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The brain's energy budget can be non-invasively assessed with different imaging modalities such as functional MRI (fMRI) and PET (fPET), which are sensitive to oxygen and glucose demands, respectively. The introduction of hybrid PET/MRI systems further enables the simultaneous acquisition of these parameters. Although a recently developed method offers the quantification of task-specific changes in glucose metabolism (CMRGlu) in a single measurement, direct comparison of the two imaging modalities is still difficult because of the different temporal resolutions. Thus, we optimized the protocol and systematically assessed shortened task durations of fPET to approach that of fMRI. Twenty healthy subjects (9 male) underwent one measurement on a hybrid PET/MRI scanner. During the scan, tasks were completed in four blocks for fMRI (4 × 30 s blocks) and fPET: participants tapped the fingers of their right hand repeatedly to the thumb while watching videos of landscapes. For fPET, subjects were randomly assigned to groups of n = 5 with varying task durations of 10, 5, 2 and 1 min, where task durations were kept constant within a measurement. The radiolabeled glucose analogue [18F]FDG was administered as 20% bolus plus constant infusion. The bolus increases the signal-to-noise ratio and leaves sufficient activity to detect task-related effects but poses additional challenges due to a discontinuity in the tracer uptake. First, three approaches to remove task effects from the baseline term were evaluated: (1) multimodal, based on the individual fMRI analysis, (2) atlas-based by removing presumably activated regions and (3) model-based by fitting the baseline with exponential functions. Second, we investigated the need to capture the arterial input function peak with automatic blood sampling for the quantification of CMRGlu. We finally compared the task-specific activation obtained from fPET and fMRI qualitatively and statistically. CMRGlu quantified only with manual arterial samples showed a strong correlation to that obtained with automatic sampling (r = 0.9996). The multimodal baseline definition was superior to the other tested approaches in terms of residuals (p < 0.001). Significant task-specific changes in CMRGlu were found in the primary visual and motor cortices (tM1 = 18.7 and tV1 = 18.3). Significant changes of fMRI activation were found in the same areas (tM1 = 16.0 and tV1 = 17.6) but additionally in the supplementary motor area, ipsilateral motor cortex and secondary visual cortex. Post-hoc t-tests showed strongest effects for task durations of 5 and 2 min (all p < 0.05 FWE corrected), whereas 1 min exhibited pronounced unspecific activation. Percent signal change (PSC) was higher for CMRGlu (∼18%–27%) compared to fMRI (∼2%). No significant association between PSC of task-specific CMRGlu and fMRI was found (r = 0.26). Using a bolus plus constant infusion protocol, the necessary task duration for reliable quantification of task-specific CMRGlu could be reduced to 5 and 2 min, therefore, approaching that of fMRI. Important for valid quantification is a correct baseline definition, which was ideal when task-relevant voxels were determined with fMRI. The absence of a correlation and the different activation pattern between fPET and fMRI suggest that glucose metabolism and oxygen demand capture complementary aspects of energy demands. •Quantification of task-specific CMRGlu with 20% bolus plus constant infusion.•Functional PET task durations down to 1 min were evaluated.•Active primary regions overlap between BOLD and CMRGlu.•No significant correlation between BOLD and CMRGlu.

