Subcortical Areas Research Articles

Computational modeling of attractor-based neural processes involved in the preparation of voluntary actions

AbstractVolition is conceived as a set of orchestrated executive functions, which can be characterized by features, such as reason-based and goal-directedness, driven by endogenous signals. The lateral prefrontal cortex (LPFC) has long been considered to be responsible for cognitive control and executive function, and its neurodynamics appears to be central to goal-directed cognition. In order to address both associative processes (i.e. reason-action and action-outcome) based on internal stimuli, it seems essential to consider the interconnectivity of LPFC and the anterior cingulate cortex (ACC). The critical placement of ACC as a hub mediates projection of afferent expectancy signals directly from brain structures associated with emotion, as well as internal signals from subcortical areas to the LPFC. Apparently, the two cortical areas LPFC and ACC play a pivotal role in the formation of voluntary behaviors. In this paper, we model the neurodynamics of these two neural structures and their interactions related to intentional control. We predict that the emergence of intention is the result of both feedback-based and competitive mechanisms among neural attractors. These mechanisms alter the dimensionalities of coexisting chaotic attractors to more stable, low dimensional manifolds as limit cycle attractors, which may result in the onset of a readiness potential (RP) in SMA, associated with a decision to act.

Distinct neural representations during a brain–machine interface and manual reaching task in motor cortex, prefrontal cortex, and striatum

Although brain–machine interfaces (BMIs) are directly controlled by the modulation of a select local population of neurons, distributed networks consisting of cortical and subcortical areas have been implicated in learning and maintaining control. Previous work in rodents has demonstrated the involvement of the striatum in BMI learning. However, the prefrontal cortex has been largely ignored when studying motor BMI control despite its role in action planning, action selection, and learning abstract tasks. Here, we compare local field potentials simultaneously recorded from primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), and the caudate nucleus of the striatum (Cd) while nonhuman primates perform a two-dimensional, self-initiated, center-out task under BMI control and manual control. Our results demonstrate the presence of distinct neural representations for BMI and manual control in M1, DLPFC, and Cd. We find that neural activity from DLPFC and M1 best distinguishes control types at the go cue and target acquisition, respectively, while M1 best predicts target-direction at both task events. We also find effective connectivity from DLPFC → M1 throughout both control types and Cd → M1 during BMI control. These results suggest distributed network activity between M1, DLPFC, and Cd during BMI control that is similar yet distinct from manual control.

Potential therapeutic benefit of spinal cord stimulation in restless legs syndrome: scoping review and mechanistic considerations.

Restless legs syndrome (RLS) is a prevalent sensorimotor disorder that can dramatically impair sleep quality, daytime function, and quality of life. Although many patients benefit from standard pharmacological therapy, some patients suffer from insufficient treatment response or medication intolerance. Novel treatment approaches are therefore necessary. Given the overlap between RLS and pain syndromes in both pathophysiological mechanisms and certain treatment options, we aimed to perform a scoping review of the available evidence on spinal cord stimulation (SCS) for RLS and discuss potential mechanistic implications. We identified a total of 16 cases of patients with RLS who underwent SCS, all from case reports or case series. The published evidence is insufficient to assess SCS efficacy in patients with RLS, but SCS remains a promising investigational therapy in RLS on the basis of its potential mitigatory effects in the central hyperexcitability of the sensorimotor cortex through neuromodulation of spinal, subcortical, and cortical areas. A call for further research in this field is presented, with suggestions for future directions and trial designs.

Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions.

Understanding how the brain's macroscale dynamics are shaped by underlying microscale mechanisms is a key problem in neuroscience. In animal models, we can now investigate this relationship in unprecedented detail by directly manipulating cellular-level properties while measuring the whole-brain response using resting-state fMRI. Here, we focused on understanding how blood-oxygen-level-dependent (BOLD) dynamics, measured within a structurally well-defined striato-thalamo-cortical circuit in mice, are shaped by chemogenetically exciting or inhibiting D1 medium spiny neurons (MSNs) of the right dorsomedial caudate putamen (CPdm). We characterize changes in both the BOLD dynamics of individual cortical and subcortical brain areas, and patterns of inter-regional coupling (functional connectivity) between pairs of areas. Using a classification approach based on a large and diverse set of time-series properties, we found that CPdm neuromodulation alters BOLD dynamics within thalamic subregions that project back to dorsomedial striatum. In the cortex, changes in local dynamics were strongest in unimodal regions (which process information from a single sensory modality) and weakened along a hierarchical gradient towards transmodal regions. In contrast, a decrease in functional connectivity was observed only for cortico-striatal connections after D1 excitation. Our results show that targeted cellular-level manipulations affect local BOLD dynamics at the macroscale, such as by making BOLD dynamics more predictable over time by increasing its self-correlation structure. This contributes to ongoing attempts to understand the influence of structure-function relationships in shaping inter-regional communication at subcortical and cortical levels.

