Multimodal identification of the mouse brain using simultaneous Ca 2+ imaging and fMRI.

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome- based identification to be successful and explored various features of these data.

Visual evoked potentials in multiple sclerosis: P100 latency and visual pathway damage including the lateral geniculate nucleus.

OBJECTIVE: To explore associations of the main component (P100) of visual evoked potentials (VEP) to pre- and postchiasmatic damage in multiple sclerosis (MS). METHODS: 31 patients (median EDSS: 2.5), 13 with previous optic neuritis (ON), and 31 healthy controls had VEP, optical coherence tomography and magnetic resonance imaging. We tested associations of P100-latency to the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell/inner plexiform layers (GCIPL), lateral geniculate nucleus volume (LGN), white matter lesions of the optic radiations (OR-WML), fractional anisotropy of non-lesional optic radiations (NAOR-FA), and to the mean thickness of primary visual cortex (V1). Effect sizes are given as marginal R2 (mR2). RESULTS: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100-latency was significantly associated with GCIPL (mR2 = 0.26), and less strongly with OR-WML (mR2 = 0.17), NAOR-FA (mR2 = 0.13) and pRNFL (mR2 = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR2 = 0.41). In ON-patients, P100-latency was significantly associated with LGN volume (mR2 = -0.56). CONCLUSIONS: P100-latency is affected by anterior and posterior visual pathway damage. In ON-patients, damage at the synapse-level (LGN) may additionally contribute to latency delay. SIGNIFICANCE: Our findings corroborate post-chiasmatic contributions to the VEP-signal, which may relate to distinct pathophysiological mechanisms in MS.

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-ß and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-ß positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

Five dominant dimensions of brain aging are identified via deep learning: associations with clinical, lifestyle, and genetic measures.

Brain aging is a complex process influenced by various lifestyle, environmental, and genetic factors, as well as by age-related and often co-existing pathologies. MRI and, more recently, AI methods have been instrumental in understanding the neuroanatomical changes that occur during aging in large and diverse populations. However, the multiplicity and mutual overlap of both pathologic processes and affected brain regions make it difficult to precisely characterize the underlying neurodegenerative profile of an individual from an MRI scan. Herein, we leverage a state-of-the art deep representation learning method, Surreal-GAN, and present both methodological advances and extensive experimental results that allow us to elucidate the heterogeneity of brain aging in a large and diverse cohort of 49,482 individuals from 11 studies. Five dominant patterns of neurodegeneration were identified and quantified for each individual by their respective (herein referred to as) R-indices. Significant associations between R-indices and distinct biomedical, lifestyle, and genetic factors provide insights into the etiology of observed variances. Furthermore, baseline R-indices showed predictive value for disease progression and mortality. These five R-indices contribute to MRI-based precision diagnostics, prognostication, and may inform stratification into clinical trials.

Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology.

BACKGROUND: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology. METHODS: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS). RESULTS: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO. CONCLUSIONS: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

Maturational trajectories of pericortical contrast in typical brain development.

In the last few years, a significant amount of work has aimed to characterize maturational trajectories of cortical development. The role of pericortical microstructure putatively characterized as the gray-white matter contrast (GWC) at the pericortical gray-white matter boundary and its relationship to more traditional morphological measures of cortical morphometry has emerged as a means to examine finer grained neuroanatomical underpinnings of cortical changes. In this work, we characterize the GWC developmental trajectories in a representative sample (n = 394) of children and adolescents (~4 to ~22 years of age), with repeated scans (1-3 scans per subject, total scans n = 819). We tested whether linear, quadratic, or cubic trajectories of contrast development best described changes in GWC. A best-fit model was identified vertex-wise across the whole cortex via the Akaike Information Criterion (AIC). GWC across nearly the whole brain was found to significantly change with age. Cubic trajectories were likeliest for 63% of vertices, quadratic trajectories were likeliest for 20% of vertices, and linear trajectories were likeliest for 16% of vertices. A main effect of sex was observed in some regions, where males had a higher GWC than females. However, no sex by age interactions were found on GWC. In summary, our results suggest a progressive decrease in GWC at the pericortical boundary throughout childhood and adolescence. This work contributes to efforts seeking to characterize typical, healthy brain development and, by extension, can help elucidate aberrant developmental trajectories.

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance.

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2-weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion-load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between-structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion-load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body-fluid markers.

Structural brain plasticity induced by early blindness.

