Caffeine, an adenosine receptor antagonist, is known to affect sleep–awake cycles, the stress response, and learning and memory. It has been suggested that caffeine influences synaptic plasticity, ...but the effects of caffeine on synaptic plasticity in the human brain remain unexplored. The present study aimed to investigate the effects of caffeine on long-term potentiation (LTP)-like effects in the primary motor cortex of healthy humans. Twelve healthy participants (six women and six men; mean age: 44.8 ± 1.5 years) underwent quadripulse magnetic stimulation with an inter-stimulus interval of 5 ms (QPS5) to induce LTP-like effects, 2 h after administration of either a caffeine (200 mg) or placebo tablet in a double-blind crossover design. We recorded motor-evoked potentials (MEPs) before and after QPS5. The degree of MEP enhancement was compared between the placebo and caffeine conditions. Neither active nor resting motor thresholds were influenced by caffeine administration. Following caffeine administration, the degree of potentiation significantly decreased in “significant responders”, whose average MEP ratios were greater than 1.24 in the placebo condition. The observed reduction in potentiation following caffeine administration is consistent with the A
2A
receptor antagonistic effect of caffeine. This is the first report of an effect of caffeine on neural synaptic plasticity in the human brain, which is consistent with the caffeine-induced plasticity reduction observed in primate studies. Because we studied only a small number of subjects, we cannot firmly conclude that caffeine reduces LTP in humans. The present results will, however, be helpful when considering further or new clinical uses of caffeine.
Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto ...basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre-SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans.
Appropriate motor performance, which must be precisely processed and timed to temporal and spatial requirements, can be studied using a synchronized tapping task. For gait rehabilitation, estimation ...of bilateral foot-tapping accuracy is important, as walking involves bilateral movements, usually antiphase, of the lower extremities. Rhythmic control of lower limb movements, such as gait, involves voluntary control and may also be automatically regulated by the central pattern generator. This study investigated the temporal synchronization of in-phase and antiphase movements using synchronized bilateral finger and foot-tapping tasks. Thirty healthy young adult volunteers were enrolled and instructed to tap the finger or foot button synchronously with the tones presented at fixed inter-stimulus intervals (ISIs). One of 10 different ISIs (250–4800 ms) was selected for each block, in which 110 tones were presented. Taps were performed by either unilateral or bilateral fingers or feet, either in-phase (to move bilateral fingers or ankles simultaneously) or antiphase (to move bilateral fingers or ankles alternately). The synchronization error (SE) and coefficient of variation (CV) of the inter-tap interval (ITI) were evaluated. In all trials with short ISIs, SEs were narrowly distributed, either clustered around 0 ms or with a slightly negative value. Although SE variability gradually increased with increasing ISI, the CV of ITI was significantly lower for antiphase movement than for unilateral or in-phase movement in the foot-tapping task, but not in the finger-tapping task. The preserved temporal synchronization for antiphase movement of the foot, but not finger tapping, may be due to the neural mechanisms underlying locomotion.
•We studied temporal synchronization of the upper and lower extremities.•We used the synchronized tapping task for both.•Stability of temporal motor control in finger-tapping task was at ISI 500–1200 ms.•Antiphase tapping was more stable than in-phase tapping for the foot but not finger.•The neural mechanism that produces rhythmic movement may differ for finger and foot.
Paired-pulse transcranial magnetic stimulation (TMS) is useful to estimate the balance between inhibitory and facilitatory circuits of the primary motor cortex (M1) in Parkinson's disease (PD). ...Results of earlier studies are, however, incongruent: some reports describe normal short-interval intracortical inhibition (SICI), but others describe reduced SICI. We hypothesize that exaggerated intracortical facilitation masks normal inhibition, and that a triple-pulse method can reveal masked inhibition in PD.
Ten PD patients who had not been exposed to dopaminergic medications were enrolled. Results were compared with those obtained from 10 age-matched healthy volunteers. We measured TMS-elicited motor evoked potential (MEP) as an index of M1 excitability. We tested SICI, intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF), which has three distinct facilitatory peaks, using the paired-pulse TMS paradigm. A triple-pulse protocol, SICI + SICF, was investigated as described in our earlier study. This protocol examined SICF in the presence of SICI, thereby allowing our test of true inhibitory influence on a specific component of MEP-generating mechanism known as I3 wave.
In PD patients, SICI estimated using the conventional method was decreased, whereas SICF was enhanced around its second peak out of the three. Results for SICI + SICF were comparable between PD patients and healthy controls, suggesting normal inhibition of I3 waves in PD patients.
We confirmed the SICF enhancement in drug naïve PD patients. We propose that I3 wave inhibition by a subthreshold pulse shown by SICI paradigm is unaffected in PD. The triple-pulse method can reveal masked inhibition.
•Short-interval intracortical inhibition (SICI) was reduced in de novo PD patients.•Short-interval intracortical facilitation (SICF) was enhanced in the PD population.•A new transcranial magnetic stimulation method, SICI + SICF, showed normal inhibition.
Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial ...magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.
