Small Brain Research Articles

Possible Effects of Bright Light Therapy on Electroencephalogram-Vigilance in the Treatment of Depression in Adolescents: A Pilot Study.

BackgroundChronotherapeutic treatments for depression, such as bright light therapy (BLT), are non-invasive and produce almost no side effects. However, study evidence for reliable neurobiological changes associated with treatment response is still rare. Several studies using EEG-vigilance indicate higher arousal and a later decline during resting state in adult depressive patients compared to healthy controls. To our knowledge, there are no study reports on EEG-vigilance in depressive youth to date.MethodsA total of 11 adolescents with depression receiving BLT were compared to 11 age and gender-matched patients with depression receiving treatment as usual (TAU). The BLT was administered in the morning for 2 weeks on five consecutive days per week. The depressive symptomatology was assessed using the Beck Depression Inventory (BDI-II) and the resting state electroencephalogram (EEG) of 20 min was recorded. EEG and BDI-II were assessed before and after 10 days of treatment. Vigilance level and vigilance decline were estimated using the VIGALL toolbox.ResultsBrain arousal increased after 10 days of bright light therapy in adolescents with depression. Severe depressive symptoms were associated with higher brain arousal levels; the BDI-II sum score correlated negatively with the amount of drowsiness.LimitationsThe sample size was small and participants’ brain arousal at baseline was not matched and differed between BLT and TAU groups.ConclusionThe BLT might have an additional effect on brain arousal. EEG-vigilance seems to be a reliable and valid marker for neurobiological changes that are probably associated with depression and its treatment and, therefore, might be of clinical relevance.

Transient receptor potential cation channel 6 deficiency leads to increased body weight and metabolic dysfunction.

Transient receptor potential cation channel 6 (TRPC6), a member of the TRPC family, is expressed in the hypothalamus and modulates cell Ca2+ influx. However, the role of TRPC6 in controlling metabolic and cardiovascular functions under normal conditions has not been previously determined. Thus the impacts of TRPC6 deletion on energy balance, metabolic, and cardiovascular regulation as well as the anorexic responses to leptin and melanocortin 3/4 receptor (MC3/4R) activation were investigated in this study. Extensive cardiometabolic phenotyping was conducted in male and female TRPC6 knockout (KO) and control mice from 6 to 24 wk of age to assess mechanisms by which TRPC6 influences regulation of energy balance and blood pressure (BP). We found that TRPC6 KO mice are heavier with greater adiposity, are hyperphagic, and have reduced energy expenditure, impaired glucose tolerance, hyperinsulinemia, and increased liver fat compared with controls. TRPC6 KO mice also have smaller brains, reduced proopiomelanocortin mRNA levels in the hypothalamus, and impaired anorexic response to leptin but not to MC3/4R activation. BP and heart rate, assessed by telemetry, were similar in TRPC6 KO and control mice, and BP responses to air-jet stress were attenuated in TRPC6 KO mice despite increased body weight and metabolic disorders that normally raise BP and increase BP responses to stress. Our results provide evidence for a novel and important role of TRPC6 in controlling energy balance, adiposity, and glucose homeostasis, which suggests that normal TRPC6 function may be necessary to link weight gain and hyperleptinemia with BP responses to acute stress.

Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons.

Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. A smaller total brain volume (β = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (β = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (β = 0.194, 95% CI 0.047-0.341), and higher MD levels (β = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (β = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (β = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

Clustering of cognitive subtypes in schizophrenia patients and their siblings: relationship with regional brain volumes

Schizophrenia patients (SZH) often show impaired cognition and reduced brain structural volumes; these deficits are also detectable in healthy relatives of SZH. However, there is considerable heterogeneity: a sizable percentage of SZH are relatively cognitively intact; clustering strategies have proved useful for categorising into cognitive subgroups. We used a clustering strategy to investigate relationships between subgroup assignment and brain volumes, in 102 SZH (N = 102) and 32 siblings of SZH (SZH-SIB), alongside 92 controls (CON) and 48 of their siblings. SZH had poorer performance in all cognitive domains, and smaller brain volumes within prefrontal and temporal regions compared to controls. We identified three distinct cognitive clusters (‘neuropsychologically normal’, ‘intermediate’, ‘cognitively impaired’) based on age- and gender-adjusted cognitive domain scores. The majority of SZH (60.8%) were assigned to the cognitively impaired cluster, while the majority of SZH-SIB (65.6%) were placed in the intermediate cluster. Greater right middle temporal volume distinguished the normal cluster from the more impaired clusters. Importantly, the observed brain volume differences between SZH and controls disappeared after adjustment for cluster assignment. This suggests an intimate link between cognitive performance levels and regional brain volume differences in SZH. This highlights the importance of accounting for heterogeneity in cognitive performance within SZH populations when attempting to characterise the brain structural abnormalities associated with the disease.

