7-Tesla evidence for columnar and rostral-caudal organization of the human periaqueductal gray response in the absence of threat: a working memory study.

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain-body communication, and is often studied for its role in "fight-or-flight" and "freezing" responses to threat. We used ultra-high field 7-Tesla fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining its in vivo function in humans during a working memory task (N = 87). Both mild and moderate cognitive demand elicited spatially similar patterns of whole brain BOLD response, and moderate cognitive demand elicited widespread BOLD increases above baseline in the brainstem. Notably, these brainstem increases were not significantly greater than those in the mild demand condition, suggesting that a subthreshold brainstem BOLD increase occurred for mild cognitive demand as well. PAG response was group-aligned and examined with subject-specific masks. In PAG, both mild and moderate demand elicited a well-defined response in ventrolateral PAG (vlPAG), a region thought to be functionally related to anticipated painful threat in humans and non-human animals-yet, the present task posed only the most minimal (if any) "threat", with the cognitive tasks used being approximately equivalent to remembering a phone number. These findings suggest that the PAG may play a more general role in visceromotor regulation, even in the absence of threat.Significance statement The periaqueductal gray (PAG) is thought to control survival-related behavior, and is typically studied using experiments that manipulate threat. Others have proposed that the PAG plays a more general role in bodily regulation, but studies examining PAG function outside of threat-based experimental contexts are rare. We used high-resolution fMRI to examine PAG response in humans during a working memory task, which involves minimal threat. Moderate cognitive demands elicited a well-defined response in ventrolateral PAG, a functional subregion thought to coordinate a "freezing" response to threat. A task where threat is minimal elicited a clear fMRI response in one of the most well-known survival circuits in the brain, which suggests the PAG supports a more general function in brain--body coordination.

Intensive whole-brain 7T MRI case study of volitional control of brain activity in deep absorptive meditation states.

Jhanas are profound states of mind achieved through advanced meditation, offering valuable insights into the nature of consciousness and tools to enhance well-being. Yet, its neurophenomenology remains limited due to methodological difficulties and the rarity of advanced meditation practitioners. We conducted a highly exploratory study to investigate the neurophenomenology of jhanas in an intensively sampled adept meditator case study (4 hr 7T fMRI collected in 27 sessions) who performed jhana meditation and rated specific aspects of experience immediately thereafter. Linear mixed models and correlations were used to examine relations among brain activity and jhana phenomenology. We identified distinctive patterns of brain activity in specific cortical, subcortical, brainstem, and cerebellar regions associated with jhana. Furthermore, we observed correlations between brain activity and phenomenological qualities of attention, jhanic qualities, and narrative processing, highlighting the distinct nature of jhanas compared to non-meditative states. Our study presents the most rigorous evidence yet that jhana practice deconstructs consciousness, offering unique insights into consciousness and significant implications for mental health and well-being.

Integrating brainstem and cortical functional architectures.

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

Integrating brainstem and cortical functional architectures.

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

Brain MRI Biomarkers in Isolated Rapid Eye Movement Sleep Behavior Disorder: Where Are We? A Systematic Review.

The increasing number of MRI studies focused on prodromal Parkinson's Disease (PD) demonstrates a strong interest in identifying early biomarkers capable of monitoring neurodegeneration. In this systematic review, we present the latest information regarding the most promising MRI markers of neurodegeneration in relation to the most specific prodromal symptoms of PD, namely isolated rapid eye movement (REM) sleep behavior disorder (iRBD). We reviewed structural, diffusion, functional, iron-sensitive, neuro-melanin-sensitive MRI, and proton magnetic resonance spectroscopy studies conducted between 2000 and 2023, which yielded a total of 77 relevant papers. Among these markers, iron and neuromelanin emerged as the most robust and promising indicators for early neurodegenerative processes in iRBD. Atrophy was observed in several regions, including the frontal and temporal cortices, limbic cortices, and basal ganglia, suggesting that neurodegenerative processes had been underway for some time. Diffusion and functional MRI produced heterogeneous yet intriguing results. Additionally, reduced glymphatic clearance function was reported. Technological advancements, such as the development of ultra-high field MRI, have enabled the exploration of minute anatomical structures and the detection of previously undetectable anomalies. The race to achieve early detection of neurodegeneration is well underway.