Dopamine, a key neuromodulator in the central nervous system, regulates cortical excitability and plasticity by interacting with glutamate and GABA receptors, which are affected by dopamine receptor subtypes (D1‐ and D2‐like). Non‐invasive brain stimulation techniques can induce plasticity and monitor cortical facilitation and inhibition in humans. In a randomized, placebo‐controlled, double‐blinded study, we investigated how dopamine and D1‐ and D2‐like receptors impact transcranial direct current stimulation (tDCS)‐induced plasticity concerning glutamatergic and GABAergic mechanisms. Eighteen healthy volunteers received 1 mA anodal (13 min) and cathodal tDCS (9 min) over the left motor cortex combined with the dopaminergic agents l‐dopa (general dopamine activation), bromocriptine (D2‐like receptor agonist), combined D2 antagonism via sulpiride and general dopaminergic activation via l‐dopa to activate D1‐like receptors, and placebo medication. Glutamate‐related cortical facilitation and GABA‐related cortical inhibition were monitored using transcranial magnetic stimulation techniques, including I–O curve, intracortical facilitation (ICF), short‐interval intracortical inhibition (SICI), and I‐wave facilitation protocols. Our results indicate that anodal tDCS alone enhanced the I–O curve and ICF while decreasing SICI. Conversely, cathodal tDCS decreased the I‐O curve and ICF while increasing SICI. General dopamine and D2 receptor activation combined with anodal tDCS decreased the I‐O curve and ICF, but enhanced SICI compared to tDCS alone. When paired with cathodal tDCS, general dopamine and D2‐like receptor activity enhancement prolonged the cathodal tDCS effect on excitability. After anodal tDCS, D1‐like receptor activation increased the I‐O curve and ICF while reducing SICI. These effects were abolished with cathodal tDCS. Dopaminergic substances combined with anodal and cathodal tDCS did not have a significant effect on I‐wave facilitation. These results suggest that D1‐like receptor activation enhanced LTP‐like plasticity and abolished LTD‐like plasticity via glutamatergic NMDA receptor enhancement, while global dopaminergic and D2‐like receptor enhancement weakened LTP‐like but strengthened LTD‐like plasticity primarily via glutamatergic NMDA receptor activity diminution. Background: Dopamine modulates cortical excitability and plasticity by influencing glutamate and GABA receptor activity. This study investigates the impact of general dopaminergic activation and D1‐ and D2‐like receptor modulation on transcranial direct current stimulation (tDCS)‐induced plasticity in humans.Methods:• Pharmacological intervention: l‐dopa (general DA activation), Bromocriptine (D2 agonist), Sulpiride + l‐dopa (D1‐like activation), and placebo.• tDCS: Anodal (1 mA, 13 min) and Cathodal (1 mA, 9 min) over the left motor cortex.• Neurophysiological measures: Glutamatergic activity (I‐O curve, ICF) and GABAergic activity (SICI, I‐wave facilitation).Results:• D2‐like receptor and global dopamine activation + anodal tDCS: decreased the I‐O curve and ICF, but enhanced SICI• D2‐like receptor and global dopamine activation + cathodal tDCS: prolonged the cathodal tDCS effect on SICI‐ICF and IO‐curve• D1‐like receptor activation + anodal tDCS: increased the I‐O curve and ICF while reducing SICI• D1‐like receptor activation + cathodal tDCS: abolished cathodal tDCS effects• No significant effect of dopaminergic substances combined with anodal and on I‐wave facilitationConclusion:D1‐like receptor activation enhanced LTP‐like plasticity and abolished LTD‐like plasticity via glutamatergic NMDA receptor enhancement, while global dopaminergic and D2‐like receptor enhancement weakened LTP‐like but strengthened LTD‐like plasticity primarily via glutamatergic NMDA receptor activity diminution.

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex. Single-cell transcriptomics of more than 20,000 cells from two functionally distinct areas of the mouse neocortex identifies 133 transcriptomic types, and provides a foundation for understanding the diversity of cortical cell types.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults.

Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting phase-locked neuronal activity, or time-frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30–200 ms after TMS) synchronization in the α- and β-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200–400 ms) α- and β-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early α-synchronization. Alprazolam and baclofen enhanced the early β-synchronization. Baclofen enhanced the late α-desynchronization, and alprazolam, diazepam and baclofen enhanced the late β-desynchronization. The observed GABAergic drug effects on TMS-induced α- and β-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS-induced oscillatory responses of motor cortex. •The response to TMS of M1 is composed of evoked and induced oscillatory activity.•TMS induced early α-/β-synchronization and late α-/β-desynchronization in M1.•GABAAergic vs. GABABergic drugs had opposite effects on early α-synchronization.•GABAAergic and GABABergic drugs enhanced the late β-desynchronization.

