Large Brain Research Articles

Does the distance to the cancer center affect psycho-oncological care and emergency visits of patients with IDH wild-type gliomas? A retrospective study.

Malignant isocitrate dehydrogenase wild-type (IDHwt) gliomas impose a high symptomatic and psychological burden. Wide distances from patients' homes to cancer centers may affect the delivery of psycho-oncological care. Here, we investigated, in a large brain tumor center with a rural outreach, the initiation of psycho-oncological care depending on spatial distance and impact of psycho-oncological care on emergency visits. Electronic patient charts, the regional tumor registry, and interviews with the primary care physicians were used to investigate clinical data, psycho-oncological care, and emergency unit visits. Interrelations with socio-demographic, clinical, and treatment aspects were investigated using univariable and multivariable binary logistic regression analysis and the Pearson's Chi-square test. Of 491, 229 adult patients of this retrospective cohort fulfilled the inclusion criteria for analysis. During the last three months of their lives, 48.9% received at least one psycho-oncological consultation, and 37.1% visited the emergency unit at least once. The distance from the cancer center did neither affect the initiation of psycho-oncological care nor the rate of emergency unit visits. Receiving psycho-oncological care did not correlate with the frequency of emergency unit visits in the last three months of life. We conclude that the distance of IDHwt glioma patients' homes from their cancer center, even in a rural area, does not significantly influence the rate of psycho-oncological care.

Radiation Necrosis Following Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy with High Biologically Effective Doses for Large Brain Metastases.

In Radiation Therapy Oncology Group 90-05, the maximum tolerated dose of single-fraction radiosurgery (SRS) for brain metastases of 21-30 mm was 18 Gy (biologically effective dose (BED) 45 Gy12). Since the patients in this study received prior brain irradiation, tolerable BED may be >45 Gy12 for de novo lesions. We investigated SRS and fractionated stereotactic radiotherapy (FSRT) with a higher BED for radiotherapy-naive lesions. Patients receiving SRS (19-20 Gy) and patients treated with FSRT (30-48 Gy in 3-12 fractions) with BED > 49 Gy12 for up to 4 brain metastases were compared for grade ≥ 2 radiation necrosis (RN). In the entire cohort (169 patients with 218 lesions), 1-year and 2-year RN rates were 8% after SRS vs. 2% and 13% after FSRT (p = 0.73) in per-patient analyses, and 7% after SRS vs. 7% and 10% after FSRT (p = 0.59) in per-lesion analyses. For lesions ≤ 20 mm (137 patients with 185 lesions), the RN rates were 4% (SRS) vs. 0% and 15%, respectively, (FSRT) (p = 0.60) in per-patient analyses, and 3% (SRS) vs. 0% and 11%, respectively, (FSRT) (p = 0.80) in per-lesion analyses. For lesions > 20 mm (32 patients with 33 lesions), the RN rates were 50% (SRS) vs. 9% (FSRT) (p = 0.012) in both per-patient and per-lesion analyses. In the SRS group, a lesion size > 20 mm was significantly associated with RN; in the FSRT group, lesion size had no impact on RN. Given the limitations of this study, FSRT with BED > 49 Gy12 was associated with low RN risk and may be safer than SRS for brain metastases > 20 mm.

Evolution of relative brain size in dogs-no effects of selection for breed function, litter size, or longevity.

Domestication is a well-known example of the relaxation of environmentally based cognitive selection that leads to reductions in brain size. However, little is known about how brain size evolves after domestication and whether subsequent directional/artificial selection can compensate for domestication effects. The first animal to be domesticated was the dog, and recent directional breeding generated the extensive phenotypic variation among breeds we observe today. Here we use a novel endocranial dataset based on high-resolution CT scans to estimate brain size in 159 dog breeds and analyze how relative brain size varies across breeds in relation to functional selection, longevity, and litter size. In our analyses, we controlled for potential confounding factors such as common descent, gene flow, body size, and skull shape. We found that dogs have consistently smaller relative brain size than wolves supporting the domestication effect, but breeds that are more distantly related to wolves have relatively larger brains than breeds that are more closely related to wolves. Neither functional category, skull shape, longevity, nor litter size was associated with relative brain size, which implies that selection for performing specific tasks, morphology, and life history does not necessarily influence brain size evolution in domesticated species.

