Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action.

The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ~ 45,000), to precisely examine red nucleus functional connectivity. Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a 'motor' structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.

Disuse-driven plasticity in the human thalamus and putamen.

Motor adaptation in cortico-striato-thalamo-cortical loops has been studied mainly in animals using invasive electrophysiology. Here, we leverage functional neuroimaging in humans to study motor circuit plasticity in the human subcortex. We employed an experimental paradigm that combined two weeks of upper-extremity immobilization with daily resting-state and motor task fMRI before, during, and after the casting period. We previously showed that limb disuse leads to decreased functional connectivity (FC) of the contralateral somatomotor cortex (SM1) with the ipsilateral somatomotor cortex, increased FC with the cingulo-opercular network (CON) as well as the emergence of high amplitude, fMRI signal pulses localized in the contralateral SM1, supplementary motor area and the cerebellum. From our prior observations, it remains unclear whether the disuse plasticity affects the thalamus and striatum. We extended our analysis to include these subcortical regions and found that both exhibit strengthened cortical FC and spontaneous fMRI signal pulses induced by limb disuse. The dorsal posterior putamen and the central thalamus, mainly CM, VLP and VIM nuclei, showed disuse pulses and FC changes that lined up with fmri task activations from the Human connectome project motor system localizer, acquired before casting for each participant. Our findings provide a novel understanding of the role of the cortico-striato-thalamo-cortical loops in human motor plasticity and a potential link with the physiology of sleep regulation. Additionally, similarities with FC observation from Parkinson Disease (PD) questions a pathophysiological link with limb disuse.

Framewise multi-echo distortion correction for superior functional MRI.

Functional MRI (fMRI) data are severely distorted by magnetic field (B0) inhomogeneities which currently must be corrected using separately acquired field map data. However, changes in the head position of a scanning participant across fMRI frames can cause changes in the B0 field, preventing accurate correction of geometric distortions. Additionally, field maps can be corrupted by movement during their acquisition, preventing distortion correction altogether. In this study, we use phase information from multi-echo (ME) fMRI data to dynamically sample distortion due to fluctuating B0 field inhomogeneity across frames by acquiring multiple echoes during a single EPI readout. Our distortion correction approach, MEDIC (Multi-Echo DIstortion Correction), accurately estimates B0 related distortions for each frame of multi-echo fMRI data. Here, we demonstrate that MEDIC's framewise distortion correction produces improved alignment to anatomy and decreases the impact of head motion on resting-state functional connectivity (RSFC) maps, in higher motion data, when compared to the prior gold standard approach (i.e., TOPUP). Enhanced framewise distortion correction with MEDIC, without the requirement for field map collection, furthers the advantage of multi-echo over single-echo fMRI.

A somato-cognitive action network alternates with effector regions in motor cortex.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Using synthetic MR images for distortion correction.

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.

Accuracy and reliability of diffusion imaging models.

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain's white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL's BedpostX [BPX], DSI Studio's Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3's Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI.

Reproducible brain-wide association studies require thousands of individuals.

Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1-3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain-behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available-with a total sample size of around 50,000 individuals-to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain-phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.

Individualized Functional Subnetworks Connect Human Striatum and Frontal Cortex.

The striatum and cerebral cortex are interconnected via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate corticostriatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited in part by the practice of averaging neuroimaging data across individuals. Here we utilized highly sampled resting-state functional connectivity MRI for individual-specific precision functional mapping (PFM) of corticostriatal connections. We identified ten individual-specific subnetworks linking cortex-predominately frontal cortex-to striatum, most of which converged with nonhuman primate tract-tracing work. These included separable connections between nucleus accumbens core/shell and orbitofrontal/medial frontal gyrus; between anterior striatum and dorsomedial prefrontal cortex; between dorsal caudate and lateral prefrontal cortex; and between middle/posterior putamen and supplementary motor/primary motor cortex. Two subnetworks that did not converge with nonhuman primates were connected to cortical regions associated with human language function. Thus, precision subnetworks identify detailed, individual-specific, neurobiologically plausible corticostriatal connectivity that includes human-specific language networks.