Ultrasound is highly biopermeable and can non-invasively penetrate deep into the brain. Stimulation with patterned low-intensity ultrasound can induce sustained inhibition of neural activity in ...humans and animals, with potential implications for research and therapeutics. Although mechanosensitive channels are involved, the cellular and molecular mechanisms underlying neuromodulation by ultrasound remain unknown. To investigate the mechanism of action of ultrasound stimulation, we studied the effects of two types of patterned ultrasound on synaptic transmission and neural network activity using whole-cell recordings in primary cultured hippocampal cells. Single-shot pulsed-wave (PW) or continuous-wave (CW) ultrasound had no effect on neural activity. By contrast, although repetitive CW stimulation also had no effect, repetitive PW stimulation persistently reduced spontaneous recurrent burst firing. This inhibitory effect was dependent on extrasynaptic-but not synaptic-GABA
receptors, and the effect was abolished under astrocyte-free conditions. Pharmacological activation of astrocytic TRPA1 channels mimicked the effects of ultrasound by increasing the tonic GABA
current induced by ambient GABA. Pharmacological blockade of TRPA1 channels abolished the inhibitory effect of ultrasound. These findings suggest that the repetitive PW low-intensity ultrasound used in our study does not have a direct effect on neural function but instead exerts its sustained neuromodulatory effect through modulation of ambient GABA levels via channels with characteristics of TRPA1, which is expressed in astrocytes.
Syntaxin-1A (stx1a) repression causes a neurodevelopmental disorder phenotype, low latent inhibition (LI) behavior, by disrupting 5-hydroxytryptaminergic (5-HTergic) systems. Herein, we discovered ...that lysine acetyltransferase (KAT) 3B increases stx1a neuronal transcription and TTK21, a KAT3 activator, induces stx1a transcription and 5-HT release in vitro. Furthermore, glucose-derived CSP-TTK21 could restore decreased stx1a expression, 5-HTergic systems in the brain, and low LI in stx1a (+/−) mice by crossing the blood-brain barrier, whereas the KAT3 inhibitor suppresses stx1a expression, 5-HTergic systems, and LI behaviors in wild-type mice. Finally, in wild-type and stx1a (−/−) mice treated with IKK inhibitors and CSP-TTK21, respectively, we show that KAT3 activator-induced LI improvement is a direct consequence of KAT3B-stx1a pathway, not a side effect. In conclusion, KAT3B can positively regulate stx1a transcription in neurons, and increasing neuronal stx1a expression and 5-HTergic systems by a KAT3 activator consequently improves the low LI behavior in the stx1a ablation mouse model.
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•KAT3B increases the stx1a transcription and 5-HT release in neurons•KAT3 activator restores decreased stx1a expression and 5-HTergic systems in stx1a (+/−) mice•KAT3 activation rescues the low LI in a mouse model of neurodevelopmental disorders•KAT3 is a therapeutic target for autistic disorders caused by epigenetic stx1a repression
The stx1a repression causes the autistic behavior, low LI, by disrupting 5-HTergic systems. Nakayama et al. reveal that KAT3B upregulates stx1a neuronal transcription and that BBB-permeable KAT3B activator, CSP-TTK21, restores decreased stx1a expression, 5-HTergic systems in the brain, and LI in stx1a abraded mouse model, providing a strategy for autism treatment.
Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought
in some cases to reflect N -methyl- d -aspartate-sensitive changes in ...synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced
plasticity depends on the prior history of cortical activity, conforming to the BienenstockâCooperâMunro (BCM) theory. However,
experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols,
often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this
study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and
then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability,
as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated
by interstimulus intervals of 1.5â1250 ms produced a range of after-effects that were compatible with changes in synaptic
plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs
for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed
effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on
QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity
reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new
possibilities for detailed examination of theories of metaplasticity in humans.
Background
The coordination between gaze and voice is closely linked when reading text aloud, with the gaze leading the reading position by a certain eye–voice lead (EVL). How this coordination is ...affected is unknown in patients with cerebellar ataxia and parkinsonism, who show oculomotor deficits possibly impacting coordination between different effectors.
Objective
To elucidate the role of the cerebellum and basal ganglia in eye–voice coordination during reading aloud, by studying patients with Parkinson’s disease (PD) and spinocerebellar degeneration (SCD).
Methods
Participants were sixteen SCD patients, 18 PD patients, and 30 age-matched normal subjects, all native Japanese speakers without cognitive impairment. Subjects read aloud Japanese texts of varying readability displayed on a monitor in front of their eyes, consisting of Chinese characters and hiragana (Japanese phonograms). The gaze and voice reading the text was simultaneously recorded by video-oculography and a microphone. A custom program synchronized and aligned the gaze and audio data in time.
Results
Reading speed was significantly reduced in SCD patients (3.53 ± 1.81 letters/s), requiring frequent regressions to compensate for the slow reading speed. In contrast, PD patients read at a comparable speed to normal subjects (4.79 ± 3.13 letters/s vs. 4.71 ± 2.38 letters/s). The gaze scanning speed, excluding regressive saccades, was slower in PD patients (9.64 ± 4.26 letters/s) compared to both normal subjects (12.55 ± 5.42 letters/s) and SCD patients (10.81 ± 4.52 letters/s). PD patients’ gaze could not far exceed that of the reading speed, with smaller allowance for the gaze to proceed ahead of the reading position. Spatial EVL was similar across the three groups for all texts (normal: 2.95 ± 1.17 letters/s, PD: 2.95 ± 1.51 letters/s, SCD: 3.21 ± 1.35 letters/s). The ratio of gaze duration to temporal EVL was lowest for SCD patients (normal: 0.73 ± 0.50, PD: 0.70 ± 0.37, SCD: 0.40 ± 0.15).
Conclusion
Although coordination between voice and eye movements and normal eye-voice span was observed in both PD and SCD, SCD patients made frequent regressions to manage the slowed vocal output, restricting the ability for advance processing of text ahead of the gaze. In contrast, PD patients experience restricted reading speed primarily due to slowed scanning, limiting their maximum reading speed but effectively utilizing advance processing of upcoming text.
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