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Clinical Neurophysiology : Official... Sep 2023Clinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed...
OBJECTIVE
Clinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed to examine associations between cerebellar tDCS-induced electric field strength, morphometric posterior fossa parameters, and skin-cerebellum distance. As a secondary objective, field characteristics were compared between cephalic and extracephalic electrode configurations.
METHODS
Electric field simulations of midline cerebellar tDCS (7 × 5 cm electrodes, current intensities of 2 mA) were performed on MRI-based head models from 37 healthy adults using buccinator, frontopolar, and lower neck reference electrodes. Average field strengths were determined in eight regions of interest (ROIs) covering the anterior and posterior vermis and cerebellar hemispheres. Besides skin-cerebellum distance, various angles were measured between posterior fossa structures. Multivariable linear regression models were used to identify predictors of field strength in different ROIs.
RESULTS
Skin-cerebellum distance and "pons angle" were independently associated with field strength in the anterior and posterior vermis. "Cerebellar angle" and skin-cerebellum distance affected field strength in anterior and posterior regions of the right cerebellar hemisphere. Field strengths in all examined cerebellar areas were highest in the frontopolar and lowest in the lower neck montage, while the opposite was found for field focality. The lower neck montage induced considerably less spreading toward anterior cerebellar regions compared with the buccinator and frontopolar montages, which resulted in a more evenly distributed field within the cerebellum.
CONCLUSION
In addition to skin-cerebellum distance, interindividual differences in posterior fossa morphometry, specifically pons and cerebellar angle, explain part of the variability in cerebellar tDCS-induced electric field strength. Furthermore, when targeting the midline cerebellum with tDCS, an extracephalic reference electrode is associated with lower field strengths and higher field focality than cephalic montages.
SIGNIFICANCE
This study identifies two novel subject-specific anatomical factors that partly determine cerebellar tDCS-induced electric field strength and reveals differences in field characteristics between electrode montages.
Topics: Adult; Humans; Transcranial Direct Current Stimulation; Cerebellum; Head; Electrodes
PubMed: 37499446
DOI: 10.1016/j.clinph.2023.06.019 -
BMC Medicine Aug 2023Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural...
Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study.
BACKGROUND
Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning.
METHODS
We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort.
RESULTS
Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons.
CONCLUSION
The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.
Topics: Humans; Depressive Disorder, Major; Genome-Wide Association Study; Anxiety Disorders; Attention Deficit Disorder with Hyperactivity; Comorbidity; Genomics
PubMed: 37542243
DOI: 10.1186/s12916-023-02920-9 -
Proceedings of the National Academy of... Dec 2023The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord...
The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord (caudal sector), and it has three main divisions: pons, cerebellum, and medulla. Using a data-driven approach, here we examine intrinsic rhombicbrain (intrarhombicbrain) network architecture that in rat consists of 52,670 possible axonal connections between 230 gray matter regions (115 bilaterally symmetrical pairs). Our analysis indicates that only 8,089 (15.4%) of these connections exist. Multiresolution consensus cluster analysis yields a nested hierarchy model of rhombicbrain subsystems that at the top level are associated with 1) the cerebellum and vestibular nuclei, 2) orofacial-pharyngeal-visceral integration, and 3) auditory connections; the bottom level has 68 clusters, ranging in size from 2 to 11 regions. The model provides a basis for functional hypothesis development and interrogation. More granular network analyses performed on the intrinsic connectivity of individual and combined main rhombicbrain divisions (pons, cerebellum, medulla, pons + cerebellum, and pons + medulla) demonstrate the mutability of network architecture in response to the addition or subtraction of connections. Clear differences between the structure-function network architecture of the rhombicbrain and forebrain-midbrain are discussed, with a stark comparison provided by the subsystem and small-world organization of the cerebellar cortex and cerebral cortex. Future analysis of the connections within and between the forebrain-midbrain and rhombicbrain will provide a model of brain neural network architecture in a mammal.
Topics: Rats; Animals; Cerebellum; Pons; Prosencephalon; Central Nervous System; Mammals
PubMed: 38109532
DOI: 10.1073/pnas.2313997120 -
Nature Human Behaviour Jan 2024The brain's arousal state is controlled by several neuromodulatory nuclei known to substantially influence cognition and mental well-being. Here we investigate whether...
The brain's arousal state is controlled by several neuromodulatory nuclei known to substantially influence cognition and mental well-being. Here we investigate whether human participants can gain volitional control of their arousal state using a pupil-based biofeedback approach. Our approach inverts a mechanism suggested by previous literature that links activity of the locus coeruleus, one of the key regulators of central arousal and pupil dynamics. We show that pupil-based biofeedback enables participants to acquire volitional control of pupil size. Applying pupil self-regulation systematically modulates activity of the locus coeruleus and other brainstem structures involved in arousal control. Furthermore, it modulates cardiovascular measures such as heart rate, and behavioural and psychophysiological responses during an oddball task. We provide evidence that pupil-based biofeedback makes the brain's arousal system accessible to volitional control, a finding that has tremendous potential for translation to behavioural and clinical applications across various domains, including stress-related and anxiety disorders.
Topics: Humans; Pupil; Arousal; Locus Coeruleus; Cognition; Biofeedback, Psychology
PubMed: 37904022
DOI: 10.1038/s41562-023-01729-z -
BioRxiv : the Preprint Server For... Nov 2023The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many...
The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed many neuronal subtypes' unique marker genes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study's translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard (http://harvard.heavy.ai:6273/) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.
PubMed: 38014113
DOI: 10.1101/2023.09.18.558047 -
Brain Sciences Sep 2023Rapid eye movement (REM) sleep is the main sleep correlate of dreaming. Ponto-geniculo-occipital (PGO) waves are a signature of REM sleep. They represent the... (Review)
Review
Rapid eye movement (REM) sleep is the main sleep correlate of dreaming. Ponto-geniculo-occipital (PGO) waves are a signature of REM sleep. They represent the physiological mechanism of REM sleep that specifically limits the processing of external information. PGO waves look just like a message sent from the pons to the lateral geniculate nucleus of the visual thalamus, the occipital cortex, and other areas of the brain. The dedicated visual pathway of PGO waves can be interpreted by the brain as visual information, leading to the visual hallucinosis of dreams. PGO waves are considered to be both a reflection of REM sleep brain activity and causal to dreams due to their stimulation of the cortex. In this review, we summarize the role of PGO waves in potential neural circuits of two major theories, i.e., (1) dreams are generated by the activation of neural activity in the brainstem; (2) PGO waves signaling to the cortex. In addition, the potential physiological functions during REM sleep dreams, such as memory consolidation, unlearning, and brain development and plasticity and mood regulation, are discussed. It is hoped that our review will support and encourage research into the phenomenon of human PGO waves and their possible functions in dreaming.
PubMed: 37759951
DOI: 10.3390/brainsci13091350 -
Neurology Nov 2023Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar...
OBJECTIVES
Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer.
METHODS
A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials.
RESULTS
Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention.
DISCUSSION
The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary.
Topics: Humans; tau Proteins; Cohort Studies; Longitudinal Studies; Pyridines; Parasomnias; Sleep Apnea, Obstructive; Positron-Emission Tomography; Alzheimer Disease; Cell Adhesion Molecules, Neuronal
PubMed: 37879939
DOI: 10.1212/WNL.0000000000207870 -
The Journal of Neuroscience : the... Aug 2023The parabrachial nuclear complex (PBN) is a nexus for aversion and for the sensory and affective components of pain perception. We have previously shown that during...
The parabrachial nuclear complex (PBN) is a nexus for aversion and for the sensory and affective components of pain perception. We have previously shown that during chronic pain PBN neurons in anesthetized rodents have amplified activity. We report a method to record from PBN neurons of behaving, head-restrained mice while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are higher in awake animals compared with urethane anesthetized mice. Fiber photometry of calcium responses from calcitonin-gene-related peptide-expressing PBN neurons demonstrates that these neurons respond to noxious stimuli. In both males and females with neuropathic or inflammatory pain, responses of PBN neurons remain amplified for at least 5 weeks, in parallel with increased pain metrics. We also show that PBN neurons can be rapidly conditioned to respond to innocuous stimuli after pairing with noxious stimuli. Finally, we demonstrate that changes in PBN neuronal activity are correlated with changes in arousal, measured as changes in pupil area. The parabrachial complex is a nexus of aversion, including pain. We report a method to record from parabrachial nucleus neurons of behaving mice while applying reproducible noxious stimuli. This allowed us to track parabrachial activity over time in animals with neuropathic or inflammatory pain. It also allowed us to show that the activity of these neurons correlates with arousal states and that these neurons can be conditioned to respond to innocuous stimuli.
Topics: Male; Female; Mice; Animals; Parabrachial Nucleus; Nociception; Wakefulness; Calcitonin Gene-Related Peptide; Chronic Pain
PubMed: 37451980
DOI: 10.1523/JNEUROSCI.0587-23.2023 -
Journal of Cerebral Blood Flow and... Jul 2023Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone...
Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca concentration, while the α agonist phenylephrine did not evoke contraction. Blocking α adrenergic receptors (αRs, which induce contraction by inhibiting cAMP production), greatly reduced the NA-evoked pericyte contraction, whereas stimulating αRs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked pericyte contraction. Noradrenaline-evoked pericyte contraction and capillary constriction are thus mediated via αRs. Consequently, αRs may not only modulate CBF in health and pathological conditions, but also contribute to CBF changes evoked by αR ligands administered in research, veterinary and clinical settings.
Topics: Pericytes; Locus Coeruleus; Capillaries; Norepinephrine; Receptors, Adrenergic, alpha-2; Axons
PubMed: 36688515
DOI: 10.1177/0271678X231152549