The Gut‐Brain Connection: The Inflammatory Role of IL‐6 Caused by a Western Diet

IntroductionAn increase in chronic proinflammatory immune activity is recognized as an increasingly fundamental element in relation to neurodegenerative disorders. Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with recent evidence suggesting the Western Diet as a source for systemic inflammation. The communication fusing the gut to brain axis has been investigated through hepcidin, derived from both hepatocytes and dendritic cells. Hepcidin could potentially play an anti‐inflammatory role in the process of gut dysbiosis through a means of either a localized approach of nutritional immunity, or a systemic approach. Similarly, IL‐6 is a part of the gut‐brain axis. The levels of IL‐6 expression are affected by the gut microbiota and therefore sought to interplay a key role in cognitive function and decline, which could ultimately lead to several neurodegenerative diseases such as Alzheimer’s. The production of IL‐6 is increased by inflammation and associated with sepsis, endotoxemia and treatment with pro inflammatory cytokines. The release of this cytokine peripherally influences the CNS by a ting on the microglia to stimulate a state of neuroinflammation. During inflammation, proinflammatory cytokine IL‐6 is released from the intestinal mucosa and activates the Vagus nerve afferents. Hence, it could conceivably be hypothesized that IL‐6 activates gastrointestinal submucosal neurons through the brain‐gut axis. The aim of this study is to conduct a systematic review of literature through the search of available online medical databases containing information pertaining to gut dysbiosis and the primary communication between the brain‐gut axis.MethodsA total of 80 articles were retrieved from the databases of Pubmed, Google Scholar and Frontiers. Our method of assessment analyzed prominent keywords in our study pertaining to the small intestines, brain, liver, hepcidin, TMAO, BDNF, iron, astrocytes, WD, microbiota, gut microbiome, gut dysbiosis, iron, inflammation, oxidative stress, IL‐6, and vagus nerve. After reading the full‐text then extracting the findings from each study, our team organized those findings of brain, liver and gut biomolecules in relation to maintaining homeostasis and prevention of inflammation. The databases were assessed fall of 2021 following exportation of articles to a bibliographical database for further screening processes.ResultsThe results of this study indicate the optimal state of a healthy brain is IL‐6, hepcidin, ferritin and iron are at baseline levels. Whereas, in a dysbiosis state likely caused by WD, the brain responds by upregulating IL‐6, hepcidin and ferritin levels.ConclusionsIt would be interesting for a future study to experimentally focus on whether hepcidin upregulation induces the downregulation of iron in the neuron, or if the upregulation of iron in the neuron induces the downregulation of hepcidin in the setting of neuroinflammation.

Regulation of Ncbe in the Choroid Plexus of Mice after Hemorrhage‐Induced Hydrocephalus

The choroid plexus (CP) is a small tissue located inside brain ventricles. It is responsible for the production of most of the cerebrospinal fluid (CSF); approximately 500 mL of CSF per day in the adult human [1, 2]. CSF production occurs as a net result of transcellular movement of salt and water, carried out by various cellular transporters.Ncbe is a sodium‐coupled bicarbonate transporter located in the basolateral membrane of the choroid plexus epithelial (CPE) cells. It transports Na+ and HCO3‐ into the cell in exchange for Cl‐. Ncbe is the main sodium loader of the cell and CSF production is probably dependent on this transporter [3].Posthemorrhagic hydrocephalus (PHH) is a pathological state, caused by an accumulation of CSF in the ventricular system following intraventricular hemorrhage. CSF buildup is caused by a disproportion in CSF production and reabsorption. This leads to an expansion of the brain ventricles. Intraventricular hemorrhage (IVH) is known to cause inflammation in the CP, which is coupled to an over‐production of CSF [4‐6].Initially we hypothesized that IVH would stimulate Ncbe in the CPE through increased protein abundance as well as transporter activity. This would lead to increased CSF formation, similar to the response found after treatment with e.g. the cyclic‐AMP agonist forskolin [7]. Our preliminary data, however, suggest that Ncbe abundance is reduced by 24% (n=4, p=0.0329) in mice in the initial stages of PHH and then normalizes.The aim of this study is to investigate which role Ncbe plays in PHH and how Ncbe knock down affects CSF production in both healthy mice and a disease model.An adeno‐associated virus (AAV) shRNA knockdown vector system has been developed to knock down Ncbe gene expression by intracerebroventricular injections. Our preliminary data shows that the CPE cells incorporate the vector when tagged with GFP.We have established an IVH model and recording of CSF secretion rates in mice. Increased CSF formation rate was validated with ventriculo‐cisternal perfusion (data shown in figure). The resulting changes in ventricular volume will be investigated using magnetic resonance imaging (MRI).We propose that Ncbe knock down inhibits CSF production and could potentially target inflammation‐dependent hypersecretion by reducing the availability of the sodium supplying the apical transporters in the CP.