SELF-SUPERVISED LEARNING WITH RADIOLOGY REPORTS, A COMPARATIVE ANALYSIS OF STRATEGIES FOR LARGE VESSEL OCCLUSION AND BRAIN CTA IMAGES.

Scarcity of labels for medical images is a significant barrier for training representation learning approaches based on deep neural networks. This limitation is also present when using imaging data collected during routine clinical care stored in picture archiving communication systems (PACS), as these data rarely have attached the high-quality labels required for medical image computing tasks. However, medical images extracted from PACS are commonly coupled with descriptive radiology reports that contain significant information and could be leveraged to pre-train imaging models, which could serve as starting points for further task-specific fine-tuning. In this work, we perform a head-to-head comparison of three different self-supervised strategies to pre-train the same imaging model on 3D brain computed tomography angiogram (CTA) images, with large vessel occlusion (LVO) detection as the downstream task. These strategies evaluate two natural language processing (NLP) approaches, one to extract 100 explicit radiology concepts (Rad-SpatialNet) and the other to create general-purpose radiology reports embeddings (DistilBERT). In addition, we experiment with learning radiology concepts directly or by using a recent self-supervised learning approach (CLIP) that learns by ranking the distance between language and image vector embeddings. The LVO detection task was selected because it requires 3D imaging data, is clinically important, and requires the algorithm to learn outputs not explicitly stated in the radiology report. Pre-training was performed on an unlabeled dataset containing 1,542 3D CTA - reports pairs. The downstream task was tested on a labeled dataset of 402 subjects for LVO. We find that the pre-training performed with CLIP-based strategies improve the performance of the imaging model to detect LVO compared to a model trained only on the labeled data. The best performance was achieved by pre-training using the explicit radiology concepts and CLIP strategy.

Could theropod dinosaurs have evolved to a human level of intelligence?

Noting that some theropod dinosaurs had large brains, large grasping hands, and likely binocular vision, paleontologist Dale Russell suggested that a branch of these dinosaurs might have evolved to a human intelligence level, had dinosaurs not become extinct. I offer reasons why the likely pallial organization in dinosaurs would have made this improbable, based on four assumptions. First, it is assumed that achieving human intelligence requires evolving an equivalent of the about 200 functionally specialized cortical areas characteristic of humans. Second, it is assumed that dinosaurs had an avian nuclear type of pallial organization, in contrast to the mammalian cortical organization. Third, it is assumed that the interactions between the different neuron types making up an information processing unit within pallium are critical to its role in analyzing information. Finally, it is assumed that increasing axonal length between the neuron sets carrying out this operation impairs its efficacy. Based on these assumptions, I present two main reasons why dinosaur pallium might have been unable to add the equivalent of 200 efficiently functioning cortical areas. First, a nuclear pattern of pallial organization would require increasing distances between the neuron groups corresponding to the separate layers of any given mammalian cortical area, as more sets of nuclei equivalent to a cortical area are interposed between the existing sets, increasing axon length and thereby impairing processing efficiency. Second, because of its nuclear organization, dinosaur pallium could not reduce axon length by folding to bring adjacent areas closer together, as occurs in cerebral cortex.

