Cerebellar Lobules Research Articles

Single Photon Computed Tomography (SPECT) Findings in Cases with Japanese Adult- Attention-Deficit/Hyperactivity Disorder (ADHD): Special Attention to Cerebellar Posterior Lobe Hypoperfusion on Iodoamphetamine (IMP) SPECT using 3 Dimensional Stereotactic Surface Projection (3D-SSP) Analysis

Single Photon Computed Tomography (SPECT) Findings in Cases with Japanese Adult- Attention-Deficit/Hyperactivity Disorder (ADHD): Special Attention to Cerebellar Posterior Lobe Hypoperfusion on Iodoamphetamine (IMP) SPECT using 3 Dimensional Stereotactic Surface Projection (3D-SSP) Analysis

Reduced volume of the left cerebellar lobule VIIb and its increased connectivity within the cerebellum predict more general psychopathology one year later via worse cognitive flexibility in children

Predicting the risk for general psychopathology (the p factor) requires the examination of multiple factors ranging from brain to cognitive skills. While an increasing number of findings have reported the roles of the cerebral cortex and executive functions, it is much less clear whether and how the cerebellum and cognitive flexibility (a core component of executive function) may be associated with the risk for general psychopathology. Based on the data from more than 400 children aged 6–12 in the Children School Functions and Brain Development (CBD) Project, this study examined whether the left cerebellar lobule VIIb and its connectivity within the cerebellum may prospectively predict the risk for general psychopathology one year later and whether cognitive flexibility may mediate such predictions in school-age children. The reduced gray matter volume in the left cerebellar lobule VIIb and the increased connectivity of this region to the left cerebellar lobule VI prospectively predicted the risk for general psychopathology and was partially mediated by worse cognitive flexibility. Deficits in cognitive flexibility may play an important role in linking cerebellar structure and function to the risk for general psychopathology.

Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency

A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation—the intercrural fissure in particular—in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency.

Chemogenetic Perturbation of the Posterior But Not Anterior Cerebellum Reduces Voluntary Ethanol Consumption.

The cerebellum communicates with brain areas critically involved in control of goal-directed behaviors including the prefrontal and orbitofrontal cortices and midbrain and basal ganglia structures. In particular, the posterior cerebellum is important for cognitive flexibility and has been implicated in alcohol and drug-related memory. We hypothesized that the cerebellum, through its multiple connections to reward-related brain circuitry, regulates alcohol consumption. To test this, we expressed inhibitory designer receptors exclusively activated by designer drugs (DREADDs) in molecular layer interneurons (MLIs) in anterior (IV-V) or posterior (VI-VIII) cerebellar lobules of male and female mice and activated them during alcohol drinking sessions. In a home-cage drinking paradigm, alcohol consumption was significantly decreased by clozapine-N-oxide (CNO) or deschloroclozapine (DCZ) administration in male mice expressing DREADDs in posterior but not anterior lobules. CNO/DCZ injections did not affect drinking in DREADD expressing female mice or in male mice expressing the control vector. Activation of DREADDs expressed in anterior or posterior lobules had no effect on sucrose or quinine consumption in male or female mice. During operant self-administration sessions, DCZ decreased the number of licks and bouts in male but not female mice expressing DREADDs in posterior lobules with no effect in control vector mice. Performance on an accelerated rotarod was unaffected by chemogenetic manipulation while distance traveled in the open field was decreased by DREADD activation in anterior but not posterior lobules. These results indicate that neuronal activity within the posterior cerebellar cortex plays an important role in the control of alcohol consumption in male mice.

Structural Cerebellar Lobules Correlates of Dystonic Head Rotation in Idiopathic Cervical Dystonia

Structural Cerebellar Lobules Correlates of Dystonic Head Rotation in Idiopathic Cervical Dystonia

Topographic organization in the cerebellar nuclei and inferior olive in relation to cerebellar hemispheric lobules in the mouse: Distinction between crus I and neighboring lobules.

