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Objective: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human., Methods: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals., Results: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission., Conclusions: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation., Significance: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The rubber hand illusion (RHI) paradigm experimentally produces an illusion of rubber hand ownership and arm shift by simultaneously stroking a rubber hand in view and a participant's visually occluded hand. It involves visual, tactile, and proprioceptive multisensory integration and activates multisensory areas in the brain, including the posterior parietal cortex (PPC). Multisensory inputs are transformed into outputs for motor control in association areas such as PPC. A behavioral study reported decreased motor performance after RHI. However, it remains unclear whether RHI modifies the interactions between sensory and motor systems and between PPC and the primary motor cortex (M1). We used transcranial magnetic stimulation (TMS) and examined the functional connections from the primary somatosensory and association cortices to M1 and from PPC to M1 during RHI. In experiment 1, short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) were measured before and immediately after a synchronous (RHI) or an asynchronous (control) condition. In experiment 2, PPC-M1 interaction was measured using two coils. We found that SAI and LAI were reduced in the synchronous condition compared with baseline, suggesting that RHI decreased somatosensory processing in the primary sensory and the association cortices projecting to M1. We also found that greater inhibitory PPC-M1 interaction was associated with stronger RHI assessed by questionnaire. Our findings suggest that RHI modulates both the early and late stages of processing of tactile afferent, which leads to altered M1 excitability by reducing the gain of somatosensory afferents to resolve conflicts among multisensory inputs. NEW & NOTEWORTHY Perception of one's own body parts involves integrating different sensory information and is important for motor control. We found decreased effects of cutaneous stimulation on motor cortical excitability during rubber hand illusion (RHI), which may reflect decreased gain of tactile input to resolve multisensory conflicts. RHI strength correlated with the degree of inhibitory posterior parietal cortex-motor cortex interaction, indicating that parietal-motor connection is involved in resolving sensory conflicts and body ownership during RHI.

Objective: Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS., Methods: The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals., Results: GPi stimulation produced 2 peaks of cortical evoked potentials with latencies of ∼10 and ∼25 milliseconds in the motor cortical area. Cortical facilitation was observed at ∼10 milliseconds after single-pulse GPi DBS, and cortical inhibition was observed after a ∼25-millisecond interval. Repetitive pairs of GPi stimulation with cortical stimulation at these 2 time intervals produced long-term potentiation-like effects in the motor cortex., Interpretation: Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation with appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. Ann Neurol 2018;83:352-362., (© 2018 American Neurological Association.)

In human, sensorimotor integration can be investigated by combining sensory input and transcranial magnetic stimulation (TMS). Short latency afferent inhibition (SAI) refers to motor cortical inhibition 20-25 ms after median nerve stimulation. We investigated the interaction between SAI and short-interval intracortical facilitation (SICF), an excitatory motor cortical circuit. Seven experiments were performed. Contrary to expectations, SICF was facilitated in the presence of SAI (SICF(SAI)). This effect is specific to SICF since there was no effect at SICF trough 1 when SICF was absent. Furthermore, the facilitatory SICF(SAI) interaction increased with stronger SICF or SAI. SAI and SICF correlated between individuals, and this relationship was maintained when SICF was delivered in the presence of SAI, suggesting an intrinsic relationship between SAI and SICF in sensorimotor integration. The interaction was present at rest and during muscle contraction, had a broad degree of somatotopic influence and was present in different interneuronal SICF circuits induced by posterior-anterior and anterior-posterior current directions. Our results are compatible with the finding that projections from sensory to motor cortex terminate in both superficial layers where late indirect (I-) waves are thought to originate, as well as deeper layers with more direct effect on pyramidal output. This interaction is likely to be relevant to sensorimotor integration and motor control., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Objective: To identify the changes in motor cortical facilitatory and inhibitory circuits in Parkinson disease (PD) by detailed studies of their time courses and interactions., Methods: Short-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) were measured with a paired-pulse paradigm using transcranial magnetic stimulation. Twelve patients with PD in both ON and OFF medication states and 12 age-matched healthy controls were tested. The first experiment tested the time course of SICF in PD and controls. The second experiment tested SICI at different times corresponding to SICF peaks and troughs to investigate whether SICI was affected by SICF., Results: SICF was increased in PD OFF state and was reduced by dopaminergic medications. The reduction in SICF from the OFF to ON state correlated with the improvement in PD motor signs. SICI was reduced in PD OFF state and was only partially normalized by dopaminergic medications. At SICF peaks, improvement in SICI with medication correlated with improvement in PD motor sign. Principal component analysis showed that variations of SICF and SICI were explained by the same principal component only in the PD OFF group, suggesting that decreased SICI in the OFF state is related to increased SICF., Conclusions: Motor cortical facilitation is increased and inhibition is decreased in PD. Increased cortical facilitation partly accounts for the decreased inhibition, but there is also impairment in synaptic inhibition in PD. Increased cortical facilitation may be a compensatory mechanism in PD.