Counter-gradient variation and the expensive tissue hypothesis explain parallel brain size reductions at high elevation in cricetid and murid rodents

To better understand functional morphological adaptations to high elevation (> 3000 m above sea level) life in both North American and African mountain-associated rodents, we used microCT scanning to acquire 3D images and a 3D morphometric approach to calculate endocranial volumes and skull lengths. This was done on 113 crania of low-elevation and high-elevation populations in species of North American cricetid mice (two Peromyscus species, n = 53), and African murid rodents of two tribes, Otomyini (five species, n = 49) and Praomyini (four species, n = 11). We tested two distinct hypotheses for how endocranial volume might vary in high-elevation populations: the expensive tissue hypothesis, which predicts that brain and endocranial volumes will be reduced to lessen the costs of growing and maintaining a large brain; and the brain-swelling hypothesis, which predicts that endocranial volumes will be increased either as a direct phenotypic effect or as an adaptation to accommodate brain swelling and thus minimize pathological symptoms of altitude sickness. After correcting for general allometric variation in cranial size, we found that in both North American Peromyscus mice and African laminate-toothed (Otomys) rats, highland rodents had smaller endocranial volumes than lower-elevation rodents, consistent with the expensive tissue hypothesis. In the former group, Peromyscus mice, crania were obtained not just from wild-caught mice from high and low elevations but also from those bred in common-garden laboratory conditions from parents caught from either high or low elevations. Our results in these mice showed that brain size responses to elevation might have a strong genetic basis, which counters an opposite but weaker environmental effect on brain volume. These results potentially suggest that selection may act to reduce brain volume across small mammals at high elevations but further experiments are needed to assess the generality of this conclusion and the nature of underlying mechanisms.

Evolutionary process toward avian-like cephalic thermoregulation system in Theropoda elucidated based on nasal structures.

It has long been discussed whether non-avian dinosaurs were physiologically closer to ectotherms or endotherms, with the internal nasal structure called the respiratory turbinate present in extant endotherms having been regarded as an important clue for this conundrum. However, the physiological function and relevance of this structure for dinosaur physiology are still controversial. Here, we found that the size of the nasal cavity relative to the head size of extant endotherms is larger than those of extant ectotherms, with that of the dromaeosaurid Velociraptor being below the extant endotherms level. The result suggests that a large nasal cavity accommodating a well-developed respiratory turbinate is primarily important as a thermoregulation apparatus for large brains characteristic of endothermic birds and mammals, and the nasal cavity of Velociraptor was apparently not large enough to carry out this role required for an endothermic-sized brain. In addition, a hypothesis that the enlargement of the nasal cavity for brain cooling has been associated with the skull modification in the theropod lineage toward modern birds is proposed herein. In particular, the reduction of the maxilla in derived avialans may have coincided with acquisition of the avian-like cephalic thermoregulation system.

Four errors and a fallacy: pitfalls for the unwary in comparative brain analyses.

Comparative analyses are the backbone of evolutionary analysis. However, their record in producing a consensus has not always been good. This is especially true of attempts to understand the factors responsible for the evolution of large brains, which have been embroiled in an increasingly polarised debate over the past three decades. We argue that most of these disputes arise from a number of conceptual errors and associated logical fallacies that are the result of a failure to adopt a biological systems-based approach to hypothesis-testing. We identify four principal classes of error: a failure to heed Tinbergen's Four Questions when testing biological hypotheses, misapplying Dobzhansky's Dictum when testing hypotheses of evolutionary adaptation, poorly chosen behavioural proxies for underlying hypotheses, and the use of inappropriate statistical methods. In the interests of progress, we urge a more careful and considered approach to comparative analyses, and the adoption of a broader, rather than a narrower, taxonomic perspective.

