Parkinson's disease (PD) is a neurodegenerative disease that includes motor impairments, such as tremor, bradykinesia, and postural instability. Although eye movement deficits are commonly found in saccade and pursuit tasks, preservation of oculomotor function has also been reported. Here we investigate specific task and stimulus conditions under which oculomotor function in PD is preserved. Sixteen PD patients and 18 healthy, age-matched controls completed a battery of movement tasks that included stationary or moving targets eliciting reactive or deliberate eye movements: pro-saccades, anti-saccades, visually guided pursuit, and rapid go/no-go manual interception. Compared with controls, patients demonstrated systematic impairments in tasks with stationary targets: pro-saccades were hypometric and anti-saccades were incorrectly initiated toward the cued target in ∼35% of trials compared with 14% errors in controls. In patients, task errors were linked to short latency saccades, indicating abnormalities i...

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception in male and female mice. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS triggered LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12–16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Bloc...

The ability to make decisions based on external information, prior knowledge, and evidence is a crucial aspect of cognition and may determine the success and survival of an organism. Despite extensive work on decision-making mechanisms/models, understanding the effects of alertness on neural and cognitive processes remain limited. Here we use EEG and behavioral modeling to characterize cognitive and neural dynamics of perceptual decision-making in awake/low alertness periods in humans (14 male, 18 female) and characterize the compensatory mechanisms as alertness decreases. Well-rested human participants, changing between full-wakefulness and low alertness, performed an auditory tone-localization task, and its behavioral dynamics were quantified with psychophysics, signal detection theory, and drift-diffusion modeling, revealing slower reaction times, inattention to the left side of space, and a lower rate of evidence accumulation in periods of low alertness. Unconstrained multivariate pattern analysis (dec...

The functional connectome fingerprint is a cluster of individualized brain functional connectivity patterns that are capable of distinguishing one individual from others. Although its existence has been demonstrated in adolescents and adults, whether such individualized patterns exist during infancy is barely investigated despite its importance in identifying the origin of the intrinsic connectome patterns that potentially mirror distinct behavioral phenotypes. To fill this knowledge gap, capitalizing on a longitudinal high-resolution structural and resting-state functional MRI dataset with 104 human infants (53 females) with 806 longitudinal scans (age, 16–876 d) and infant-specific functional parcellation maps, we observe that the brain functional connectome fingerprint may exist since infancy and keeps stable over months during early brain development. Specifically, we achieve an ∼78% individual identification rate by using ∼5% selected functional connections, compared with the best identification rate ...

The superficial dorsal horn (SDH) of the spinal cord represents the first site of integration between innocuous and noxious somatosensory stimuli. According to gate control theory, diverse populations of excitatory and inhibitory interneurons within the SDH are activated by distinct sensory afferents, and their interplay determines the net nociceptive output projecting to higher pain centers. Although specific SDH cell types are ill-defined, numerous classifications schemes find that excitatory and inhibitory neurons fundamentally differ in their morphology, electrophysiology, neuropeptides, and pain-associated plasticity; yet little is known about how these neurons respond over a range of "natural" innocuous and noxious stimuli. To address this question, we applied an in vivo imaging approach in male mice where the genetically encoded calcium indicator GCaMP6s was expressed either in vGluT2-positive excitatory or vIAAT-positive inhibitory neurons. We found that inhibitory neurons were markedly more sensit...

Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) by synaptic or pharmacological stimulation, induces LTD, but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro . Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses of male mice. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost, whereas spine...

Highly correlated firing of primary afferent inputs and lamina I projection neurons evokes synaptic long-term potentiation (LTP), a mechanism by which ascending nociceptive transmission can be amplified at the level of the spinal dorsal horn. However, the degree to which neuromodulatory signaling shapes the temporal window governing spike-timing-dependent plasticity (STDP) at sensory synapses onto projection neurons remains unclear. The present study demonstrates that activation of spinal D1/D5 dopamine receptors (D1/D5Rs) creates a highly permissive environment for the production of LTP in male and female adult mouse spinoparabrachial neurons by promoting non-Hebbian plasticity. Bath application of the mixed D1/D5R agonist SKF82958 unmasked LTP at STDP pairing intervals that normally fail to alter synaptic efficacy. Furthermore, during D1/D5R signaling, action potential discharge in projection neurons became dispensable for LTP generation, and primary afferent stimulation alone was sufficient to induce st...

Predictive coding accounts of brain functions profoundly influence current approaches to perceptual synthesis. However, a fundamental paradox has emerged, that may be very relevant for understanding hallucinations, psychosis, or cognitive inflexibility: in some situations, surprise or prediction error-related responses can decrease when predicted, and yet, they can increase when we know they are predictable. This paradox is resolved by recognizing that brain responses reflect precision-weighted prediction error. This presses us to disambiguate the contributions of precision and prediction error in electrophysiology. To meet this challenge for the first time, we appeal to a methodology that couples an original experimental paradigm with fine dynamic modeling. We examined brain responses in healthy human participants ( N = 20; 10 female) to unexpected and expected surprising sounds, assuming that the latter yield a smaller prediction error but much more amplified by a larger precision weight. Importantly, ad...

The hippocampus is a locus of working memory (WM) with anterior and posterior subregions that differ in their transcriptional and external connectivity patterns. However, the involvement and functional connections between these subregions in WM processing are poorly understood. To address these issues, we recorded intracranial EEG from the anterior and the posterior hippocampi in humans (seven females and seven males) who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated low-frequency activity in both the anterior and posterior hippocampus and by increased theta/alpha band (3–12 Hz) phase synchronization between anterior and posterior subregions. Cross-frequency and Granger prediction analyses consistently showed that the correct WM trials were associated with theta/alpha band-coordinated unidirectional influence from the posterior to the anterior hippocampus. In contrast, WM errors were associated with bidirectional interactions between the anterior and post...