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.

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.

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.

Long-Term Improvement of Parkinson Disease Motor Symptoms Derived From Lesions of Prelemniscal Fiber Tract Components.

BACKGROUND: Prelemniscal radiations (Raprl) are composed of different fiber tracts, connecting the brain stem and cerebellum with basal ganglia and cerebral cortex. In Parkinson disease (PD), lesions in Raprl induce improvement of tremor, rigidity, and bradykinesia in some patients, while others show improvement of only 1 or 2 symptoms, suggesting different fiber tracts mediate different symptoms. OBJECTIVE: To search for correlations between improvements of specific symptoms with surgical lesions of specific fiber tract components of Raprl in patients with PD. METHODS: A total of 10 patients were treated with unilateral radiofrequency lesions directed to Raprl. The improvement for tremor, rigidity, bradykinesia, posture, and gait was evaluated at 24 to 33 mo after operation through the Unified Parkinson's Disease Rating Scale (UPDRS) score, and the precise location and extension of lesions through structural magnetic resonance imaging and probabilistic tractography at 6 to 8 mo postsurgery. Correlation between percentage of fiber tract involvement and percentage of UPDRS-III score improvement was evaluated through Spearman's correlation coefficient. RESULTS: Group average improvement was 86% for tremor, 62% for rigidity, 56% for bradykinesia, and 45% for gait and posture. Improvement in global UPDRS score correlated with extent of lesions in fibers connecting with contralateral cerebellar cortex and improvement of posture and gait with fibers connecting with contralateral deep cerebellar nuclei. Lesion of fibers connecting the globus pallidum with pedunculopontine nucleus induced improvement of gait and posture over other symptoms. CONCLUSION: Partial lesion of Raprl fibers resulted in symptom improvement at 2-yr follow-up. Lesions of selective fiber components may result in selective improvement of specific symptoms.

Prelemniscal Lesion for Selective Improvement of Parkinson Disease Tremor.

BACKGROUND: Selective improvement of symptoms may be required when treating Parkinson disease (PD) patients with a predominantly monosymptomatic clinical picture. OBJECTIVE: To define a target in prelemniscal radiation fibers (Raprl) related to the physiopathology of tremor evidenced by tractography. CASE REPORT: We report a patient with predominant unilateral rest and postural tremor, diagnosed as PD based on 80% improvement induced by the administration of L-DOPA/carbidopa, subsequently complicated by motor fluctuations, L-DOPA dyskinesia, and a reduced ON period. A stereotactic radiofrequency lesion was made for tremor control, and postoperative diffusion-weighted imaging (DWI) demonstrated the precise location and extension of the lesioned tract. RESULTS: Perfect control of the tremor was achieved with the patient OFF medication; this has lasted for 5 years, without hypotonia in the treated extremities. DWI revealed a 3.0-mm lesion at the base of the nucleus ventralis intermedius (Vim) interrupting cerebellar-Vim fibers sparing the cerebellar ventralis oralis posterior nucleus component. CONCLUSION: Selective improvement of symptoms is feasible in patients with a predominantly monosymptomatic PD clinical presentation.

Anatomic characterization of prelemniscal radiations by probabilistic tractography: implications in Parkinson's disease.

To characterize the anatomical connectivity of the prelemniscal radiations (Raprl), a white matter region within the posterior subthalamic area (PSA) that is an effective neurosurgical target for treating motor symptoms of Parkinson's disease (PD). Diffusion-weighted images were acquired from twelve healthy subjects using a 3T scanner. Constrained spherical deconvolution, a method that allows the distinction of crossing fibers within a voxel, was used to compute track-density images with sufficient resolution to accurately delineate distinct PSA regions and probabilistic tractography of Raprl in both hemispheres. Raprl connectivity was reproducible across all subjects and showed fibers traversing through this region towards primary and supplementary motor cortices, the orbitofrontal cortex, ventrolateral thalamus, and the globus pallidus, cerebellum and dorsal brainstem. All brain regions reached by Raprl fibers are part of motor circuits involved in the pathophysiology of PD; while these fiber systems converge at the level of the PSA, they can be spatially segregated. Fibers of distinct and specific motor control networks are identified within Raprl. The description of this anatomical crossroad suggests that, in the future, tractography could allow deep brain stimulation or lesional therapies in white matter targets according to individual patient's symptoms.

Metabolic Changes Induced by Electrical Stimulation of Prelemniscal Radiations for the Treatment of Parkinson Disease.

OBJECTIVE: The aim of this work was to study mechanisms of action of electrical stimulation of prelemniscal radiations (Raprl) in the treatment of Parkinson disease, using 2-deoxy-2-fluoro-D-glucose (18F-FDG) Positron Emission Tomography (PET/CT). Materialand Methods: Five patients with PD and predominant unilateral tremor, rigidity and bradykinesia underwent deep brain stimulation (DBS) in contralateral Raprl that improved symptoms from 82.4 to 94.5%. 18F-FDG PET studies were performed before electrode implantation and after DBS therapy. Changes in metabolic activity in PET were evaluated by the maximal standardized uptake value (MSUV) and statistical parametric mapping (SPM) for regions of interest (ROIs) ipsilateral and contralateral to the stimulation site. ROIs were derived from a preoperative probabilistic tractography and included primary motor, supplementary motor and orbitofrontal cortices: Raprl, ventrolateral thalamus, putamen and cerebellum. RESULTS: No significant MSUV changes occurred in ROIs contralateral to Raprl-DBS. In contrast, MSUV decreased ipsilateral to DBS in Raprl, the thalamus, and the primary and supplementary motor cortices. SPM analysis showed metabolic changes which were significantly different after DBS therapy in all ROIs ipsilateral to DBS compared to those in the contralateral side. CONCLUSION: Raprl-DBS decreases the metabolic activity of areas anatomically related to its fiber composition. Improvement of symptoms may result from a decrease in pathological overactivity of circuits related to the ROIs.