Relative brain size is associated with natal dispersal rate and species' vulnerability to climate change in seabirds

The cognitive buffer hypothesis proposes that species with larger brains (relative to their body size) exhibit greater behavioural flexibility, conferring an advantage in unpredictable or novel environments. Therefore, behavioural flexibility – and relative brain size – are likely to be important predictors of a species' vulnerability to anthropogenic pressures and, ultimately, extinction risk. However, current evidence linking brain size to species' vulnerability and extinction risk is inconclusive. Furthermore, studies examining the relationship between relative brain size and behavioural flexibility have mainly focused on foraging innovations, whilst other forms of behavioural flexibility remain unexplored. In this study, we collate species‐specific information and examine links between relative brain size, rates of natal and adult dispersal (a measure of flexibility in breeding site fidelity), vulnerability to six anthropogenic threats and extinction risk for 131 species of seabird. We focused our study on seabirds, a highly threatened group that displays large variation in both relative brain size and dispersal behaviour. We found a significant positive relationship between relative brain size and natal dispersal rate, suggesting that relative brain size could enhance flexibility in breeding site choice in seabirds, consistent with the cognitive buffer hypothesis. However, this relationship does not persist when we consider adult dispersal, possibly reflecting constraints imposed by mate selection and knowledge transfer in seabirds. We also show that relative brain size is negatively associated with vulnerability to climate change. These findings have immediate application for predicting interspecific variation in species' vulnerability to climate change and identifying priority species for conservation.

SAFESTEREO: phase II randomized trial to compare stereotactic radiosurgery with fractionated stereotactic radiosurgery for brain metastases

BackgroundStereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases.MethodsPatients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15–24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life.DiscussionCurrently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure.Trial registrationClincalTrials.gov, trial registration number: NCT05346367, trial registration date: 26 April 2022.

Identifying Unique Symptom Groups Following Mild Traumatic Brain Injury Using the Neurobehavioral Symptom Inventory and PTSD Checklist-5 in Military Personnel: A Bifactor Analysis.

To identify both shared and unique groups of posttraumatic stress and postconcussive symptoms using bifactor analysis. Two large military outpatient traumatic brain injury (TBI) rehabilitation clinics in the Southwestern United States. A sample of 1476 Active Duty Service Members seeking treatment for a mild TBI sustained more than 30 days previously, without history of moderate or severe TBI, who completed measures of postconcussive and posttraumatic stress symptoms assessed at clinic intake. Observational, correlational study with data taken from an institutional review board-approved clinical registry study. Neurobehavioral Symptom Inventory (NSI) and Posttraumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) ( DSM-V ) (PCL-5). Concurrent measures were Patient Health Questionnaire (PHQ-8), Pittsburgh Sleep Quality Index (PSQI), and Headache Impact Test (HIT-6). Results identified a bifactor model demonstrating unique posttraumatic stress, depressive, cognitive, and neurological/somatic symptom groups that were still evident after accounting for a universal factor representing general distress. These symptom groups were differentially related to concurrently measured clinical outcomes. Use of a bifactor structure may help derive clinically useful signals from self-reported symptoms among Active Duty Service Members seeking outpatient treatment for mild TBI.

Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals.

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it controls proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay and identify one CRE that likely co-evolves with cortical folding in Old World monkeys and apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species.

Correction: The Evolution of Brain Size in Ectothermic Tetrapods: Large Brain Mass Trades-Off with Lifespan in Reptiles

Correction: The Evolution of Brain Size in Ectothermic Tetrapods: Large Brain Mass Trades-Off with Lifespan in Reptiles

Autism spectrum disorder and brain volume link through a set of mTOR-related genes.

Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N=2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N=23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N=46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N=46,350) and intracranial volume (N=25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p=.0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p=.027), despite the absence of a significant genome-wide correlation (p=.81). This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.

Magnetic resonance imaging of organ iron before and after correction of iron deficiency in patients with heart failure.