Small Brains, Small Skulls: Effect of Cortex Specific Overexpression of BAF170 on the Mouse Cranium

Cephalization is an important evolutionary and developmental process. Integration of the brain and skull throughout development and evolution produces brains that fit tightly within skulls. We sought to explore brain/skull integration using a mouse model that produces a small brain. Mammalian BAF170 is an intrinsic factor controlling cortical size, and cortex specific overexpression of BAF170 (conditional overexpression) which results in a mouse model in which cortical growth is inhibited. We looked at BAF170cOE mice and their unaffected littermates (controls) at various ages during cortical development, including embryonically at E15.5, as well as early post‐natal timepoints (P0, P14) as the cortex grows dramatically, and timepoints approaching complete cortical and skull growth (P28, P42). Using histological sections, we determined that the area of the cortex and number of nuclei within the cortex were reduced in BAF170cOE mice as compared to unaffected littermates, particularly at post‐natal time points. Using Euclidian Distance Matrix Analysis, we found no difference in skull form embryonically. Mediolateral dimensions of skulls of BAF170cOE mice were reduced by 3‐10% at P0 as compared to controls. At the later post‐natal time‐points (P14, P28, P42) there were significant differences in skull form between genotypes. Skulls of BAF170cOE mice were reduced by almost 20% along the anteroposterior and mediolateral axes. Our data show that the BAF170cOE mouse has a cortex that is reduced in size due to fewer nuclei resulting from overexpression of BAF170. The skull is not a direct target of the BAF170 gene, yet it responds to the change in brain size and shape by adjusting its size and contours to match the brain. The mechanisms that enable that coordination, a target for our future investigation, hold the key to understanding the evolution of human skull shape and encephalization. Additionally, these investigations may identify possible targets for treatment or prevention of craniofacial birth defects.

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce. To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection. This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated. Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection. Median overall survival. From the whole cohort of patients with NSCLC (N = 384), 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001). Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients.

P628. Hippocampal Volume, FKBP5 Genetic Risk Alleles, and Childhood Trauma Interact to Increase Vulnerability to Chronic Multisite Musculoskeletal Pain

Chronic multisite musculoskeletal pain (CMP) is common and highly morbid. However, vulnerability factors for CMP are poorly understood. We tested the hypothesis that both small hippocampal brain volume and genetic risk alleles in a key stress system gene, FKBP5, increase vulnerability for CMP.

Hippocampal volume, FKBP5 genetic risk alleles, and childhood trauma interact to increase vulnerability to chronic multisite musculoskeletal pain

Chronic multisite musculoskeletal pain (CMP) is common and highly morbid. However, vulnerability factors for CMP are poorly understood. Previous studies have independently shown that both small hippocampal brain volume and genetic risk alleles in a key stress system gene, FKBP5, increase vulnerability for chronic pain. However, little is known regarding the relationship between these factors and CMP. Here we tested the hypothesis that both small hippocampal brain volume and FKBP5 genetic risk, assessed using the tagging risk variant, FKBP5rs3800373, increase vulnerability for CMP. We used participant data from 36,822 individuals with available genetic, neuroimaging, and chronic pain data in the UK Biobank study. Although no main effects were observed, the interaction between FKBP5 genetic risk and right hippocampal volume was associated with CMP severity (β = −0.020, praw = 0.002, padj = 0.01). In secondary analyses, severity of childhood trauma further moderated the relationship between FKBP5 genetic risk, right hippocampal brain volume, and CMP (β = −0.081, p = 0.016). This study provides novel evidence that both FKBP5 genetic risk and childhood trauma moderate the relationship between right hippocampal brain volume and CMP. The data increases our understanding of vulnerability factors for CMP and builds a foundation for further work assessing causal relationships that might drive CMP development.