Association of Sleep Disturbances With Brain Amyloid and Tau Burden, Cortical Atrophy, and Cognitive Dysfunction Across the AD Continuum.

Patients with Alzheimer disease (AD) frequently suffer from various sleep disturbances. However, how sleep disturbance is associated with AD and its progression remains poorly investigated. We investigated the association of total sleep time with brain amyloid and tau burden, cortical atrophy, cognitive dysfunction, and their longitudinal changes in the AD spectrum. In this retrospective cohort study, we enrolled participants on the AD spectrum who were positive on 18F-florbetaben (FBB) PET. All participants underwent the Pittsburgh Sleep Quality Index, brain MRI, FBB PET, 18F-flortaucipir (FTP) PET, and detailed neuropsychological testing. In addition, a subset of participants completed follow-up assessments. We analyzed the association of total sleep time with the baseline and longitudinal FBB-standardized uptake value ratio (SUVR), FTP-SUVR, cortical thickness, and cognitive domain composite scores. We examined 138 participants on the AD spectrum (15 with preclinical AD, 62 with prodromal AD, and 61 with AD dementia; mean age 73.4 ± 8.0 years; female 58.7%). Total sleep time was longer in the AD dementia group (7.4 ± 1.6 hours) compared with the preclinical (6.5 ± 1.4 hours; p = 0.026) and prodromal groups (6.6 ± 1.4 hours; p = 0.001), whereas other sleep parameters did not differ between groups. Longer total sleep time was not associated with amyloid accumulation but rather with tau accumulation, especially in the amygdala, hippocampus, basal forebrain, insular, cingulate, occipital, inferior temporal cortices, and precuneus. Longer total sleep time predicted faster tau accumulation in Braak regions V-VI (β = 0.016, p = 0.007) and disease progression to mild cognitive impairment or dementia (hazard ratio = 1.554, p = 0.024). Longer total sleep time was also associated with memory deficit (β = -0.19, p = 0.008). Prolonged total sleep time was associated with tau accumulation in sleep-related cortical and subcortical areas as well as memory dysfunction. It also predicted faster disease progression with tau accumulation. Our study highlights the clinical importance of assessing total sleep time as a marker for disease severity and prognosis in the AD spectrum.

A - 128 Sex Differences in CBF in a Pediatric Sample of Depression: a SPECT Analysis.

The present study aims to determine whether there are differences in cerebral blood flow (CBF) levels in females versus males with depression. The data for this study was derived from an archival SPECT database. Participants in the female group (n = 140, Mage = 14.48) were like those in the male group (n = 241, Mage = 13.77). Multiple independent t-tests were performed between the female and male groups on the CBF levels in the left and right sides of the cerebellum, cingulum, frontal, occipital, parietal, and temporal lobes, and subcortical areas. CBF levels in males were higher than those of females in the following areas: the left and right sides of the cerebellum, and occipital lobe, the right side of the parietal lobe, and the temporal lobe. CBF levels in females were higher than those of males in the following areas: the left and right sides of the cingulum, the vermis, and the subcortical areas. While females had higher CBF in subcortical areas, the findings regarding higher CBF levels in males raise questions regarding prior literature which suggested that females have higher CBF than males in studies of depression subjects. These differences may be due to the differences in how males and females cope with depressive symptoms. Sex differences in CBF may suggest a contributing factor in the relationship between sex and responsiveness to antidepressant medication, ketamine treatment, and transcranial magnetic stimulation.

B - 22 Cerebral Blood Flow in Patients with Autism Spectrum Disorder.