Intravenous iron therapy (IVIT) is known to improve functional status in chronic heart failure (CHF) patients. The exact mechanism is not completely understood. We correlated magnetic resonance imaging (MRI) patterns of T2* iron signal in various organs to systemic iron and exercise capacity (EC) in CHF before and after IVIT. We prospectively analysed 24 patients with systolic CHF for T2* MRI pattern of the left ventricle (LV), small and large intestines, spleen, liver, skeletal muscle, and brain for iron. In 12 patients with iron deficiency (ID), we restored iron deficit by IVIT using ferric carboxymaltose. The effects after 3months were analysed by spiroergometry and MRI. Patients with vs. without ID showed lower blood ferritin, haemoglobin (76±63 vs. 196±82μg/L and 12.3±1.1 vs. 14.2±1.1g/dL, all P<0.002), and in trend a lower transferrin saturation (TSAT) (19.1 [13.1; 28.2] vs. 25.1 [21.3; 29.1] %, P=0.05). Spleen and liver iron was lower as expressed by higher T2* value (71.8 [66.4; 93.1] vs. 36.9 [32.9; 51.7] ms, P<0.002 and 33.5±5.9 vs. 28.8±3.9ms, and P<0.03). There was a strong trend for a lower cardiac septal iron content in ID (40.6 [33.0; 57.3] vs. 33.7 [31.3; 40.2] ms, P=0.07). After IVIT, ferritin, TSAT, and haemoglobin increased (54 [30; 104] vs. 235 [185; 339] μg/L, 19.1 [13.1; 28.2] vs. 25.0 [21.0; 33.7] %, 12.3±1.1 vs. 13.3±1.3g/L, all P<0.04). Peak VO2 improved (18.2±4.2 vs. 20.9±3.8mL/min/kg-1 , P=0.05). Higher peak VO2 at anaerobic threshold was associated with higher blood ferritin, reflecting higher metabolic exercise capacity after therapy (r=0.9, P=0.0009). Increase in EC was associated with haemoglobin increase (r=0.7, P=0.034). LV iron increased by 25.4% (48.5 [36.2; 64.8] vs. 36.2 [32.9; 41.9] ms, P<0.04). Spleen and liver iron increased by 46.4 and 18.2%, respectively (71.8 [66.4; 93.1] vs. 38.5 [22.4; 76.9] ms, P<0.04 and 33.5±5.9 vs. 27.4±8.6ms, P<0.007). Iron in skeletal muscle, brain, intestine, and bone marrow remained unchanged (29.6 [28.6; 31.2] vs. 30.4 [29.7; 30.7] ms, P=0.7, 81.0±6.3 vs. 82.9±9.9ms, P=0.6, 34.3±21.4 vs. 25.3±14.1ms, P=0.2, 9.4 [7.5; 21.8] vs. 10.3 [6.7; 15.7] ms, P=0.5 and 9.8±1.5 vs. 13.7±8.9ms, P=0.1). CHF patients with ID showed lower spleen, liver, and in trend lower cardiac septal iron. After IVIT, iron signal of the left ventricle as well as spleen and liver increased. Improvement in EC was associated with increase in haemoglobin after IVIT. In ID, liver, spleen, and brain but not heart iron were associated with markers of systemic ID.

Extractive foraging behaviour in woodpeckers evolves in species that retain a large ancestral brain

Identifying ecological factors that influence brain size evolution is a major challenge in organismal biology. The extractive foraging hypothesis proposes that large brains are more likely to evolve in taxa that extract prey items from hard-to-access substrates, but this idea has received relatively little attention. Here, we provide a comprehensive test of the extractive foraging hypothesis in woodpeckers, a family of relatively large-brained birds that contains many species that feed on wood-boring larvae extracted from trees. Our results show strong support for the extractive foraging hypothesis. First, woodpeckers that use extractive foraging have relatively larger brains compared to species that forage using other tactics. Second, our comparative analyses suggest not only that big brains are the likely ancestral phenotype among all woodpecker taxa, but also that this trait is associated with innovation in foraging behaviour. We suspect that retaining an ancestral large brain likely increases the probability that a given species evolves to become an extractive forager who eats largely wood-boring larvae, given that species that transitioned to a small brain evolved different diets. Thus, the extractive foraging hypothesis likely applies to woodpeckers because of a historical contingency (large brains) that sets the stage for behavioural innovations to better exploit ecological opportunities.