Dynamic finite-element simulations reveal early origin of complex human birth pattern

Human infants are born neurologically immature, potentially owing to conflicting selection pressures between bipedal locomotion and encephalization as suggested by the obstetrical dilemma hypothesis. Australopithecines are ideal for investigating this trade-off, having a bipedally adapted pelvis, yet relatively small brains. Our finite-element birth simulations indicate that rotational birth cannot be inferred from bony morphology alone. Based on a range of pelvic reconstructions and fetal head sizes, our simulations further imply that australopithecines, like humans, gave birth to immature, secondary altricial newborns with head sizes smaller than those predicted for non-human primates of the same body size especially when soft tissue thickness is adequately approximated. We conclude that australopithecines required cooperative breeding to care for their secondary altricial infants. These prerequisites for advanced cognitive development therefore seem to have been corollary to skeletal adaptations for bipedal locomotion that preceded the appearance of the genus Homo and the increase in encephalization.

Brain Metastases from Gynecologic Malignancies

Background and Objectives: To present a series of brain metastases from gynecologic primaries and provide a summary of the relevant literature. Materials and Methods: We retrospectively review 18 patients with histologically confirmed brain metastases from gynecologic primaries and summarize the largest series of relative reports. Results: Six brain metastases were of endometrial primary and 12 of ovarian primary. In 3 cases (16.7%), diagnosis of brain metastases was made at presentation of the gynecologic primary; in the others, median time to development of brain metastasis was 34 (range, 6–115) months. Median survival after brain metastasis diagnosis was 5 (range, 1–89) months. Favorable prognostic factors were better performance status (p = 0.04) and, marginally, smaller metastasis size (p = 0.06). No differences in brain metastases between endometrial and ovarian primaries were found, except for the time interval from primary to brain metastases diagnosis, which was shorter for endometrial tumors (p = 0.05). A comprehensive summary of previous studies is provided. Conclusions: Performance status and smaller brain metastases size are good prognostic factors. Endometrial cancer brain metastases develop earlier than ovarian cancer brain metastases.

Ipsilateral blooming of microbleeds after Hyperintense Acute Reperfusion Marker sign in an ischemic Stroke patient, a case report

BackgroundHyperintense Acute Reperfusion Marker (HARM) is a hyperintense subarachnoid signal on FLAIR MRI sequence caused by gadolinium contrast leakage into the subpial space. While, on FLAIR, HARM may mimic subarachnoid hemorrhage, it is differentiated from it on computed tomography (CT) and SWAN MRI sequences. Cerebral microbleeds are black, rounded spots on SWAN caused by blood-products deposition following red blood cell leakage from small cerebral vessels brain. Both microbleeds and HARM carry important prognostic implication as they are associated with blood-brain barrier disruption and an increased risk of intracerebral hemorrhage.Case presentationA 79-year-old man presented with aphasia and right hemiparesis due to ischemic stroke with left middle cerebral artery occlusion. Admission NIHSS score was 7, and he was successfully treated by intravenous thrombolysis and mechanical thrombectomy. On day 1, his clinical condition worsened, and he had an urgent gadolinium-enhanced MRI. There was no evidence of early recurrence, nor of hemorrhage on SWAN or on FLAIR. Left middle cerebral artery was permeable. The patient was anticoagulated for newly diagnosed atrial fibrillation, and a second MRI following a generalized tonic-clonic seizure showed multiple left hemispheric diffusion-weighted imaging (DWI) hyperintense spots and a left hemispheric sub-arachnoid hyperintensity on FLAIR, compatible with a subarachnoid hemorrhage. This diagnosis was excluded by SWAN MRI sequence and a normal cerebral CT the same day. The diagnosis of HARM was retained. At day 9, patient’s condition improved, and a control MRI did not show evidence of HARM. However, numerous microbleeds were detected in the left hemisphere only (ipsilateral with HARM and stroke).ConclusionsThis case highlights first of all the importance of differentiating HARM and subarachnoid hemorrhage, especially in an anticoagulated patient with clinical aggravation. Secondly, it is crucial to identify microbleeds and understand their pathophysiology, as they are associated with higher risk of hemorrhage and stroke recurrence in ischemic stroke patients. Finally, the mono-hemispheric appearance of microbleeds in this case suggests for the first time that, in some acute ischemic stroke patients, a relationship between HARM and cerebral microbleeds may exist.