Short interval intracortical facilitation (SICF) can be elicited by transcranial magnetic stimulation (TMS) of the motor cortex (M1) with a suprathreshold first stimulus (S1) followed by a subthreshold second stimulus (S2). SICF occurs at three distinct phases and is likely to be related to the generation of indirect (I) waves. Short interval intracortical inhibition (SICI) is an inhibitory phenomenon and intracortical facilitation (ICF) is an excitatory phenomenon occurring in the M1 that can be studied with TMS. We studied the interactions between SICI/ICF and SICF in 17 healthy subjects. Six experiments were conducted. The first experiment examined the effects of different S1 intensities on SICI, ICF and SICF at three peaks. The effects of SICI on SICF were tested by a triple-pulse TMS protocol in the second experiment. We performed Experiments 3-5 to further test the interactions between SICI and SICF with various strengths of SICI, at SICF peaks and troughs, and with SICF generated by different current direction which preferentially generates late I waves. The effects of ICF on SICF were examined in Experiment 6. The results showed that ICF and SICF decreased whereas SICI increased with higher S1 intensities. SICI facilitated SICF mediated by late I waves both at the peaks and the troughs of SICF. The increase of SICF in the presence of SICI correlated to the strength of SICI. ICF decreased the third peak of SICF. We conclude that SICI facilitates SICF at neuronal circuits responsible for generating late I waves through disinhibition, while ICF may have the opposite effects.

Bradykinesia, characterized by slowness and decreased amplitude of movement, is often considered the most important deficit in Parkinson's disease (PD). The current clinical rating of bradykinesia in PD, based on the motor subscale of the Unified Parkinson's disease Rating Scale (UPDRS-III), does not individually weigh the impairments in speed and amplitude of rapid alternating movements. We sought to categorize movement in PD to determine whether speed and amplitude have different relationships to current measures of motor impairment and disability. Categories of speed and amplitude (normal, slow/low, and very-slow/very-low) were ascertained using an electromagnetic tracking device. Amplitude was disproportionally more affected than speed in the "off" state. UPDRS-III and the Schwab & England disability scale were worst in patients with very impaired amplitude and best in patients with normal amplitude. A similarly graded relationship was not found for categories of speed impairment. The examiner clinical global impression of change mirrored "off" state amplitude but not speed categories. Levodopa, however, normalized speed to a greater extent than amplitude. Our observations suggest that amplitude and speed impairments may be associated with different functional aspects in PD and deserve separate clinical assessment., ((c) 2009 Movement Disorder Society.)

Intracortical inhibitory and facilitatory circuits, interhemispheric inhibitory circuits and corticospinal excitability for both distal and proximal muscles were investigated in seven patients with corticobasal syndrome (CBS) and seven healthy volunteers. Transcranial magnetic stimulation was performed with surface electromyogram recorded from first dorsal interosseous muscle and biceps brachii muscle on both sides in patients and the on right side in controls. Motor thresholds and motor-evoked potential recruitment curves in both muscles at rest and during contraction were not significantly different between CBS and controls, although there was a trend for higher threshold on the more affected side in first dorsal interosseous in CBS. CBS patients had loss of short-interval intracortical inhibition bilaterally in distal and proximal muscles, reduced transcallosal inhibition from both hemispheres measured by ipsilateral silent period and paired pulse method in first dorsal interosseous, and by ipsilateral silent period in biceps brachii. Intracortical facilitation and contralateral silent period duration were not significantly changed. In conclusion, CBS patients had deficits in intracortical and interhemispheric inhibition in the representations for both distal and proximal upper limb muscles bilaterally with relative sparing of motor cortical output pathways.