Neural Ensemble Fragmentation in the Anesthetized Drosophila Brain.

General anesthetics cause a profound loss of behavioral responsiveness in all animals. In mammals, general anesthesia is induced in part by the potentiation of endogenous sleep-promoting circuits, although "deep" anesthesia is understood to be more similar to coma (Brown et al., 2011). Surgically relevant concentrations of anesthetics, such as isoflurane and propofol, have been shown to impair neural connectivity across the mammalian brain (Mashour and Hudetz, 2017; Yang et al., 2021), which presents one explanation why animals become largely unresponsive when exposed to these drugs. It remains unclear whether general anesthetics affect brain dynamics similarly in all animal brains, or whether simpler animals, such as insects, even display levels of neural connectivity that could be disrupted by these drugs. Here, we used whole-brain calcium imaging in behaving female Drosophila flies to investigate whether isoflurane anesthesia induction activates sleep-promoting neurons, and then inquired how all other neurons across the fly brain behave under sustained anesthesia. We were able to track the activity of hundreds of neurons simultaneously during waking and anesthetized states, for spontaneous conditions as well as in response to visual and mechanical stimuli. We compared whole-brain dynamics and connectivity under isoflurane exposure to optogenetically induced sleep. Neurons in the Drosophila brain remain active during general anesthesia as well as induced sleep, although flies become behaviorally inert under both treatments. We identified surprisingly dynamic neural correlation patterns in the waking fly brain, suggesting ensemble-like behavior. These become more fragmented and less diverse under anesthesia but remain wake-like during induced sleep.SIGNIFICANCE STATEMENT When humans are rendered immobile and unresponsive by sleep or general anesthetics, their brains do not shut off - they just change how they operate. We tracked the activity of hundreds of neurons simultaneously in the brains of fruit flies that were anesthetized by isoflurane or genetically put to sleep, to investigate whether these behaviorally inert states shared similar brain dynamics. We uncovered dynamic patterns of neural activity in the waking fly brain, with stimulus-responsive neurons constantly changing through time. Wake-like neural dynamics persisted during induced sleep but became more fragmented under isoflurane anesthesia. This suggests that, like larger brains, the fly brain might also display ensemble-like behavior, which becomes degraded rather than silenced under general anesthesia.

Surgical Procedure for Implantation of Opto-Array in Nonhuman Primates.

Optogenetics allows precise temporal control of neuronal activity in the brain. Engineered viral vectors are routinely used to transduce neurons with light-sensitive opsins. However, reliable virus injection and light delivery in animals with large brains, such as nonhuman primates, has proven challenging. The Opto-Array is a novel yet simple device that is used to deliver light to extended regions of the cortex surface for high-throughput behavioral optogenetics in large brains. Here we present protocols for surgical delivery of virus (Basic Protocol 1) and implantation of the Opto-Array (Basic Protocol 2) in two separate surgeries in a rhesus monkey's inferior temporal cortex. As a proof of concept, we measured the behavioral performance of an animal detecting cortical optogenetic stimulations (Basic Protocol 3) with different illumination power and duration using the Opto-Array. The animal was able to detect the optogenetic stimulation for all tested illumination powers and durations. Regression analysis also showed both power and duration of illumination significantly modulate the detectability of the optogenetic stimulation. The outcome of this approach is superior to the standard practice of injecting and recording through a chamber for large areas of the cortex surface. Moreover, the chronic nature of the Opto-Array allows perturbation of neuronal activity of the same site across multiple sessions because it is highly stable; thus, data can be pooled over months. The detailed surgical method presented here makes it possible to use optogenetics to modulate neuronal activity across large regions of the cortex surface in the nonhuman primate brain. This method also lays the groundwork for future attempts to use optogenetics to restore vision in humans. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Virus injection surgery Basic Protocol 2: Opto-Array implantation surgery Basic Protocol 3: Cortical Perturbation Detection (CPD) task behavioral training.