A volume-independent conformity index for stereotactic radiosurgery.

To develop a volume-independent conformity metric called the Gaussian Weighted Conformity Index (GWCI) to evaluate stereotactic radiosurgery/radiotherapy (SRS/SRT) plans for small brain tumors. A signed bi-directional local distance (BLD) between the prescription isodose line and the target contour is determined for each point along the tumor contour (positive distance represents under-coverage). A similarity score function (SF) is derived from Gaussian function, penalizing under- and over-coverage at each point by assigning standard deviations of the Gaussian function. Each point along the dose line contour is scored with this SF. The average of the similarity scores determines the GWCI. A total of 40 targets from 18 patients who received Gamma-Knife SRS/SRT treatments were analyzed to determine appropriate penalty criteria. The resulting GWCIs for test cases already deemed clinically acceptable are presented and compared to the same cases scored with the New Conformity Index to determine the influence of tumor volumes on the two conformity indices (CIs). A total of four penalty combinations were tested based on the signed BLDs from the 40 targets. A GWCI of 0.9 is proposed as a cutoff for plan acceptability. The GWCI exhibits no target volume dependency as designed. A limitation of current CIs, volume dependency, becomes apparent when applied to SRS/SRT plans. The GWCI appears to be a more robust index, which penalizes over- and under-coverage of tumors and is not skewed by the tumor volume.

Fast Learners: One Trial Olfactory Learning in Insects

Despite their comparatively small brains, insects are able to survive and thrive in their environment. In the past, it was thought that insects are driven mainly by their instincts. However, today it is well established that they possess unique abilities to learn and use their experience in future decisions. Like many higher animals insects are able to acquire and retain information on when and where to forage, which mate to choose, where to lay their eggs and how to navigate in complex habitats. Learning can be surprisingly fast with only one single encounter with a suitable food source or oviposition site shaping an insect's preference for up to a lifetime. In this review, we discuss the scope and limits of insect learning, focusing in specific on olfactory learning, and we raise the question whether currently used learning paradigms in artificial lab set-ups are able to answer all ecologically relevant questions.

Outcomes of Hypofractionated Stereotactic Radiotherapy for Small and Moderate-Sized Brain Metastases: A Single-Institution Analysis.

BackgroundStereotactic radiosurgery (SRS) is the standard treatment for limited intracranial metastases. With the advent of frameless treatment delivery, fractionated stereotactic radiotherapy (FSRT) has become more commonly implemented given superior control and toxicity rates for larger lesions. We reviewed our institutional experience of FSRT to brain metastases without size restriction.MethodsWe performed a retrospective review of our institutional database of patients treated with FSRT for brain metastases. Clinical and dosimetric details were abstracted. All patients were treated in 3 or 5 fractions using LINAC-based FSRT, did not receive prior cranial radiotherapy, and had at least 6 months of MRI follow-up. Overall survival was estimated using the Kaplan–Meier method. Local failure and radionecrosis cumulative incidence rates were estimated using a competing risks model with death as the competing risk. Univariable and multivariable analyses using Fine and Gray’s proportional subdistribution hazards regression model were performed to determine covariates predictive of local failure and radionecrosis.ResultsWe identified 60 patients and 133 brain metastases treated at our institution from 2016 to 2020. The most common histologies were lung (53%) and melanoma (25%). Most lesions were >1 cm in diameter (84.2%) and did not have previous surgical resection (88%). The median duration of imaging follow-up was 9.8 months. The median survival for the whole cohort was 20.5 months. The local failure at 12 months was 17.8% for all lesions, 22.1% for lesions >1 cm, and 13.7% for lesions ≤1 cm (p = 0.36). The risk of radionecrosis at 12 months was 7.1% for all lesions, 13.2% for lesions >1 cm, and 3.2% for lesions ≤1 cm (p = 0.15).ConclusionsFSRT is safe and effective in the treatment of brain metastases of any size with excellent local control and toxicity outcomes. Prospective evaluation against single-fraction SRS is warranted for all lesion sizes.