The current study aims to investigate whether hyperactivity is present in the parietal lobe of individuals with autism spectrum disorder (ASD). The data for this study was derived from an archival SPECT database. Participants in the ASD group (n = 91, Mage = 10.07, 78% male, 20.9% female, 1.1% others) were like those in the control group (n = 2983, Mage = 12.20, 69.7% male, 30% female, 0.3% other). Multiple independent t-tests were performed between the ASD and control groups on CBF levels in the left and right sides of the parietal lobe. Statistically significant differences existed between the ASD and control groups on CBF levels as follows: left and right side of the cerebellum, frontal lobe, occipital lobe, temporal lobe, vermis, and subcortical areas. In all cases, CBF was higher in the control group than in the ASD group. Findings suggest lower CBF within these areas in individuals with ASD may lead to why children with ASD have difficulties regulating emotions, over sensitivity to auditory stimuli, hand posturing, toe walking, or repetitive behaviors (such as flapping). These areas with lower CBF also lead to poorer memory functioning; these findings may suggest children with ASD have limited ability to remember large amount of information which may suggest why children with ASD have specific interests.

Volumetric brain correlates of gait associated with cognitive decline in community-dwelling older adults.

To determine the extent to which the regional brain volumes associated with slow gait speed can inform subsequent cognitive decline in older adults from the Rush Memory and Aging Project. We utilized deformation-based morphometry (DBM) in a whole-brain exploratory approach to identify the regional brain volumes associated with gait speed assessed over a short distance during an in-home assessment. We created deformation scores to summarize the gait-associated regions and entered the scores into a series of longitudinal mixed effects models to determine the extent to which deformation predicted change in cognition over time, controlling for associations between gait and cognition. In 438 older adults (81 ± 7; 76% female), DBM revealed that slower gait speed was associated with smaller volumes across frontal white matter, temporal grey matter, and subcortical areas and larger volumes in the ventricles during the same testing cycle. When a subset was followed over multiple (5 ± 2) years, slower gait speed was also associated with annual declines in global cognition, executive functioning, and memory abilities. Several of the gait-related brain structures were associated with these declines in cognition; however, larger ventricles and smaller medial temporal lobe volumes proved most robust and attenuated the association between slow gait and cognitive decline. Regional brain volumes in the ventricles and temporal lobe associated with both slow gait speed and faster cognitive decline have potential to improve risk stratification for cognitive decline in older adults.

Identification of cognitive load-dependent activation patterns using working memory task-based fMRI at various levels of difficulty

Working memory, which is regarded as the foundation of cognitive processes, is a system that stores, processes, and manipulates information in short intervals of time that are actually needed for daily functioning. This study aimed to assess the brain activity of healthy controls (HC) while performing the N-back task, which is one of the most popularly used tests for evaluating working memory along with functional magnetic resonance imaging (fMRI). In this regard, we collected fMRI data from right-handed individuals in a 3.0 T scanner during the Persian version of the visual variant N-back task performance with three levels of complexity varied throughout the experiment (1, 2, and 3-back conditions) to increase the cognitive demands. The statistical parametric mapping (SPM12) software was used to analyze fMRI data for the identification of cognitive load-dependent activation patterns based on contrast images obtained from different levels of task difficulty. Our findings showed that as cognitive complexity increased, the number of significant activation clusters and cluster extent increased in several areas distributed in the cerebellum, frontoparietal lobes, insula, SMA, and lenticular nucleus, the majority of which are recognized for their role in working memory. Furthermore, deactivation patterns during 1-, 2-, and 3-back vs. 0-back contrasts revealed significant clusters in brain regions that are mostly described as being part of the default mode network (DMN). Based on previous research, our results supported the recognized involvement of the mentioned cortical and subcortical areas in various types or levels of N-back tasks. This study found that altering activation patterns by increasing task difficulty could aid in evaluating the various stages of cognitive dysfunction in many brain diseases such as multiple sclerosis (MS) and Alzheimer's disease by comparing controls in future studies to apply early appropriate treatment strategies.

Philosophy of Body: Movement and Thought

Human thinking is modeled on the body in much the same way as hominid thinking was (Sheets-Johnstone, 1990, 4, 25). The hominid experience of moving was the cornerstone of the experience of the precinct of I can. The experience of I can subsequently formed the basis for corporeal and topological concepts. These, in turn, generated analogical insights. One sees, accordingly, not only an intermingling of the bodily experience and discernment, but also everywhere indications of analogical thinking at the root of hominid tool-building. Self-movement is the mainspring of one’s experience of oneself as an agent endowed with free-will-related activities. It is the creative fount of one’s ideas of space and time. The phenomenon of moving oneself structures how one knows the world. Moving oneself is a manner of coming to knowledge. The Lives of species-specific bodies are built on thinking in movement. Studies provide ample evidence to show a fundamental correlation between motor and cognitive development. This developmental correlation is also found in both the prefrontal cortex and the cerebellum. Both cognitive and motor developments reveal a prolonged developmental timetable. Both the prefrontal cortex and the cerebellum attain maturity much later. Studies by Adele Diamond and others show that the cerebellum is not only involved in motor operations but also in cognitive functions. Conversely, the prefrontal cortex, with (the help of) its connection with the cortical and subcortical areas that are critical for movement control, is involved in both motor and cognitive functions. Thus both motor and cognitive behaviours seem to belong together; and the body appears crucially involved in the activities of the mind (Diamond, 2000, 44, 49; Bushnell & Boudreau, 1993, 1008, 1015-1017; Burns et al., 2004, 19-29)