Disrupted structural brain networks across psychiatric disorders determined using multivariate graph analyses

IntroductionIdentifying the specific brain pattern characterizing psychiatric disorders could lead us to precise diagnostic process, better treatment plan and outcome prediction. Structural covariance is a graph-analysis method with which disruptions in large scale brain network organization can be observed. More studies, employing this method in psychiatry, are still needed.ObjectivesThe current study aims to investigate how the main psychiatric disorders – schizophrenia, major depressive disorder, bipolar disorder, affect brain circuitry by means of multivariate graph theory, more specifically – structural covariance. We hypothesized that specific abnormalities in the brain circuits would be found in separate diagnostic entities.Methods164 subjects were included with schizophrenia-SCH (n=17), bipolar disorder-BD(n=25), major depressive disorder–MDD(n=68) and a healthy control group-HC(n=54). Each participant provided a written informed consent and the study protocol was approved by the University’s Ethics Committee. High resolution structural MRI was acquired, and preprocessing was performed using SPM 12 toolbox. The structural covariance method was applied consisting of calculation of the correlation across subjects between the different pairs of regions by using the gray matter average volume. We used the threshold statistic to binarize the covariance matrix and transform it into an adjacency matrix. This allows us to compare psychiatric disorders at a network level by calculating measures such as authorities, hubs and outdegree.Results61 statistically significant regions were found for the whole sample. The matrices of the four groups were compared according to their ‘authorities’ ,‘hubs’ and ‘outdegree’ as first, second and third ranking variables, respectively. In the group comparison between HC and BD patients the top five significant regions were Planum temporale (PT), Putamen, Precuneus (PreCu), Calcarine cortex (Calc_cor) and Postcentral gyrus medial segment (PostCGms). The MDD group demonstrated the following regions with most significant difference including Precentral gyrus (PreCG), Entorhinal area (EntA), Amygdala (Amy), Anterior cingulate gyrus (ACC), Anterior insula (AI). While SCH grop was charachterized by ACC, PreCG – medial segment, PostCGms, anterior orbital gyrus, and frontal pole.ConclusionsThe results of our study demonstrated that schizophrenia and mood disorders have specific disturbances in brain network structural organization, affecting hubs of default mode network, salience network, motor, sensory and visual cortex, as well as limbic system. These alterations might elucidate the pathophysiological mechanisms of common symptoms of the disorders under investigation including perceptual, affective and cognitive disturbances.Disclosure of InterestNone Declared

NeuRegenerate: A Framework for Visualizing Neurodegeneration.

Recent advances in high-resolution microscopy have allowed scientists to better understand the underlying brain connectivity. However, due to the limitation that biological specimens can only be imaged at a single timepoint, studying changes to neural projections over time is limited to observations gathered using population analysis. In this article, we introduce NeuRegenerate, a novel end-to-end framework for the prediction and visualization of changes in neural fiber morphology within a subject across specified age-timepoints. To predict projections, we present neuReGANerator, a deep-learning network based on cycle-consistent generative adversarial network (GAN) that translates features of neuronal structures across age-timepoints for large brain microscopy volumes. We improve the reconstruction quality of the predicted neuronal structures by implementing a density multiplier and a new loss function, called the hallucination loss. Moreover, to alleviate artifacts that occur due to tiling of large input volumes, we introduce a spatial-consistency module in the training pipeline of neuReGANerator. Finally, to visualize the change in projections, predicted using neuReGANerator, NeuRegenerate offers two modes: (i) neuroCompare to simultaneously visualize the difference in the structures of the neuronal projections, from two age domains (using structural view and bounded view), and (ii) neuroMorph, a vesselness-based morphing technique to interactively visualize the transformation of the structures from one age-timepoint to the other. Our framework is designed specifically for volumes acquired using wide-field microscopy. We demonstrate our framework by visualizing the structural changes within the cholinergic system of the mouse brain between a young and old specimen.