Mirror movements (MM) occur in early, asymmetric Parkinson's disease (PD). To examine the pathophysiology of MM in PD, we studied 13 PD patients with MM (PD-MM), 7 PD patients without MM (PD-NM), and 14 normal subjects. Cross-correlogram did not detect common synaptic input to motoneuron pools innervating homologous hand muscles in PD-MM patients. Transcranial magnetic stimulation studies showed no significant difference in ipsilateral motor-evoked potentials between PD-MM patients and normal subjects. The MM side of PD-MM patients showed a slower increase in ipsilateral silent period area with higher level of muscle contraction than the non-MM side and normal subjects. There was less interhemispheric inhibition (IHI) at long interstimulus intervals of 20 to 50 ms in PD-MM than PD-NM. IHI reduced short interval intracortical inhibition in normal subjects and PD-NM, but not in PD-MM. IHI significantly increased intracortical facilitation in PD-MM and PD-NM patients, but not in normal subjects. Our results suggest that MM in PD is due to activation of the contralateral motor cortex. PD-MM patients had reduced transcallosal inhibitory effects on cortical output neurons and on intracortical inhibitory circuits compared to PD-NM patients and controls. These deficits in transcallosal inhibition may contribute to MM in PD patients.

Background: Peripheral sensory stimulation at the wrist inhibits the motor cortex as measured by transcranial magnetic stimulation at interstimulus intervals of approximately 20 ms (short latency afferent inhibition [SAI]) and 200 ms (long latency afferent inhibition [LAI]). Previous studies suggested that reduced SAI in Parkinson disease (PD) reflects adverse effect of dopaminergic medications and reduced LAI may be related to nondopaminergic manifestations of PD. We hypothesize that subthalamic nucleus (STN) deep brain stimulation (DBS) may correct these deficiencies., Methods: We studied the effects of STN DBS on SAI and LAI in seven PD patients and age-matched controls. PD patients were studied in an off medication followed by an on medication session, with the stimulator switched on or off in random order in each session., Results: In the on medication session, SAI was reduced in the stimulator off condition and was restored by STN DBS. LAI was partially normalized by STN DBS in the medication on condition., Conclusions: Subthalamic nucleus (STN) stimulation improves short latency afferent inhibition, suggesting that it could normalize pathways that are adversely affected by dopaminergic medications. The effect of STN stimulation on long latency afferent inhibition suggests that it may influence nondopaminergic pathways involved in sensorimotor integration.

We studied the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) on the excitability of interhemispheric connections in 13 right-handed healthy volunteers. TMS was performed using figure-eight coils, and surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. A paired-pulse method with a conditioning stimulus (CS) to the motor cortex (M1) followed by a test stimulus to the opposite M1 was used to study the interhemispheric inhibition (ppIHI). Both CS and TS were adjusted to produce motor-evoked potentials of approximately 1 mV in the contralateral FDI muscles. After baseline measurement of right-to-left IHI (pre-RIHI) and left-to-right IHI (pre-LIHI), rTMS was applied over left M1 at 1 Hz with 900 stimuli at 115% of resting motor threshold. After rTMS, ppIHI was studied using both the pre-rTMS CS (post-RIHI and post-LIHI) and an adjusted post-rTMS CS set to produce 1-mV motor evoked potentials (MEPs; post-RIHI(adj) and post-LIHI(adj)). The TS was set to produce 1-mV MEPs. There was a significant reduction in post-LIHI (P = 0.0049) and post-LIHI(adj) (P = 0.0169) compared with pre-LIHI at both interstimulus intervals of 10 and 40 ms. Post-RIHI was significantly reduced compared with pre-RIHI (P = 0.0015) but pre-RIHI and post-RIHI(adj) were not significantly different. We conclude that 1-Hz rTMS reduces IHI in both directions but is predominantly from the stimulated to the unstimulated hemisphere. Low-frequency rTMS may be used to modulate the excitability of IHI circuits. Treatment protocols using low-frequency rTMS to reduce cortical excitability in neurological and psychiatric conditions need to take into account their effects on IHI.

Whether there is a projection from the primary motor cortex (M1) to upper facial muscles and how the facial M1 area is modulated by intracortical inhibitory and facilitatory circuits remains controversial. To assess these issues, we applied transcranial magnetic stimulation (TMS) to the M1 and recorded from resting and active contralateral (C-OOc) and ipsilateral orbicularis oculi (I-OOc), and contralateral (C-Tr) and ipsilateral triangularis (I-Tr) muscles in 12 volunteers. In five subjects, the effects of stimulating at different scalp positions were assessed. Paired TMS at interstimulus intervals (ISIs) of 2 ms were used to elicit short interval intracortical inhibition (SICI) and ISI of 10 ms for intracortical facilitation (ICF). Long interval intracortical inhibition (LICI) was evaluated at ISIs between 50 and 200 ms, both at rest and during muscle activation. The silent period (SP) was also determined. C-OOc and I-OOc responses were recorded in all subjects. The optimal position for eliciting C-OOc responses was lateral to the hand representation in all subjects and MEP amplitude markedly diminished when the coil was placed 2 cm away from the optimal position. For the I-OOc, responses were present in more scalp sites and the latency decreased with more anterior placement of the coil. C-Tr response was recorded in 10 out of 12 subjects and the I-Tr muscle showed either no response or low amplitude response, probably due to volume conduction. SICI and ICF were present in the C-OOc and C-Tr, but not in the I-OOc muscle. Muscle activation attenuated SICI and ICF. LICI at rest showed facilitation at 50 ms ISI in all muscles, but there was no significant inhibition at other ISIs. There was no significant inhibition or facilitation with the LICI protocol during muscle contraction. The SP was present in the C-OOc, C-Tr and I-OOc muscles and the mean durations ranged from 92 to 104 ms. These findings suggest that the I-OOc muscle response is probably related to the first component (R1) of the blink reflex. There is M1 projection to the contralateral upper and lower facial muscles in humans and the facial M1 area is susceptible to cortical inhibition and facilitation, similar to limb muscles.

To investigate the mechanism of action of deep brain stimulation (DBS), the authors studied the effects of thalamic DBS on the cerebellothalamocortical (CTC) pathway. With DBS turned off, excitability of the CTC pathway was reduced. Turning DBS on resulted in facilitation of the CTC pathway. Therefore, thalamic DBS appears to activate rather than inhibit the target area.

Sensory abnormalities have been reported in Parkinson's disease and may contribute to the motor deficits. Peripheral sensory stimulation inhibits the motor cortex, and the effects depend on the interstimulus interval (ISI) between the sensory stimulus and transcranial magnetic stimulation (TMS) to the motor cortex. Short latency afferent inhibition (SAI) occurs at an ISI of approximately 20 ms, and long latency afferent inhibition (LAI) at an ISI of approximately 200 ms. We studied SAI and LAI in 10 Parkinson's disease patients with the aim of assessing whether sensorimotor processing is altered in Parkinson's disease. Patients were studied on and off medication, and the findings were compared with 10 age-matched controls. Median nerve and middle finger stimulation were delivered 20-600 ms before TMS to the contralateral motor cortex. The motor evoked potentials were recorded from the relaxed first dorsal interosseous (FDI) muscle. SAI was normal in Parkinson's disease patients off dopaminergic medications, but it was reduced on the more affected side in Parkinson's disease patients on medication. LAI was reduced in Parkinson's disease patients compared with controls independent of their medication status. LAI reduced long interval intracortical inhibition in normal subjects but not in Parkinson's disease patients. The different results for SAI and LAI indicate that it is likely that separate mechanisms mediate these two forms of afferent inhibition. SAI probably represents the direct interaction of a sensory signal with the motor cortex. This pathway is unaffected by Parkinson's disease but is altered by dopaminergic medication in Parkinson's disease patients and may contribute to the side effects of dopaminergic drugs. LAI probably involves other pathways such as the basal ganglia or cortical association areas. This defective sensorimotor integration may be a non-dopaminergic manifestation of Parkinson's disease.

The neonatal Fc receptor (FcRn) is a key receptor involved in the transcytosis of IgG across the maternal-fetal barrier. The level of IgG varies considerably among newborn infants. Since other Fc gamma receptors show single nucleotide functional variants, we determined whether common variant alleles exist for the FcRn. Direct sequence analysis was performed on PCR-amplified complementary DNA (cDNA) isolated from ten placental mRNAs (20 alleles examined). Two synonymous nucleotide polymorphisms were detected from the same source. A G251T and C707T substitution, reflecting amino acid positions Pro19 and Arg171 of the mature polypeptide, did not alter the amino acid encoded. No other nucleotide substitutions or sequence variations were observed. Thus, the variation in IgG transport is not due to common variant alleles among the human population. Due to the limited number of samples tested (n=20), low-frequency alleles would go undetected by chance alone when q has a frequency < or = 0.14. It is unlikely that low-frequency variant alleles, if present, are responsible for the major variation seen in the transcytosis of IgG.