Quantitative Analysis of BrainAge using Neuroimaging Data to Estimate Radiation-Induced Brain Aging and Associations with Cognitive Changes in Brain Metastases Patients

Radiotherapy is critical in brain tumor management yet causes accelerated aging via irreparable damage to white matter, cortex, and subcortical areas. BrainAGE is an open-source machine learning tool that analyses morphology from raw quantitative structural MRI to generate a predictive 'BrainAge' value, enabling analyses of patients with neurodegenerative diseases. We assessed the utility of this algorithm in measuring brain age morphology in brain metastases patients on a clinical trial, analyzed differences in BrainAge and chronological age, and explored associations with cognitive performance. We analyzed pre-SRS high-resolution T1-weighted noncontrast volumetric MRI in patients with brain metastases (n = 57, median age 63 years, range 20-87) treated on a prospective clinical trial of cognitive-sparing SRS. The BrainAGE machine learning tool processed images to derive a BrainAge; it reliably generates this value using a Gaussian Processes regression, with a robust neurotypical training cohort. We examined correlations between BrainAge and chronological age with regression. Brain-predicted age gap (Brain-Gap) was calculated, defined as the difference between a patient's BrainAge and chronological age. We assessed cognitive function at baseline pre-SRS with a comprehensive battery of validated tests across multiple domains performed by a neuropsychologist, including memory (HVLT total), executive function (COWAT category fluency), and language (COWAT letter fluency). Raw test scores were scaled to T-scores adjusting for age, sex, and education level per testing norms. We examined if Brain-Gap was associated with cognitive performance pre-SRS. BrainAGE software was robust, estimating a BrainAge for all input MRI sequences. We found a strong correlation between BrainAge and chronological age (r-squared = 0.82). The Brain-Gap median value was 0.84 and the mean was -0.90, in years (range -18.30-11.36 years). Brain-Gap was not significantly associated with cognitive performance across the three tests at the pre-SRS timepoint. Among patients with impaired cognition (T<35), there was no significant difference in BrainAge relative to chronological age. To our knowledge, this is the first study utilizing the BrainAGE model as a biomarker of neuroanatomical age for brain tumors patients. Existing publications had lesion-free cohorts. Our results show that BrainAge was reliably associated with chronologic age in brain metastases patients pre-SRS. The Brain-Gap difference was minimal at baseline, and we found no significant association with pre-SRS cognitive performance. Future studies will examine this biomarker after SRS to look for individual aging radiation effects and prediction for cognitive changes after therapy.

The Impact of Cerebral Ischemia on Antioxidant Enzymes Activity and Neuronal Damage in the Hippocampus.

Cerebral ischemia and subsequent reperfusion, leading to reduced blood supply to specific brain areas, remain significant contributors to neurological damage, disability, and mortality. Among the vulnerable regions, the subcortical areas, including the hippocampus, are particularly susceptible to ischemia-induced injuries, with the extent of damage influenced by the different stages of ischemia. Neural tissue undergoes various changes and damage due to intricate biochemical reactions involving free radicals, oxidative stress, inflammatory responses, and glutamate toxicity. The consequences of these processes can result in irreversible harm. Notably, free radicals play a pivotal role in the neuropathological mechanisms following ischemia, contributing to oxidative stress. Therefore, the function of antioxidant enzymes after ischemia becomes crucial in preventing hippocampal damage caused by oxidative stress. This study explores hippocampal neuronal damage and enzymatic antioxidant activity during ischemia and reperfusion's early and late stages.

Relationships between Late-Life Blood Pressure and Cerebral Microinfarcts in Octogenarians: An Observational Autopsy Study.