The parallel closed-loop topographic connections between subareas of the inferior olive (IO), cerebellar cortex, and cerebellar nuclei (CN) define the fundamental modular organization of the cerebellum. The cortical modules or zones are organized into longitudinal zebrin stripes which are extended across transverse cerebellar lobules. However, how cerebellar lobules, which are related to the cerebellar functional localization, are incorporated into the olivo-cortico-nuclear topographic organization has not been fully clarified. In the present study, we analyzed the lobular topography in the CN and IO by making 57 small bidirectional tracer injections in the lateral zebrin-positive stripes equivalent with C2, D1, and D2 zones in every hemispheric lobule in zebrin stripe-visualized mice. C2, D1, and D2 zones were connected to the lateral part of the posterior interpositus nucleus (lPIN), and caudal and rostral parts of the lateral nucleus (cLN, rLN), respectively, and from the rostral part of the medial accessory olive (rMAO), and ventral and dorsal lamellas of the PO (vPO, dPO), respectively, as reported. Within these areas, crus I was specifically connected to the ventral parts of the lPIN, cLN, and rLN, and from the rostrolateral part of the rMAO and the lateral parts of the vPO and dPO. The results indicated that the cerebellar modules have lobule-related subdivisions and that crus I is topographically distinct from other lobules. We speculate that crus I and crus I-connected subdivisions in the CN and IO are involved more in nonmotor functions than other neighboring areas in the mouse.

Resting-state perfusion in motor and fronto-limbic areas is linked to diminished expression of emotion and speech in schizophrenia

Negative symptoms (NS) are a core component of schizophrenia affecting community functioning and quality of life. We tested neural correlates of NS considering NS factors and consensus subdomains. We assessed NS using the Clinical Assessment Interview for Negative Symptoms and the Scale for Assessment of Negative Symptoms. Arterial spin labeling was applied to measure resting-state cerebral blood flow (rCBF) in 47 schizophrenia patients and 44 healthy controls. Multiple regression analyses calculated the relationship between rCBF and NS severity. We found an association between diminished expression (DE) and brain perfusion within the cerebellar anterior lobe and vermis, and the pre-, and supplementary motor area. Blunted affect was linked to fusiform gyrus and alogia to fronto-striatal rCBF. In contrast, motivation and pleasure was not associated with rCBF. These results highlight the key role of motor areas for DE. Considering NS factors and consensus subdomains may help identifying specific pathophysiological pathways of NS.

Altered regional homogeneity and homotopic connectivity in Chinese breast cancer survivors with fear of cancer recurrence: A resting-state fMRI study

BackgroundFear of cancer recurrence (FCR) is one of the most distressing concerns for breast cancer survivors, but the neural mechanism underlying FCR remains unclear. MethodsWe conducted a cross-sectional study and recruited 62 breast cancer survivors varying in FCR (31 high-FCR individuals and 31 low-FCR individuals) and compared neuroimaging findings. Data from 3 low-FCR subjects were excluded because they did not complete all experiments. All the participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). Regional homogeneity (ReHo) and voxel-mirrored homotopic connectivity (VMHC) were assessed. ResultsBreast cancer survivors with high and low FCR significantly differed in the ReHo of the left caudate nucleus and precuneus as well as in the VMHC of the posterior cerebellar lobe, superior frontal gyrus, orbital frontal gyrus, inferior frontal gyrus, occipital gyrus, inferior parietal lobule and frontal middle gyrus. FCR was negatively correlated with the mean ReHo of the left caudate nucleus (r = −0.501, p < 0.001) and positively correlated with the mean ReHo of the right precuneus (r = 0.505, p < 0.001). In addition, FCR was positively correlated with the mean VMHC of the bilateral superior occipital gyrus (r = 0.438, p < 0.001). ConclusionThese findings suggest that the left caudate nucleus, right precuneus and bilateral superior occipital gyrus are involved in FCR, which may provide preliminary evidence to improve the present understanding of the neural mechanisms of FCR.

Examination of the Development and Asymmetry of the Cerebellum and Its Lobules in Individuals Aged 1-18 Years: A Retrospective MRI Study.