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 ​mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits’ muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging. [Display omitted] •A sub-millimeter fMRI method is developed to image neural microcircuitry in humans.•The method can capture large FOVs with thin slices for ‛columnar’ and ‛laminar’ mapping.•An analysis pipeline is developed to investigate topographical representations that have only been visible in animals so far.•Novel findings include a mirrored finger representation in the human motor cortex.

Brain regions are often topographically connected: nearby locations within one brain area connect with nearby locations in another area. Mapping these connection topographies, or ‘connectopies’ in short, is crucial for understanding how information is processed in the brain. Here, we propose principled, fully data-driven methods for mapping connectopies using functional magnetic resonance imaging (fMRI) data acquired at rest by combining spectral embedding of voxel-wise connectivity ‘fingerprints’ with a novel approach to spatial statistical inference. We apply the approach in human primary motor and visual cortex, and show that it can trace biologically plausible, overlapping connectopies in individual subjects that follow these regions' somatotopic and retinotopic maps. As a generic mechanism to perform inference over connectopies, the new spatial statistics approach enables rigorous statistical testing of hypotheses regarding the fine-grained spatial profile of functional connectivity and whether that profile is different between subjects or between experimental conditions. The combined framework offers a fundamental alternative to existing approaches to investigating functional connectivity in the brain, from voxel- or seed-pair wise characterizations of functional association, towards a full, multivariate characterization of spatial topography. •We propose methods for mapping individualised connectopies using resting-state fMRI.•These methods include a spatial statistics approach for inference over connectopies.•The approach can tease apart overlapping connectopies that coexist within an area.•We demonstrate the methods in somatotopic and retinotopic cortex.

Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble. A new light-activated probe that targets recently active neuronal spines for manipulation induces shrinkage of recently potentiated spines following a motor learning task; spine shrinkage disrupted learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour. Memory tracked using synaptic optogenetics It has long been speculated that changes in spine stability and potentiation are the structural correlates of memory, but tools to help link these structural changes to specific memories have not been available. Akiko Hayashi-Takagi et al . have developed a new light-activated probe that targets recently active spines for manipulation. Optically induced shrinkage of recently potentiated spines following a motor learning task is seen to disrupt learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour.

Cognitive control, which is critical for goal‐directed behavior, involves resolving conflicts between competing stimuli and is influenced by neurotransmitter interactions within cortico‐subcortical areas. This study investigated the relationship between baseline amino acid transmitter levels and interference control, focusing on the effects of experimentally enhancing catecholaminergic signaling. Using a double‐blind, placebo‐controlled crossover design with two dosage groups, n = 71 healthy human adults underwent proton magnetic resonance spectroscopy once to assess baseline GABA+ and Glx levels in the anterior cingulate cortex (ACC), striatum, and supplementary motor area (SMA). Participants then performed a subliminally primed flanker task inducing different scales of conflict twice while EEG was recorded: once after receiving a placebo (lactase) and once more under either low (0.25 mg/kg) or medium (0.50 mg/kg) doses of methylphenidate (MPH), which modulates the catecholaminergic and amino acid transmitter systems driving cognitive and interference control. Medium MPH doses were more effective than low doses at reducing subliminal interference effects, highlighting dose‐specific behavioral improvements. Higher striatal GABA+ levels led to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels were associated with better interference control at medium doses, suggesting a dose‐dependent shift from striatal to ACC dominance in conflict resolution. Neurophysiological (EEG data) analyses revealed increased theta‐band (TBA) and alpha‐band activity (ABA) overlapping in the mid‐superior‐frontal and inferior‐frontal clusters under conditions of heightened cognitive control demands. The findings highlight that whether and how amino acid transmitter levels in cognitive control‐relevant regions modulate interference conflicts depends on the degree of catecholaminergic signaling. We found medium methylphenidate doses (0.5 mg/kg) to be more effective than low doses (0.25 mg/kg) at reducing subliminal interference effects, with higher striatal GABA+ levels leading to better interference control at low doses, while lower ACC GABA+ and GABA+/Glx levels led to better interference control at medium doses.