It is well established that early blindness results in behavioural adaptations. While the functional effects of visual deprivation have been well researched, anatomical studies are scarce. The aim of this study was to investigate whole brain structural plasticity in a mouse model of congenital blindness. Volumetric analyses were conducted on high-resolution MRI images and histological sections from the same brains. These morphometric measurements were compared between anophthalmic and sighted ZRDBA mice obtained by breeding ZRDCT and DBA mice. Results from MRI analyses using the Multiple Automatically Generated Templates (MAGeT) method showed smaller volume for the primary visual cortex and superior colliculi in anophthalmic compared with sighted mice. Deformation-based morphometry revealed smaller volumes within the dorsal lateral geniculate nuclei and the lateral secondary visual cortex and larger volumes within olfactory areas, piriform cortex, orbital areas and the amygdala, in anophthalmic compared with sighted mice. Histological analyses revealed a larger volume for the amygdala and smaller volume for the superior colliculi, primary visual cortex and medial secondary visual cortex, in anophthalmic compared with sighted mice. The absence of superficial visual layers of the superior colliculus and the thinner cortical layer IV of the primary and secondary visual cortices may explain the smaller volume of these areas, although this was observed in a limited sample. The present study shows large-scale brain plasticity in a mouse model of congenital blindness. In addition, the congruence of MRI and histological findings support the use of MRI to investigate structural brain plasticity in the mouse.

Deformation-based shape analysis of the hippocampus in the semantic variant of primary progressive aphasia and Alzheimer's disease.

BACKGROUND: Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer's disease (AD). METHODS: We measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit. RESULTS: Comparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus. DISCUSSION: Our study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA.

Damage of the lateral geniculate nucleus in MS: Assessing the missing node of the visual pathway.

OBJECTIVE: To study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function. METHODS: In this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell-inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR-FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision. RESULTS: LGN volume was reduced in patients vs HC (165.5 ± 45.5 vs 191.4 ± 47.7 mm3, B = -25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman ρ = -0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = -133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 × 10-5, SE = 0.03, p = 0.998), but it correlated with HRR color vision (ρ = 0.39, p = 0.032). CONCLUSIONS: LGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI.

Subiculum volumes associated with memory function in the oldest-old individuals aged 95 years and older.

AIM: Few cohort studies targeting the oldest-old individuals have been carried out. The subiculum in the hippocampus is thought to be related to memory function, and atrophy of this structure might result in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Thus, we sought to examine the relationship between subiculum volumes and memory function in individuals aged ≥95 years, using a novel cognitive examination called the Addenbrooke's Cognitive Examination III (ACE-III) and an advanced magnetic resonance imaging analytical method, Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeTbrain), to measure hippocampal subfield volumes. METHODS: A part of the cohort data of the Arakawa 95+ study for the oldest-old aged ≥95 years was used. A total of 10 individuals completed all of the examinations. The MAGeT brain was applied to estimate the subfield volumes of the hippocampus. Correlation analyses and multiple regression analyses were carried out to examine a relationship among ACE-III memory scores and the subfield volumes in the hippocampus, including the subiculum. RESULTS: There was a significant relationship between ACE-III memory scores and subdivision volumes. Regression analyses showed that subiculum volumes were associated with ACE-III memory scores in the oldest-old individuals (ß = 0.721, P = 0.019; F1, 8 = 8.67, adjusted R2 = 0.46). CONCLUSIONS: The subiculum might play a pivotal role in memory function in the oldest-old individuals aged ≥95 years. The present finding warrants further research including larger sample sizes. Geriatr Gerontol Int 2019; 19: 347-351.

Longitudinal changes in cocaine intake and cognition are linked to cortical thickness adaptations in cocaine users.

BACKGROUND: Cocaine use has been consistently associated with decreased gray matter volumes in the prefrontal cortex. However, it is unclear if such neuroanatomical abnormalities depict either pre-existing vulnerability markers or drug-induced consequences. Thus, this longitudinal MRI study investigated neuroplasticity and cognitive changes in relation to altered cocaine intake. METHODS: Surface-based morphometry, cocaine hair concentration, and cognitive performance were measured in 29 cocaine users (CU) and 38 matched controls at baseline and follow-up. Based on changes in hair cocaine concentration, CU were classified either as Decreasers (n = 15) or Sustained Users (n = 14). Surface-based morphometry measures did not include regional tissue volumes. RESULTS: At baseline, CU displayed reduced cortical thickness (CT) in lateral frontal regions, and smaller cortical surface area (CSA) in the anterior cingulate cortex, compared to controls. In Decreasers, CT of the lateral frontal cortex increased whereas CT within the same regions tended to further decrease in Sustained Users. In contrast, no changes were found for CSA and subcortical structures. Changes in CT were linked to cognitive performance changes and amount of cocaine consumed over the study period. CONCLUSIONS: These results suggest that frontal abnormalities in CU are partially drug-induced and can recover with decreased substance use. Moreover, recovery of frontal CT is accompanied by improved cognitive performance confirming that cognitive decline associated with cocaine use is potentially reversible.

Concussion induces focal and widespread neuromorphological changes.

Concussion induces transient, and oftentimes chronic, lingering impairment to mental functioning, which must be driven by some underlying neurobiological perturbation - however, the physical changes related to sequelae are difficult to detect. Previous imaging studies on concussion have focused on alterations to cortical anatomy, but few have examined the cerebrum, subcortex, and cerebellum. Here, we present an analysis of these structures in a single cohort (all males, 21 patients, 22 controls) using MRI and diagnosed with a single-concussive episode in the acute and sub-acute stages of injury. Structural images were segmented into 78 cortical brain regions and 81,924 vertices using the CIVET algorithm. Subcortical volumetric analyses of the cerebellum, thalamus, globus pallidus, caudate and putamen were conducted following segmentation. Participants with concussion were found to have reduced white and grey matter volume, total cortical volume, as well as cortical thinning, primarily in left frontal areas. No differences were observed in the cerebellum or subcortical structures. In conclusion, just a single concussive episode induces measurable changes in brain structure manifesting as diffuse and local patterns of altered neuromorphometry.