Mid-life high blood pressure (BP) is a risk factor for cerebral microinfarcts. Less is known about the relationship between late-life BP and cerebral microinfarcts, the examination of which is the objective of the current study. This case-control study analyzed data from 551 participants (94.6% aged ≥80 years; 58.6% women) in the Adult Changes in Thought (ACT) study who had autopsy data on microinfarcts and four values of systolic and diastolic blood pressure (SBP and DBP) before death. Using the average of four values, SBP was categorized using 10 mmHg intervals; a trend was defined as a ≥10 mmHg rise or fall from the first to fourth values (average gap of 6.5 years). Multivariable-adjusted regression models were used to examine the associations of BP and microinfarcts, adjusting for age, sex, last BP-to-death time, APOE genotype, and antihypertensive medication use. Microinfarcts were present in 274 (49.7%) participants; there were multiple in 51.8% of the participants, and they were located in cortical areas in 40.5%, subcortical areas in 29.6%, and both areas in 29.9% of the participants. All SBP categories (reference of 100-119 mmHg) and both SBP trends were associated with higher odds of both the presence and number of microinfarcts. The magnitude of these associations was numerically greater for subcortical than cortical microinfarcts. Similar associations were observed with DBP. These hypothesis-generating findings provide new information about the overall relationship between BP and cerebral microinfarcts in octogenarians.

Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Brain Response to Interferential Current Compared with Alternating Current Stimulation.

Temporal interference (TI) stimulation, which utilizes multiple external electric fields with amplitude modulation for neural modulation, has emerged as a potential noninvasive brain stimulation methodology. However, the clinical application of TI stimulation is inhibited by its uncertain fundamental mechanisms, and research has previously been restricted to numerical simulations and immunohistology without considering the acute in vivo response of the neural circuit. To address the characterization and understanding of the mechanisms underlying the approach, we investigated instantaneous brainwide activation patterns in response to invasive interferential current (IFC) stimulation compared with low-frequency alternative current stimulation (ACS). Results demonstrated that IFC stimulation is capable of inducing regional neural responses and modulating brain networks; however, the activation threshold for significantly recruiting a neural response using IFC was higher (at least twofold) than stimulation via alternating current, and the spatial distribution of the activation signal was restricted. A distinct blood oxygenation level-dependent (BOLD) response pattern was observed, which could be accounted for by the activation of distinct types of cells, such as inhibitory cells, by IFC. These results suggest that IFC stimulation might not be as efficient as conventional brain modulation methods, especially when considering TI stimulation as a potential alternative for stimulating subcortical brain areas. Therefore, we argue that a future transcranial application of TI on human subjects should take these implications into account and consider other stimulation effects using this technique.

Synaptic crossroads: navigating the circuits of movement

The anterior lateral motor area (ALM) is crucial in preparing and executing voluntary movements through its diverse neuronal subpopulations that target different subcortical areas. A recent study by Xu et al. utilized an elaborate viral tracing strategy in mice to provide comprehensive whole-brain maps of monosynaptic inputs to the major descending pathways of ALM.

Assessment of the glymphatic function in children with attention-deficit/hyperactivity disorder.

Whether the alternation of the glymphatic system exists in neurodevelopmental disease still remains unclear. In this study, we investigated structural and functional changes in the glymphatic system in the treatment-naïve attention-deficit/hyperactivity disorder (ADHD) children by quantitatively measuring the Virchow-Robin spaces (VRS) volume and diffusion tensor image-analysis along the perivascular space (DTI-ALPS). Forty-seven pediatric ADHD patients and 52 age- and gender-matched typically developing (TD) children were recruited in this prospective study. The VRS volume was calculated using a semi-automated approach in axial T2-weighted images. Diffusivities along the x-, y-, and z-axes in the projection, association, and subcortical neural fiber areas were measured. The ALPS index, a ratio that accentuated water diffusion along the perivascular space, was calculated. The Mann-Whitney U test was used to compare the quantitative parameters; Pearson's correlation was used to analyze the correlation with clinical symptoms. The cerebral VRS volume (mean, 15.514mL vs. 11.702mL) and the VRS volume ratio in the ADHD group were larger than those in the TD group (all p < 0.001). The diffusivity along the x-axis in association fiber area and ALPS index were significantly smaller in the ADHD group vs. TD group (mean, 1.40 vs.1.59, p < 0.05 after false discovery rate adjustment). Besides, the ALPS index was related to inattention symptoms of ADHD (r = - 0.323, p < 0.05). Our study suggests that the glymphatic system alternation may participate in the pathogenesis of ADHD, which may be a new research direction for exploring the mechanisms of psycho-behavioral developmental disorders. Moreover, the VRS volume and ALPS index could be used as the metrics for diagnosing ADHD. Considering the potential relevance of the glymphatic system for exploring the mechanisms of attention deficit/hyperactivity, the Virchow-Robin spaces volume and the analysis along the perivascular space index could be used as additional metrics for diagnosing the disorder. • Increased Virchow-Robin space volume and decreased analysis along the perivascular space index were found in the treatment-naïve attention-deficit/hyperactivity disorder children. • The results of this study indicate that the glymphatic system alternation may have a valuable role in the pathogenesis of attention-deficit/hyperactivity disorder. • The analysis along the perivascular space index is correlated with inattention symptoms of attention-deficit/hyperactivity disorder children.

