as well as in source space, with peaks in left posterior regions. Our results demonstrate that the FPVS paradigm can elicit robust English word-discrimination responses in EEG and MEG within only a few minutes of recording time. Together with source estimation, this can provide novel insights into the neural basis of visual word recognition in healthy and clinical populations. | | 8:31a |
Distinct neuromodulatory effects of endogenous orexin and dynorphin corelease on projection-defined ventral tegmental dopamine neurons.
Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues and circuit-specific signaling drives different aspects of motivated behavior. Orexins (ox; also known as hypocretin) and dynorphin (dyn) are co-expressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors, respectively. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the co-released peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LHox/dyn neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregates based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch clamp electrophysiology in male and female orexincre mice we showed a diverse response of LHox/dyn optical stimulation on VTADA neuronal firing, that are not mediated by fast transmitter release and are blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA projecting VTADA neurons, optical stimulation of LHox/dyn inputs in the VTA bidirectionally affects firing of either lAcbSh or mAchSh projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.
Significance StatementThe mesolimbic dopamine (DA) system is known to play a crucial role in motivation and reward-learning and receives neuromodulatory input from the lateral hypothalamus (LH). We show that optical stimulation of the orexin-containing LH input in the VTA releases both orexin and dynorphin to bidirectionally alter VTADA firing. Furthermore, orexin and dynorphin differentially modulate firing of DA inputs to the basolateral amygdala, whereby dynorphin predominates, or to the nucleus accumbens which is sensitive to both neuromodulators. Our findings contribute to a more comprehensive understanding of the neuromodulatory effects of coreleased LH orexin and dynorphin on the VTADA system. | | 8:31a |
Co-activation of LIN28A and CTNNB1 disturbs cortical neuronal migration and pia mater integrity
Developmental signalling pathways act in stage and tissue dependent relation and mis-activation can drive tumour formation. The RNA-binding protein LIN28A maintains stemness and is overexpressed in embryonal brain tumours. Activating mutations of CTNNB1 - the WNT pathway effector - have been reported in respective brain tumours. The aim of this study was to investigate the interplay of these oncogenic proteins during embryonal brain development.
The combination of both oncogenic factors did not lead to brain tumour formation but resulted in disturbed lamination and impaired cell migration in the cerebral cortex. Spatially resolved proteome analysis revealed imbalances of the extracellular matrix protein LAMB1 and its receptors RPSA and ITGB1 accompanied by a porous pial border and overmigration of neural cells. Cajal-Retzius cells were misplaced in deeper cortex regions without affecting general REELIN levels and additional reduced levels of -DYSTROGLYCAN.
Taken together, the interplay of LIN28A and CTNNB1 resulted in a cortical migration disorder showing histomorphological and molecular similarities to human Cobblestone lissencephaly (type 2), highlighting novel implications of the oncogene LIN28A in extracellular matrix integrity. | | 8:31a |
Uncovering Individualized Cerebellar Atrophy Pattern and Behavioral Links in Children with Brainstem Tumor
BackgroundBrainstem tumors are rare and result in enduring behavioral issues, posing challenges for patients and surgeons. Despite similarities in symptoms to those resulting from cerebellar injuries, limited research has investigated cerebellar changes in patients with brainstem tumors.
MethodsHere, we employed U-Net-based segmentation to analyze the cerebellum in 26 regions, assessing individual volume deviations. Additionally, we developed a behavior prediction model using the total outlier count (tOC) index and brain volume as features.
FindingsOur normative model results revealed that most patients exhibited negative deviation in most cerebellar regions, particularly in lobule Right V, Left I-III, Right X, and Left X. The results found a significant association between a higher tOC and severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Further analysis showed that smaller cerebellar regions correlated strongly with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules such as Right X, V, IV, and VIIB, along with Left IX, VIII, and X exerted the greatest influence on social problems, whereas regions including Left V, Right IV, and Vermis VI and VIII were most impactful on withdrawal behavior.
InterpretationIn summary, our study revealed cerebellar atrophy patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.
FundingThis study was supported by the STI2030-Major Projects 2021ZD0200201 and Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (grant ID: JYY202X-X).
Research in ContextOur previous neuropsychological research has demonstrated that patients with brainstem tumors exhibit a wide range of cognitive and behavioral abnormalities, which closely resemble cerebellar cognitive affective syndrome (CCAS). Dines et al. hypothesized, based on cognitive impairment observed in patients with brainstem injury, that the brainstem, as an integral part of the cerebellar-cortex pathway, plays a role in cognitive processing. Consequently, brainstem injury may lead to cerebellar dysfunction. Previous studies have also reported that gangliocytoma located in the brainstem can cause ipsilateral cerebellar atrophy. These findings suggest that cerebellar injury may be present in patients with brainstem tumors. However, no systematic studies have investigated the pattern of cerebellar injury in these patients and its association with cognitive and behavioral disorders.
Added value of this studyThis study revealed the pattern of cerebellar heterogeneity in patients with brainstem tumors. Further, this study provides evidences for the cerebellums role beyond motor control, underscoring its involvement in complex social behaviors. This study provides insight into automatic cerebellar segmentation algorithm applied to patients dataset.
Implications of all the available evidenceThis study is first to successfully apply machine learning for segmenting deformed cerebellums, providing a reference for future large-sample studies of diseased cerebellum and brainstems. Moreover, this study provides evidence that the brainstem and cerebellum are involved in complex cognitive processing. Future research should focus on developing personalized treatment and rehabilitation programs for patients with brainstem tumors and cerebellar injury to improve their prognosis. | | 5:15p |
Optogenetic hedonic hotspots in orbitofrontal cortex and insula: causing enhancement of sweetness liking
Hedonic hotspots are brain subregions that causally amplify the hedonic impact of palatable tastes, measured as increases in affective orofacial liking reactions to sweetness. Previously, two cortical hedonic hotspots in orbitofrontal cortex and insula were identified by neurochemical stimulation using opioid or orexin microinjections. Here we used optogenetic stimulation in rats as an independent neurobiological technique for activating cortical hedonic hotspots to identify hedonic functions and map boundaries. We report that channelrhodopsin stimulations within rostral orbitofrontal and caudal insula hotspots doubled the number of hedonic liking reactions elicited by sucrose taste. This independently confirms their robust functional identity as causal amplifiers of hedonic liking and confirms their anatomical boundaries. Additionally, we confirmed an intervening suppressive hedonic coldstrip, to stretching from caudal orbitofrontal cortex to rostral insula. By contrast to localized hedonic hotspots for liking enhancement, motivational wanting for reward, measured as laser self-stimulation, was mediated by more widely distributed anatomical sites. |
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