Cortical and subcortical mapping of the allostatic-interoceptive system in the human brain: replication and extension with 7 Tesla fMRI.

The brain continuously anticipates the energetic needs of the body and prepares to meet those needs before they arise, a process called allostasis. In support of allostasis, the brain continually models the internal state of the body, a process called interoception. Using published tract-tracing studies in non-human animals as a guide, we previously identified a large-scale system supporting allostasis and interoception in the human brain with functional magnetic resonance imaging (fMRI) at 3 Tesla. In the present study, we replicated and extended this system in humans using 7 Tesla fMRI (N = 91), improving the precision of subgenual and pregenual anterior cingulate topography as well as brainstem nuclei mapping. We verified over 90% of the anatomical connections in the hypothesized allostatic-interoceptive system observed in non-human animal research. We also identified functional connectivity hubs verified in tract-tracing studies but not previously detected using 3 Tesla fMRI. Finally, we demonstrated that individuals with stronger fMRI connectivity between system hubs self-reported greater interoceptive awareness, building on construct validity evidence from our earlier paper. Taken together, these results strengthen evidence for the existence of a whole-brain system supporting interoception in the service of allostasis and we consider the implications for mental and physical health.

In vivo structural connectome of arousal and motor brainstem nuclei by 7 Tesla and 3 Tesla MRI.

Brainstem nuclei are key participants in the generation and maintenance of arousal, which is a basic function that modulates wakefulness/sleep, autonomic responses, affect, attention, and consciousness. Their mechanism is based on diffuse pathways ascending from the brainstem to the thalamus, hypothalamus, basal forebrain and cortex. Several arousal brainstem nuclei also participate in motor functions that allow humans to respond and interact with the surrounding through a multipathway motor network. Yet, little is known about the structural connectivity of arousal and motor brainstem nuclei in living humans. This is due to the lack of appropriate tools able to accurately visualize brainstem nuclei in conventional imaging. Using a recently developed in vivo probabilistic brainstem nuclei atlas and 7 Tesla diffusion-weighted images (DWI), we built the structural connectome of 18 arousal and motor brainstem nuclei in living humans (n = 19). Furthermore, to investigate the translatability of our findings to standard clinical MRI, we acquired 3 Tesla DWI on the same subjects, and measured the association of the connectome across scanners. For both arousal and motor circuits, our results showed high connectivity within brainstem nuclei, and with expected subcortical and cortical structures based on animal studies. The association between 3 Tesla and 7 Tesla connectivity values was good, especially within the brainstem. The resulting structural connectome might be used as a baseline to better understand arousal and motor functions in health and disease in humans.

Structural connectivity of autonomic, pain, limbic, and sensory brainstem nuclei in living humans based on 7 Tesla and 3 Tesla MRI.