Locating causal hubs of memory consolidation in spontaneous brain network in male mice

Memory consolidation after learning involves spontaneous, brain-wide network reorganization during rest and sleep, but how this is achieved is still poorly understood. Current theory suggests that the hippocampus is pivotal for this reshaping of connectivity. Using fMRI in male mice, we identify that a different set of spontaneous networks and their hubs are instrumental in consolidating memory during post-learning rest. We found that two types of spatial memory training invoke distinct functional connections, but that a network of the sensory cortex and subcortical areas is common for both tasks. Furthermore, learning increased brain-wide network integration, with the prefrontal, striatal and thalamic areas being influential for this network-level reconfiguration. Chemogenetic suppression of each hub identified after learning resulted in retrograde amnesia, confirming the behavioral significance. These results demonstrate the causal and functional roles of resting-state network hubs in memory consolidation and suggest that a distributed network beyond the hippocampus subserves this process.

Cannabinoid receptor gene CNR1 is downregulated in subcortical brain samples and upregulated in blood samples of individuals with schizophrenia: A participant data systematic meta-analysis.

Cannabis use leads to symptom exacerbation in schizophrenia patients, and endocannabinoid ligands have been studied as tentative schizophrenia therapeutics. Here, we aimed to characterise the connection between schizophrenia and the cannabinoid receptor 1 gene (CNR1) and explore possible mechanisms affecting its expression in schizophrenia. We performed a participant data systematic meta-analysis of CNR1 gene expression and additional endocannabinoid system genes in both brain (subcortical areas) and blood samples. We integrated eight brain sample datasets (overall 316 samples; 149 schizophrenia and 167 controls) and two blood sample datasets (overall 90 samples; 53 schizophrenia and 37 controls) while following the PRISMA meta-analysis guidelines. CNR1 was downregulated in subcortical regions and upregulated in blood samples of patients with schizophrenia. CNR2 and genes encoding endocannabinoids synthesis and degradation did not show differential expression in the brain or blood, except fatty acid amide hydrolase (FAAH), which showed a downregulation trend in blood. In addition, the brain expression levels of CNR1 and three GABA receptor genes, GABRA1, GABRA6 and GABRG2, were positively correlated (R = .57, .36, .54; p = 2.7 × 10-14 , 6.9 × 10-6 and 1.1 × 10-12 , respectively). Brain CNR1 downregulation and the positive correlation with three GABA receptor genes suggest an association with GABA neurotransmission and possible effects on negative schizophrenia symptoms. Further studies are required for clarifying the opposite CNR1 dysregulation in the brain and blood of schizophrenia patients and the potential of endocannabinoid ligands as schizophrenia therapeutics.

Generation and propagation of bursts of activity in the developing basal ganglia.

The neonatal brain is characterized by intermittent bursts of oscillatory activity interspersed by relative silence. Although well-characterized for many cortical areas, to what extent these propagate and interact with subcortical brain areas is largely unknown. Here, early network activity was recorded from the developing basal ganglia, including motor/somatosensory cortex, dorsal striatum, and intralaminar thalamus, during the first postnatal weeks in mice. An unsupervised detection and classification method revealed two main classes of bursting activity, namely spindle bursts and nested gamma spindle bursts, characterized by oscillatory activity at ~ 10 and ~ 30Hz frequencies, respectively. These were reliably identified across all three brain regions and exhibited region-specific differences in their structural, spectral, and developmental characteristics. Bursts of the same type often co-occurred in different brain regions and coherence and cross-correlation analyses reveal dynamic developmental changes in their interactions. The strongest interactions were seen for cortex and striatum, from the first postnatal week onwards, and cortex appeared to drive burst events in subcortical regions. Together, these results provide the first detailed description of early network activity within the developing basal ganglia and suggest that cortex is one of the main drivers of activity in downstream nuclei during this postnatal period.