Developmental studies of cerebellar lobules were limited. To our knowledge, structural asymmetry has not been studied in immature cerebellar lobules in the 1-18 age group. This study investigated the effect of age and gender on the volumetric development and asymmetry of the global cerebellum and cerebellar lobules in children and adolescents. In this retrospective study, we included 670 individuals [376 (56.1%) males] aged 1-18years with normal brain MRIs between 2012 and 2021. volBrain CERES automatically segmented the right and left sides of the cerebellar lobules on three-dimensional T1-weighted MRIs. Volume and asymmetry data from individuals in 16 different age ranges were compared with SPSS (ver.28). The absolute volumetric development of the total cerebellum was consistent with the "S" development model in both sexes. The developmental trajectories of the cerebellar lobules were different from each other and showed sexual dimorphism. In the 1-18 age group, the absolute volumes of the total cerebellum and cerebellar lobules were significantly greater in males (p < 0.05). Absolute volumes of lobules IV, VIIB, VIIIA and VIIIB in the age groups had more gender differences. However, sexual dimorphism was insignificant in the cerebellum's total and lobular relative volume. Lobules IV, V, VI, VIIIA and VIIIB had left > right asymmetry and other lobules and total cerebellum had right > left asymmetry. This study confirmed the developmental heterogeneity and sexual dimorphism in the cerebellar lobules. It also provided volumetric data of the immature cerebellum to enable comparison in various neurological and neuropsychiatric diseases.

Connectome-based predictive modeling: A new approach of predicting individual critical thinking ability

Critical thinking (i.e., CT), which is a metacognitive process, encompasses seven dimensions: truth-seeking, open-mindedness, analyticity, systematicity, self-confidence, inquisitiveness, and maturity. It enables individuals to arrive at reasonable conclusions and make well-informed decisions. Despite being regarded as a fundamental survival skill and a crucial element of higher education, the neural mechanism responsible for a highly critical brain remains unclear.To address this, we recruited 80 Chinese native speakers, half of whom majored in liberal arts and half in science. They underwent a resting-state fMRI scan and completed a classic CT scale. Using connectome-based predictive modeling, we identified brain connectivity patterns associated with high and low CT dispositions. Then a support vector machine model was trained to classify individuals’ gender and major from the top 20 edges respectively for high- and low CT networks.Results showed that the high CT network included limbic, temporal, parietal, and cerebellum lobes. The limbic and parietal lobes of high CT networks positively predicted overall and each dimensions of CT scores. Specifically, the connectivity between the left parahippocampal gyrus and right precuneus cortex significantly predicted the open-mindedness score, the connectivity between the bilateral hippocampal gyrus significantly predicted the systematicity score, and the connectivities between the right precuneus cortex and left superior parietal lobule, right middle temporal gyrus and right superior parietal lobule were found to significantly predict individual cognitive maturity. And the top 20 edges of high CT networks could distinguish participants' major but not gender, while the top 20 edges of low CT networks could not distinguish either.These above results suggest that CT dispositions can be forecasted from a person's distinctive mapping of brain connections, with the limbic lobe of the high CT network predicting open-mindedness and systematicity scores, which share common neural mechanisms with creative thinking, and the parietal lobe positively predicting self-reported cognitive maturity.

Functional changes in the salience network of patients with amnesic mild cognitive impairment before and after repetitive transcranial magnetic stimulation.

Amnestic mild cognitive impairment (aMCI) is considered to be the prodromal stage of Alzheimer's disease (AD). The precuneus (PCUN) may be an imaging marker for monitoring the progression of AD. Meanwhile, cognitive impairment in AD patients is closely related to functional connectivity (FC) changes in the salience network (SN). We hypothesize that there are specific neuroimaging biomarkers in the SN and that FC changes in aMCI patients after repetitive transcranial magnetic stimulation (rTMS) intervention are associated with cognitive function. The purpose of this study was to first investigate the pattern of functional changes in aMCI patients and healthy controls (HCs) and then compare the functional changes in aMCI patients before and after rTMS targeting to PCUN and its correlation with cognitive function. Thirty-six HCs and 61 aMCIs were recruited for our study. Eleven people in the aMCI group received rTMS intervention 5 days a week for 4 weeks. Using the right anterior insula as the seed-of-interest, we first compared FC changes in HC and aMCI patients and then compared cognitive function in aMCI patients before and after rTMS. The above is the functional connection analysis of seed-to-voxel. Moreover, we investigated the FC changes in aMCI patients after rTMS intervention and its correlation with cognitive function. Compared with HC, the aMCI group showed altered FC in bilateral parahippocampal gyrus, bilateral inferior parietal lobule, left middle frontal gyrus, and left middle temporal gyrus. Moreover, rTMS at PCUN improved the cognitive function of aMCI patients, which was related to the altered FC in posterior cerebellar lobes (CPL). Our findings suggest that rTMS targeting PCUN is a promising, noninvasive approach to ameliorating cognitive dysfunction in aMCI patients, and that this cognitive improvement is accompanied by brain connectivity modulation.