Smoking normalizes cerebral blood flow and oxygen consumption after 12-hour abstention.

Acute nicotine administration stimulates [(14)C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO2. At the end of the abstention period, global grey-matter CBF and CMRO2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO2 had increased by 11%. Regional analysis showed that CMRO2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO2 had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO2 during acute abstention may mediate the cognitive changes described in chronic smokers.

Identifying craniofacial features associated with prenatal exposure to androgens and testing their relationship with brain development.

We used magnetic resonance (MR) images obtained in same-sex and opposite-sex dizygotic twins (n = 119, 8 years of age) to study possible effects of prenatal androgens on craniofacial features. Using a principal component analysis of 19 craniofacial landmarks placed on the MR images, we identified a principal component capturing craniofacial features that distinguished females with a presumed differential exposure to prenatal androgens by virtue of having a male (vs. a female) co-twin (Cohen's d = 0.76). Subsequently, we tested the possibility that this craniofacial "signature" of prenatal exposure to androgens predicts brain size, a known sexually dimorphic trait. In an independent sample of female adolescents (singletons; n = 462), we found that the facial signature predicts up to 8% of variance in brain size. These findings are consistent with the organizational effects of androgens on brain development and suggest that the facial signature derived in this study could complement other indirect measures of prenatal exposure to androgens.

Longitudinal four-dimensional mapping of subcortical anatomy in human development.

Growing access to large-scale longitudinal structural neuroimaging data has fundamentally altered our understanding of cortical development en route to human adulthood, with consequences for basic science, medicine, and public policy. In striking contrast, basic anatomical development of subcortical structures such as the striatum, pallidum, and thalamus has remained poorly described--despite these evolutionarily ancient structures being both intimate working partners of the cortical sheet and critical to diverse developmentally emergent skills and disorders. Here, to begin addressing this disparity, we apply methods for the measurement of subcortical volume and shape to 1,171 longitudinally acquired structural magnetic resonance imaging brain scans from 618 typically developing males and females aged 5-25 y. We show that the striatum, pallidum, and thalamus each follow curvilinear trajectories of volume change, which, for the striatum and thalamus, peak after cortical volume has already begun to decline and show a relative delay in males. Four-dimensional mapping of subcortical shape reveals that (i) striatal, pallidal, and thalamic domains linked to specific fronto-parietal association cortices contract with age whereas other subcortical territories expand, and (ii) each structure harbors hotspots of sexually dimorphic change over adolescence--with relevance for sex-biased mental disorders emerging in youth. By establishing the developmental dynamism, spatial heterochonicity, and sexual dimorphism of human subcortical maturation, these data bring our spatiotemporal understanding of subcortical development closer to that of the cortex--allowing evolutionary, basic, and clinical neuroscience to be conducted within a more comprehensive developmental framework.

Blindsight mediated by an S-cone-independent collicular pathway: an fMRI study in hemispherectomized subjects.

The purpose of our study was to investigate the ability to process achromatic and short-wavelength-sensitive cone (S-cone)-isolating (blue-yellow) stimuli in the blind visual field of hemispherectomized subjects and to demonstrate that blindsight is mediated by a collicular pathway that is independent of S-cone inputs. Blindsight has been described as the ability to respond to visual stimuli in the blind visual field without conscious awareness [Weiskrantz, L., Warrington, E. K., Sanders, M. D., & Marshall, J. Visual capacity in the hemianopic field following a restricted occipital ablation. Brain, 97, 709-728, 1974]. The roles of the subcortical neural structures in blindsight, such as the pulvinar and the superior colliculus, have been debated and an underlying neural correlate has yet to be confirmed. Using fMRI, we tested the ability to process visual stimuli that isolated the achromatic and short-wavelength-sensitive (S-)-cone pathways in three subjects: one control subject, one hemispherectomized subject with blindsight, and one hemispherectomized subject without blindsight. We demonstrated that (1) achromatic and S-cone-isolating stimuli presented to the normal visual hemifield of hemispherectomized subjects and to both visual hemifields of the control subject activated contralateral visual areas (V1/V2), as expected; (2) achromatic stimulus presentation but not S-cone-isolating stimulus presentation to the blind hemifield of the subject with blindsight activated visual areas FEF/V5; (3) whereas the cortical activation of the control subject was enhanced by an additional stimulus (achromatic and S-cone isolating) presented in the contralateral visual field, activation pattern of the subject with blindsight was enhanced by achromatic stimuli only. We conclude that the human superior colliculus is blind to the S-cone-isolating stimuli, and blindsight is mediated by an S-cone-independent collicular pathway.