Autonomic, pain, limbic, and sensory processes are mainly governed by the central nervous system, with brainstem nuclei as relay centers for these crucial functions. Yet, the structural connectivity of brainstem nuclei in living humans remains understudied. These tiny structures are difficult to locate using conventional in vivo MRI, and ex vivo brainstem nuclei atlases lack precise and automatic transformability to in vivo images. To fill this gap, we mapped our recently developed probabilistic brainstem nuclei atlas developed in living humans to high-spatial resolution (1.7 mm isotropic) and diffusion weighted imaging (DWI) at 7 Tesla in 20 healthy participants. To demonstrate clinical translatability, we also acquired 3 Tesla DWI with conventional resolution (2.5 mm isotropic) in the same participants. Results showed the structural connectome of 15 autonomic, pain, limbic, and sensory (including vestibular) brainstem nuclei/nuclei complex (superior/inferior colliculi, ventral tegmental area-parabrachial pigmented, microcellular tegmental-parabigeminal, lateral/medial parabrachial, vestibular, superior olivary, superior/inferior medullary reticular formation, viscerosensory motor, raphe magnus/pallidus/obscurus, parvicellular reticular nucleus-alpha part), derived from probabilistic tractography computation. Through graph measure analysis, we identified network hubs and demonstrated high intercommunity communication in these nuclei. We found good (r = .5) translational capability of the 7 Tesla connectome to clinical (i.e., 3 Tesla) datasets. Furthermore, we validated the structural connectome by building diagrams of autonomic/pain/limbic connectivity, vestibular connectivity, and their interactions, and by inspecting the presence of specific links based on human and animal literature. These findings offer a baseline for studies of these brainstem nuclei and their functions in health and disease, including autonomic dysfunction, chronic pain, psychiatric, and vestibular disorders.

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI.

Despite remarkable advances in mapping the functional connectivity of the cortex, the functional connectivity of subcortical regions is understudied in living humans. This is the case for brainstem nuclei that control vital processes, such as autonomic, limbic, nociceptive and sensory functions. This is because of the lack of precise brainstem nuclei localization, of adequate sensitivity and resolution in the deepest brain regions, as well as of optimized processing for the brainstem. To close the gap between the cortex and the brainstem, on 20 healthy subjects, we computed a correlation-based functional connectome of 15 brainstem nuclei involved in autonomic, limbic, nociceptive, and sensory function (superior and inferior colliculi, ventral tegmental area-parabrachial pigmented nucleus complex, microcellular tegmental nucleus-prabigeminal nucleus complex, lateral and medial parabrachial nuclei, vestibular and superior olivary complex, superior and inferior medullary reticular formation, viscerosensory motor nucleus, raphe magnus, pallidus, and obscurus, and parvicellular reticular nucleus - alpha part) with the rest of the brain. Specifically, we exploited 1.1mm isotropic resolution 7 Tesla resting-state fMRI, ad-hoc coregistration and physiological noise correction strategies, and a recently developed probabilistic template of brainstem nuclei. Further, we used 2.5mm isotropic resolution resting-state fMRI data acquired on a 3 Tesla scanner to assess the translatability of our results to conventional datasets. We report highly consistent correlation coefficients across subjects, confirming available literature on autonomic, limbic, nociceptive and sensory pathways, as well as high interconnectivity within the central autonomic network and the vestibular network. Interestingly, our results showed evidence of vestibulo-autonomic interactions in line with previous work. Comparison of 7 Tesla and 3 Tesla findings showed high translatability of results to conventional settings for brainstem-cortical connectivity and good yet weaker translatability for brainstem-brainstem connectivity. The brainstem functional connectome might bring new insight in the understanding of autonomic, limbic, nociceptive and sensory function in health and disease.

Functional connectome of arousal and motor brainstem nuclei in living humans by 7 Tesla resting-state fMRI.

Brainstem nuclei play a pivotal role in many functions, such as arousal and motor control. Nevertheless, the connectivity of arousal and motor brainstem nuclei is understudied in living humans due to the limited sensitivity and spatial resolution of conventional imaging, and to the lack of atlases of these deep tiny regions of the brain. For a holistic comprehension of sleep, arousal and associated motor processes, we investigated in 20 healthy subjects the resting-state functional connectivity of 18 arousal and motor brainstem nuclei in living humans. To do so, we used high spatial-resolution 7 Tesla resting-state fMRI, as well as a recently developed in-vivo probabilistic atlas of these nuclei in stereotactic space. Further, we verified the translatability of our brainstem connectome approach to conventional (e.g. 3 Tesla) fMRI. Arousal brainstem nuclei displayed high interconnectivity, as well as connectivity to the thalamus, hypothalamus, basal forebrain and frontal cortex, in line with animal studies and as expected for arousal regions. Motor brainstem nuclei showed expected connectivity to the cerebellum, basal ganglia and motor cortex, as well as high interconnectivity. Comparison of 3 Tesla to 7 Tesla connectivity results indicated good translatability of our brainstem connectome approach to conventional fMRI, especially for cortical and subcortical (non-brainstem) targets and to a lesser extent for brainstem targets. The functional connectome of 18 arousal and motor brainstem nuclei with the rest of the brain might provide a better understanding of arousal, sleep and accompanying motor functions in living humans in health and disease.

Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging.

BACKGROUND: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. OBJECTIVE: To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. METHODS: Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. RESULTS: In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. CONCLUSIONS: The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages. © 2021 International Parkinson and Movement Disorder Society.

Location of Subcortical Microbleeds and Recovery of Consciousness After Severe Traumatic Brain Injury.

BACKGROUND: In patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (arousal nuclei) are implicated in coma pathogenesis and are compatible with coma recovery. METHODS: We mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 tesla susceptibility-weighted images (SWI) in 12 patients with acute severe TBI who presented in coma and recovered consciousness within 6 months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at 6 months. RESULTS: There was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%), and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within nonarousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale-Extended scores. CONCLUSION: These results suggest resilience of arousal mechanisms in the human brain after severe TBI.

Probabilistic Atlas of the Mesencephalic Reticular Formation, Isthmic Reticular Formation, Microcellular Tegmental Nucleus, Ventral Tegmental Area Nucleus Complex, and Caudal-Rostral Linear Raphe Nucleus Complex in Living Humans from 7 Tesla Magnetic Resonance Imaging.

Introduction: The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. Yet, these nuclei are difficult to identify with magnetic resonance imaging (MRI) of living humans. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive ultra-high-field MRI. Methods: We acquired single-subject, multicontrast (diffusion and T2-weighted), 1.1-mm isotropic resolution, 7 Tesla MRI images of 12 healthy subjects. After preprocessing and alignment to the stereotactic space, these images were used to delineate (in each subject) the nuclei of interest based on the image contrast as well as on neighboring nuclei and landmarks. Nucleus labels were averaged across subjects to yield probabilistic labels. The latter were further validated by assessment of the label inter-rater agreement, internal consistency, and volume. Results: Labels were delineated for each nucleus with good overlap across subjects. The inter-rater agreement and internal consistency were below (p < 10-8) the linear spatial imaging resolution (1.1 mm), thus validating the generated probabilistic atlas labels. The volumes of our labels did not differ from literature volumes (p < 0.05), further validating our atlas. Discussion and Conclusion: The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes. Impact statement The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive, ultra-high-field magnetic resonance imaging. The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes.

Ultra High Field fMRI of Human Superior Colliculi Activity during Affective Visual Processing.

Research on rodents and non-human primates has established the involvement of the superior colliculus in defensive behaviours and visual threat detection. The superior colliculus has been well-studied in humans for its functional roles in saccade and visual processing, but less is known about its involvement in affect. In standard functional MRI studies of the human superior colliculus, it is challenging to discern activity in the superior colliculus from activity in surrounding nuclei such as the periaqueductal gray due to technological and methodological limitations. Employing high-field strength (7 Tesla) fMRI techniques, this study imaged the superior colliculus at high (0.75 mm isotropic) resolution, which enabled isolation of the superior colliculus from other brainstem nuclei. Superior colliculus activation during emotionally aversive image viewing blocks was greater than that during neutral image viewing blocks. These findings suggest that the superior colliculus may play a role in shaping subjective emotional experiences in addition to its visuomotor functions, bridging the gap between affective research on humans and non-human animals.

Ascending arousal network connectivity during recovery from traumatic coma.