Frailty Is Associated With Cognitive Decline Independent of Cerebral Small Vessel Disease and Brain Atrophy

BackgroundTo examine the effect of frailty on cognitive decline independent of cerebral small vessel disease (cSVD) and brain atrophy, and whether associations between neuropathology and cognition differed depending on frailty status.MethodsThe Tasmanian Study of Cognition and Gait was a population-based longitudinal cohort study with data collected at 3 phases from 2005 to 2012. Participants aged 60–85 were randomly selected from the electoral roll. Various data were used to operationalize a 36-item frailty index (FI) at baseline. Brain MRI was undertaken to obtain baseline measures of neuropathology. A neuropsychological battery was used to assess cognition at each time point. Generalized linear mixed models were used to examine the effect of frailty and MRI measures on cognition over time. The associations between MRI measures and cognition were explored after stratifying the sample by baseline frailty status. All analyses were adjusted for age, sex, and education.ResultsA total of 385 participants were included at baseline. The mean age was 72.5 years (standard deviation [SD] 7.0), 44% were female (n = 171). In fully adjusted linear mixed models, frailty (FI × time β −0.001, 95% confidence interval [CI] −0.003, −0.001, p = .03) was associated with decline in global cognition, independent of brain atrophy, and cSVD. The association between cSVD and global cognition was significant only in those with low levels of frailty (p = .03).ConclusionThese findings suggest that frailty is an important factor in early cognitive dysfunction, and measuring frailty may prove useful to help identify future risk of cognitive decline.

Small brains predisposed Late Quaternary mammals to extinction

The Late Quaternary witnessed a dramatic wave of large mammal extinctions, that are usually attributed to either human hunting or climatic change. We hypothesized that the large mammals that survived the extinctions might have been endowed with larger brain sizes than their relatives, which could have conferred enhanced behavioral plasticity and the ability to cope with the rapidly changing Late Quaternary environmental conditions. We assembled data on brain sizes of 291 extant mammal species plus 50 more that went extinct during the Late Quaternary. Using logistic, and mixed effect models, and controlling for phylogeny and body mass, we found that large brains were associated with higher probability to survive the Late Quaternary extinctions, and that extant species have brains that are, on average, 53% larger when accounting for order as a random effect, and 83% when fitting a single regression line. Moreover, we found that models that used brain size in addition to body size predicted extinction status better than models that used only body size. We propose that possessing a large brain was an important, yet so far neglected characteristic of surviving megafauna species.

Callosal Fiber Length Scales with Brain Size According to Functional Lateralization, Evolution, and Development.

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling, the degree to which fiber length varies according to brain size, was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (∼2000 human subjects, including both sexes). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findings highlight an interaction between interhemispheric communication and organizational and adaptive principles underlying brain development and evolution.SIGNIFICANCE STATEMENT Brain size varies across evolution, development, and individuals. Relative to small brains, the neural fiber length in large brains is inevitably increased, but the degree of such increase may differ between fiber tracts. Such a difference, if it exists, is valuable for understanding adaptive neural principles in large versus small brains during evolution and development. The present study showed a substantial difference in the length increase between the callosal fibers that connect the two hemispheres, replicated in two large healthy cohorts. Together, our study demonstrates that reorganization of interhemispheric fibers length according to brain size is intrinsically related to fiber composition, functional lateralization, cortical myelin content, and evolutionary and developmental expansion.

Recent Technical Advances in Accelerating the Clinical Translation of Small Animal Brain Imaging: Hybrid Imaging, Deep Learning, and Transcriptomics.

Small animal models play a fundamental role in brain research by deepening the understanding of the physiological functions and mechanisms underlying brain disorders and are thus essential in the development of therapeutic and diagnostic imaging tracers targeting the central nervous system. Advances in structural, functional, and molecular imaging using MRI, PET, fluorescence imaging, and optoacoustic imaging have enabled the interrogation of the rodent brain across a large temporal and spatial resolution scale in a non-invasively manner. However, there are still several major gaps in translating from preclinical brain imaging to the clinical setting. The hindering factors include the following: (1) intrinsic differences between biological species regarding brain size, cell type, protein expression level, and metabolism level and (2) imaging technical barriers regarding the interpretation of image contrast and limited spatiotemporal resolution. To mitigate these factors, single-cell transcriptomics and measures to identify the cellular source of PET tracers have been developed. Meanwhile, hybrid imaging techniques that provide highly complementary anatomical and molecular information are emerging. Furthermore, deep learning-based image analysis has been developed to enhance the quantification and optimization of the imaging protocol. In this mini-review, we summarize the recent developments in small animal neuroimaging toward improved translational power, with a focus on technical improvement including hybrid imaging, data processing, transcriptomics, awake animal imaging, and on-chip pharmacokinetics. We also discuss outstanding challenges in standardization and considerations toward increasing translational power and propose future outlooks.