Parallel hippocampal-parietal circuits for self- and goal-oriented processing.

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.

Cingulo-opercular control network and disused motor circuits joined in standby mode.

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.

Differences in paracingulate connectivity associated with epileptiform discharges and uncontrolled seizures in genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) frequently continue to have seizures despite appropriate clinical management. GGE is associated with changes in the resting-state networks modulated by clinical factors such as duration of disease and response to treatment. However, the effect of generalized spike and wave discharges (GSWDs) and/or seizures on resting-state functional connectivity (RSFC) is not well understood. METHODS: We investigated the effects of GSWD frequency (in GGE patients), GGE (patients vs. healthy controls), and seizures (uncontrolled vs. controlled) on RSFC using seed-based voxel correlation in simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) (EEG/fMRI) data from 72 GGE patients (23 with uncontrolled seizures) and 38 healthy controls. We used seeds in paracingulate cortex, thalamus, cerebellum, and posterior cingulate cortex to examine changes in cortical-subcortical resting-state networks and the default mode network (DMN). We excluded from analyses time points surrounding GSWDs to avoid possible contamination of the resting state. RESULTS: (1) Higher frequency of GSWDs was associated with an increase in seed-based voxel correlation with cortical and subcortical brain regions associated with executive function, attention, and the DMN; (2) RSFC in patients with GGE, when compared to healthy controls, was increased between paracingulate cortex and anterior, but not posterior, thalamus; and (3) GGE patients with uncontrolled seizures exhibited decreased cerebellar RSFC. SIGNIFICANCE: Our findings in this large sample of patients with GGE (1) demonstrate an effect of interictal GSWDs on resting-state networks, (2) provide evidence that different thalamic nuclei may be affected differently by GGE, and (3) suggest that cerebellum is a modulator of ictogenic circuits.

Reduced default mode network connectivity in treatment-resistant idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsy (IGE) resistant to treatment is common, but its neuronal correlates are not entirely understood. Therefore, the aim of this study was to examine resting-state default mode network (DMN) functional connectivity in patients with treatment-resistant IGE. METHODS: Treatment resistance was defined as continuing seizures despite an adequate dose of valproic acid (valproate, VPA). Data from 60 epilepsy patients and 38 healthy controls who underwent simultaneous electroencephalography (EEG) and resting-state functional magnetic resonance imaging (fMRI) were included (EEG/fMRI). Independent component analysis (ICA) and dual regression were used to quantify DMN connectivity. Confirmatory analysis using seed-based voxel correlation was performed. KEY FINDINGS: There was a significant reduction of DMN connectivity in patients with treatment-resistant epilepsy when compared to patients who were treatment responsive and healthy controls. Connectivity was negatively correlated with duration of epilepsy. SIGNIFICANCE: Our findings in this large sample of patients with IGE indicate the presence of reduced DMN connectivity in IGE and show that connectivity is further reduced in treatment-resistant epilepsy. DMN connectivity may be useful as a biomarker for treatment resistance.

Moderating effects of music on resting state networks.

Resting state networks (RSNs) are spontaneous, synchronous, low-frequency oscillations observed in the brains of subjects who are awake but at rest. A particular RSN called the default mode network (DMN) has been shown to exhibit changes associated with neurological disorders such as temporal lobe epilepsy or Alzheimer's disease. Previous studies have also found that differing experimental conditions such as eyes-open versus eyes-closed can produce measurable changes in the DMN. These condition-associated changes have the potential of confounding the measurements of changes in RSNs related to or caused by disease state(s). In this study, we use fMRI measurements of resting-state connectivity paired with EEG measurements of alpha rhythm and employ independent component analysis, undirected graphs of partial spectral coherence, and spatiotemporal regression to investigate the effect of music-listening on RSNs and the DMN in particular. We observed similar patterns of DMN connectivity in subjects who were listening to music compared with those who were not, with a trend toward a more introspective pattern of resting-state connectivity during music-listening. We conclude that music-listening is a valid condition under which the DMN can be studied.