BACKGROUND: It is not currently possible to predict which patients will develop chronic disorders of consciousness (DoC) after severe traumatic brain injury (TBI). Although the ascending arousal network (AAN) supports human consciousness, it is unknown which AAN pathways must be preserved for patients to recover consciousness. METHODS: Sixteen patients with acute traumatic coma and 16 matched healthy controls were scanned with high angular resolution diffusion imaging (HARDI). All patients recovered consciousness (Recovery Cohort). Nine were scanned longitudinally: first in the ICU (Acute), then at ≥5 months post-injury (Follow-up). Six separate patients with post-traumatic DoC were scanned ≥5 months post-injury (Chronic DoC Cohort). For each AAN pathway, we computed the median relative change in Acute-to-Follow-up Connectivity Probability (CP) in the Recovery Cohort. We then used Wilcoxon tests with Bonferroni correction to compare CP in each AAN pathway in the Recovery Cohort at Follow-up versus the Chronic DoC Cohort. In an exploratory analysis, we used principal component analysis (PCA) to determine whether linear combinations of AAN CP values could separate the Chronic DoC Cohort from the Recovery Cohort and the healthy controls. RESULTS: In the Recovery Cohort, the largest relative AAN CP changes were in the brainstem-to-thalamus (median [IQR] = 0.7 [0.09, 0.9]) and forebrain-to-occipital lobe (-0.8 [-0.9, -0.8]) pathways. The AAN connections that differed in the cross-sectional analysis between the Recovery Cohort at Follow-up and the Chronic DoC Cohort included brainstem-to-hypothalamus (W = 53, PBonf = 0.02), brainstem-to-temporal lobe (W = 52, PBonf = 0.04), and thalamus-to-temporal lobe (W = 54, PBonf = 0.009). Plotting the first two principal components of AAN connectivity resulted in a linear separation of Chronic DoC patients from other study groups. CONCLUSIONS: We provide evidence for a longitudinal increase in brainstem-thalamic connectivity during recovery of consciousness after traumatic coma. Cross-sectional analyses revealed that brainstem-hypothalamus, brainstem-temporal lobe, and thalamus-temporal lobe connectivity differed between patients who recovered consciousness and those with a chronic DoC. These observations provide the basis for further investigation into AAN connectivity as a biomarker for recovery of consciousness after traumatic coma.

Individual Resting-State Brain Networks Enabled by Massive Multivariate Conditional Mutual Information.

Individual-level resting-state networks (RSNs) based on resting-state fMRI (rs-fMRI) are of great interest due to evidence that network dysfunction may underlie some diseases. Most current rs-fMRI analyses use linear correlation. Since correlation is a bivariate measure of association, it discards most of the information contained in the spatial variation of the thousands of hemodynamic signals within the voxels in a given brain region. Subject-specific functional RSNs using typical rs-fMRI data, are therefore dominated by indirect connections and loss of spatial information and can only deliver reliable connectivity after group averaging. While bivariate partial correlation can rule out indirect connections, it results in connectivity that is too sparse due to lack of sensitivity. We have developed a method that uses all the spatial variation information in a given parcel by employing a multivariate information-theoretic association measure based on canonical correlations. Our method, multivariate conditional mutual information (mvCMI) reliably constructs single-subject connectivity estimates showing mostly direct connections. Averaging across subjects is not needed. The method is applied to Human Connectome Project data and compared to diffusion MRI. The results are far superior to those obtained by correlation and partial correlation.

Disruption of the ascending arousal network in acute traumatic disorders of consciousness.

OBJECTIVE: To determine whether ascending arousal network (AAn) connectivity is reduced in patients presenting with traumatic coma. METHODS: We performed high-angular-resolution diffusion imaging in 16 patients with acute severe traumatic brain injury who were comatose on admission and in 16 matched controls. We used probabilistic tractography to measure the connectivity probability (CP) of AAn axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus, and basal forebrain. To assess the spatial specificity of CP differences between patients and controls, we also measured CP within 4 subcortical pathways outside the AAn. RESULTS: Compared to controls, patients showed a reduction in AAn pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain. When each pathway was examined individually, brainstem-hypothalamus and brainstem-thalamus CPs, but not brainstem-forebrain CP, were significantly reduced in patients. Only 1 subcortical pathway outside the AAn showed reduced CP in patients. CONCLUSIONS: We provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. Our findings support current conceptual models of coma as being caused by subcortical AAn injury. AAn connectivity mapping provides an opportunity to advance the study of human coma and consciousness.