Mapping a brain parasite: occurrence and spatial distribution in fish encephalon

Parasites, especially brain-encysting trematodes, can have an impact on host behaviour, facilitating the transmission to next host and completion of the life cycle, but insufficient research has been done on whether specific brain regions are targeted. Using Cardiocephaloides longicollis as a laboratory model, the precise distribution of metacercariae in experimentally-infected, wild and farmed fish was mapped. The brain regions targeted by this parasite were explored, also from a histologic perspective, and potential pathogenic effects were evaluated. Experimental infections allowed to reproduce the natural infection intensity of C. longicollis, with four times higher infection intensity at the higher dose (150 vs 50 cercariae). The observed metacercarial distribution, similar among all fish groups, may reflect a trematode species-specific pattern: metacercariae occur with highest density in the optic lobe area (primarily infecting the periventricular gray zone of optic tectum) and the medulla oblongata, whereas other areas such as the olfactory lobes and cerebellar lobes may be occupied when the more frequently invaded parts of the brain were crowded. Mono- and multicysts (i.e. formed either with a single metacercaria, or with 2-25 metacercariae encapsulated together) may be formed depending on the aggregation and timing of metacercariae arrival, with minor host inflammatory response. Larvae of C. longicollis colonizing specific brain areas may have an effect on the functions associated with these areas, which are generally related to sensory and motor functions, but are also related to other host fitness traits such as school maintenance or recognition of predators. The detailed information on the extent and distribution of C. longicollis in fish encephalon sets the ground to understand the effects of brain parasites on fish, but further investigation to establish if C. longicollis, through purely mechanical damage (e.g., occupation, pressure and displacement), has an actual impact on host behaviour remains to be tested under controlled experimental conditions.

Multiunit Recording of Cerebellar Cortex in Autistic Male Rats during Social Interaction in Enriched Environments

Autism in humans is a lifelong behavioral disorder that typically manifests in early infancy, primarily affecting boys. It arises from neurodevelopmental changes that significantly impact social behavior, with the cerebellum being one of the principal affected regions. In this study, we investigated the cerebellum in an autism animal model, recording the multiunit activity of cerebellar vermis lobules 6 and 7 (L6 and L7) in male rats with autism-like behavior induced by postnatal valproate treatment. Two groups were formed: control (Ctrl) and experimental (VPA) males, which were further divided based on their living conditions into standard (Std) or enriched environments (EE). Social arenas were used for recording purposes. Both groups and lobules showed increased multiunit amplitude during social interaction (SI) and vertical exploration (VE), with higher amplitudes observed in VPA males. Interestingly, the EE significantly reduced the amplitude during SI, suggesting that EE promotes neural plasticity, resulting in improved social responses with fewer activated neurons, meaning improved activity with less energy consumption. Consequently, EE proves to be a valuable strategy for addressing the challenges associated with autism behavior.

The structural connectivity mapping of the intralaminar thalamic nuclei

The intralaminar nuclei of the thalamus play a pivotal role in awareness, conscious experience, arousal, sleep, vigilance, as well as in cognitive, sensory, and sexual processing. Nonetheless, in humans, little is known about the direct involvement of these nuclei in such multifaceted functions and their structural connections in the brain. Thus, examining the versatility of structural connectivity of the intralaminar nuclei with the rest of the brain seems reasonable. Herein, we attempt to show the direct structural connectivity of the intralaminar nuclei to diencephalic, mesencephalic, and cortical areas using probabilistic tracking of the diffusion data from the human connectome project. The intralaminar nuclei fiber distributions span a wide range of subcortical and cortical areas. Moreover, the central medial and parafascicular nucleus reveal similar connectivity to the temporal, visual, and frontal cortices with only slight variability. The central lateral nucleus displays a refined projection to the superior colliculus and fornix. The centromedian nucleus seems to be an essential component of the subcortical somatosensory system, as it mainly displays connectivity via the medial and superior cerebellar peduncle to the brainstem and the cerebellar lobules. The subparafascicular nucleus projects to the somatosensory processing areas. It is interesting to note that all intralaminar nuclei have connections to the brainstem. In brief, the structural connectivity of the intralaminar nuclei aligns with the structural core of various functional demands for arousal, emotion, cognition, sensory, vision, and motor processing. This study sheds light on our understanding of the structural connectivity of the intralaminar nuclei with cortical and subcortical structures, which is of great interest to a broader audience in clinical and neuroscience research.

Neuroimaging correlates of postural instability in Progressive Supranuclear Palsy

ObjectiveWe aimed to identify the brain structures associated with postural instability (PI) in Progressive Supranuclear Palsy (PSP). MethodsForty-seven PSP patients and 45 control subjects were enrolled in this study. PI was assessed using the items 27 and 28 of the PSP rating scale (postural instability score, PIS). PSP patients were compared with controls using voxel-based morphometry (VBM). In PSP patients, LASSO regression model was used to investigate associations between VBM-based Region-Of-Interest grey matter (GM) volumes and different categories of the PSP rating scale. A whole-brain multi-regression analysis was also used to identify brain areas where GM volumes correlated with the PIS in PSP patients. ResultsVBM analysis showed widespread GM atrophy (fronto-temporal-parietal-occipital regions, limbic lobes, insula, cerebellum, and basal ganglia) in PSP patients compared with control subjects. In PSP patients, LASSO regression analysis showed associations of the right cerebellar lobules IV-V with ocular motor category score, and the left Rolandic area with bulbar category score, while the right inferior frontal gyrus (IFG) was negatively correlated with the PIS. The whole-brain multi-regression analysis identified the right IFG as the only area significantly associated with the PIS. ConclusionsIn our study, two different approaches demonstrated that the IFG volume was associated with PIS in PSP patients, suggesting that this area may play a role in the pathophysiological mechanisms underlying PI. Our findings may have important implications for developing optimal Transcranial Magnetic Stimulation protocols targeting IFG in parkinsonism with postural disorders.

Impact of duraplasty on clinical outcome in surgical management of chiari malformation type I

: In Chiari malformation type I (CIM), the cerebellar tonsils and the medial parts of the inferior cerebellar lobules are displaced downward through the foramen magnum into the upper cervical spinal canal. The primary surgical treatment for the Chiari I malformation is foramen magnum decompression. This study was undertaken to assess the clinical outcome in terms of clinical symptoms improvement in patients with Chiari malformation type I treated with foramen magnum decompression with duraplasty vs. primary repair of dura.: A total of 32, 24 patients retrospectively and 8 cases prospectively were studied after being diagnosed and operated on for Chiari malformation type I. Patients with Chiari types II, III, and IV were not allowed to participate. Before and one year after surgery, a questionnaire was utilized to measure improvements in neck pain and impairment caused by it, head aches and disability caused by it, and overall health. The findings of both groups' questionnaires were analysed and compared.: The third decade (34.38%) was the most prevalent age group for presentations, followed by the fourth decade (31.25 %). The ratio of males to females was 1.2:1. Sensory disturbances were the most frequent presenting symptom, found in 25 patients (78.13%), and followed by neck discomfort in 14 patients (43.75%). Leg weakness was the most frequent symptom, which was reported in 20 patients (62.50%). The foramen magnum decompression and duraplasty was done in 18 patients, whereas the foramen magnum decompression and primary repair was done in 14 patients. In the duraplasty group, there were greater problems. The Duraplasty group had an overall clinical improvement rate of 88.89%, while the non duraplasty group had a lower overall clinical improvement rate of 50%. Specific complaints such as neck discomfort improved at a comparable rate (88.89%) in the duraplasty group compared to the non-duraplasty group (80%).: Although foramen magnum decompression with duraplasty is preferable to foramen magnum decompression with primary repair, duraplasty is associated with a slightly greater risk of complication. Selected patients benefit from foramen magnum decompression alone, but further prospective randomized control studies are needed to learn more.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

A characteristic cerebellar biosignature for bipolar disorder, identified with fully automatic machine learning

BackgroundTranscriptomic profile differences between patients with bipolar disorder and healthy controls can be identified using machine learning and can provide information about the potential role of the cerebellum in the pathogenesis of bipolar disorder.With this aim, user-friendly, fully automated machine learning algorithms can achieve extremely high classification scores and disease-related predictive biosignature identification, in short time frames and scaled down to small datasets. MethodA fully automated machine learning platform, based on the most suitable algorithm selection and relevant set of hyper-parameter values, was applied on a preprocessed transcriptomics dataset, in order to produce a model for biosignature selection and to classify subjects into groups of patients and controls. The parent GEO datasets were originally produced from the cerebellar and parietal lobe tissue of deceased bipolar patients and healthy controls, using Affymetrix Human Gene 1.0 ST Array. ResultsPatients and controls were classified into two separate groups, with no close-to-the-boundary cases, and this classification was based on the cerebellar transcriptomic biosignature of 25 features (genes), with Area Under Curve 0.929 and Average Precision 0.955. The biosignature includes both genes connected before to bipolar disorder, depression, psychosis or epilepsy, as well as genes not linked before with any psychiatric disease. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed participation of 4 identified features in 6 pathways which have also been associated with bipolar disorder. ConclusionAutomated machine learning (AutoML) managed to identify accurately 25 genes that can jointly – in a multivariate–fashion - separate bipolar patients from healthy controls with high predictive power. The discovered features lead to new biological insights. Machine Learning (ML) analysis considers the features in combination (in contrast to standard differential expression analysis), removing both irrelevant as well as redundant markers, and thus, focusing to biological interpretation.

Association of cerebellar volume with cognitive and motor function in adults with congenital heart disease

IntroductionPatients with congenital heart disease (CHD) are at risk for cognitive and motor function impairments, brain injury, and smaller total brain volumes. The specific vulnerability of the cerebellum and its role in cognitive and motor functions in adults with congenital heart disease is not well defined.MethodsForty-three patients with CHD and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive, executive (EF), and motor function assessment. Cerebellar volumes were obtained using EasyMeasure and SUIT Toolbox. Associations between cerebellar volumes and cognitive and motor function were calculated using linear models.ResultsGeneral cognitive and pure motor functions were lower in patients compared to controls (P < 0.05). Executive functions were within the normal range. While total cerebellar volumes and the anterior lobes were similar in patients and controls (P > 0.1), the posterior cerebellar lobe was smaller in patients with more complex CHD (P = 0.006). Smaller posterior cerebellar gray matter was not associated with cognitive functions. Smaller anterior cerebellar gray matter was not significantly related to motor functions (P > 0.1).ConclusionIn adults with CHD, cerebellar volume was largely unimpaired. Patients with more complex CHD may be vulnerable to changes in the posterior cerebellar gray matter. We found no significant contribution of cerebellar gray matter to cognitive and motor impairments. More advanced imaging techniques are necessary to clarify the contribution of the cerebellum to cognitive and motor functions.

PTPδ is a presynaptic organizer for the formation and maintenance of climbing fiber to Purkinje cell synapses in the developing cerebellum.

Functionally mature neural circuits are shaped during postnatal development by eliminating redundant synapses formed during the perinatal period. In the cerebellum of neonatal rodents, each Purkinje cell (PC) receives synaptic inputs from multiple (more than 4) climbing fibers (CFs). During the first 3 postnatal weeks, synaptic inputs from a single CF become markedly larger and those from the other CFs are eliminated in each PC, leading to mono-innervation of each PC by a strong CF in adulthood. While molecules involved in the strengthening and elimination of CF synapses during postnatal development are being elucidated, much less is known about the molecular mechanisms underlying CF synapse formation during the early postnatal period. Here, we show experimental evidence that suggests that a synapse organizer, PTPδ, is required for early postnatal CF synapse formation and the subsequent establishment of CF to PC synaptic wiring. We showed that PTPδ was localized at CF-PC synapses from postnatal day 0 (P0) irrespective of the expression of Aldolase C (Aldoc), a major marker of PC that distinguishes the cerebellar compartments. We found that the extension of a single strong CF along PC dendrites (CF translocation) was impaired in global PTPδ knockout (KO) mice from P12 to P29-31 predominantly in PCs that did not express Aldoc [Aldoc (-) PCs]. We also demonstrated via morphological and electrophysiological analyses that the number of CFs innervating individual PCs in PTPδ KO mice were fewer than in wild-type (WT) mice from P3 to P13 with a significant decrease in the strength of CF synaptic inputs in cerebellar anterior lobules where most PCs are Aldoc (-). Furthermore, CF-specific PTPδ-knockdown (KD) caused a reduction in the number of CFs innervating PCs with decreased CF synaptic inputs at P10-13 in anterior lobules. We found a mild impairment of motor performance in adult PTPδ KO mice. These results indicate that PTPδ acts as a presynaptic organizer for CF-PC formation and is required for normal CF-PC synaptic transmission, CF translocation, and presumably CF synapse maintenance predominantly in Aldoc (-) PCs. Furthermore, this study suggests that the impaired CF-PC synapse formation and development by the lack of PTPδ causes mild impairment of motor performance.