In vivo Probabilistic Structural Atlas of the Inferior and Superior Colliculi, Medial and Lateral Geniculate Nuclei and Superior Olivary Complex in Humans Based on 7 Tesla MRI.

Despite extensive neuroimaging research of primary sensory cortices involved in auditory and visual functions, subcortical structures within these domains, such as the inferior and superior colliculi, the medial and lateral geniculate nuclei and the superior olivary complex, are currently understudied with magnetic resonance imaging (MRI) in living humans. This is because a precise localization of these nuclei is hampered by the limited contrast and sensitivity of conventional neuroimaging methods for deep brain nuclei. In this work, we used 7 Tesla multi-modal (T2-weighted and diffusion fractional anisotropy) 1.1 mm isotropic resolution MRI to achieve high sensitivity and contrast for single-subject brainstem and thalamic nuclei delineation. After precise coregistration to stereotactic space, we generated an in vivo human probabilistic atlas of auditory (medial geniculate nucleus, inferior colliculus, and superior olivary complex) and visual (lateral geniculate nucleus and superior colliculus) subcortical nuclei. We foresee the use of this atlas as a tool to precisely identify the location and shape of auditory/visual deep nuclei in research as well as clinical human studies.

Functional Involvement of Human Periaqueductal Gray and Other Midbrain Nuclei in Cognitive Control.

Recent theoretical advances have motivated the hypothesis that the periaqueductal gray (PAG) participates in behaviors that involve changes in the autonomic control of visceromotor activity, including during cognitively demanding tasks. We used ultra-high-field (7 tesla) fMRI to measure human brain activity at 1.1 mm resolution while participants completed a working memory task. Consistent with prior work, participants were less accurate and responded more slowly with increasing memory load-signs of increasing task difficulty. Whole-brain fMRI analysis revealed increased activity in multiple cortical areas with increasing working memory load, including frontal and parietal cortex, dorsal cingulate, supplementary motor area, and anterior insula. Several dopamine-rich midbrain nuclei, such as the substantia nigra and ventral tegmental area, also exhibited load-dependent increases in activation. To investigate PAG involvement during cognitive engagement, we developed an automated method for segmenting and spatially normalizing the PAG. Analyses using cross-validated linear support vector machines showed that the PAG discriminated high versus low working memory load conditions with 95% accuracy in individual subjects based on activity increases in lateral and ventrolateral PAG. Effect sizes in the PAG were comparable in magnitude to those in many of the cortical areas. These findings suggest that cognitive control is not only associated with cortical activity in the frontal and parietal lobes, but also with increased activity in the subcortical PAG and other midbrain regions involved in the regulation of autonomic nervous system function.SIGNIFICANCE STATEMENT Functional neuroimaging in humans has shown that cognitive control engages multiple corticostriatal networks and brainstem nuclei, but theoretical advances suggest that the periaqueductal gray (PAG) should also be engaged during cognitively demanding tasks. Recent advances in ultra-high-field fMRI provided an opportunity to obtain the first evidence that increased activation of intermediate and rostral portions of lateral and ventrolateral PAG columns in humans is modulated by cognitive load. These findings suggest that cognitive control is not solely mediated by activity in the cortex, but that midbrain structures important for autonomic regulation also play a crucial role in higher-order cognition.

Dependence of resting-state fMRI fluctuation amplitudes on cerebral cortical orientation relative to the direction of B0 and anatomical axes.

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B0-field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B0, is about +70% at the pial surface at 7T and +11% at 3T. The B0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about -30% at the pial surface at 7T and about -13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI.