Using transcranial magnetic stimulation (TMS), previous work has established that motor cortical inhibitory and facilitatory circuits are aberrant in patients with Parkinson’s disease (PD). Three ...such circuits are short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF) and short latency afferent inhibition (SAI). They assess GABAAergic, glutamatergic and cholinergic function, respectively. Importantly, these circuits interact with each other and their interactions can be tested using a triple-pulse TMS paradigm, which elicits one circuit in the presence of another. However, these interactions have not been studied in PD.
14 right-handed PD patients (10 males; 65.1 ± 8.0 years) were studied ON and OFF dopaminergic medication. Unified Parkinson’s Disease Rating Scale Part III was used to assess disease severity. 14 right-handed, age-matched healthy participants (8 males; 64.4 ± 7.3 years) served as controls. Surface electromyography measured target muscle (first dorsal interosseous) motor evoked potentials generated by TMS of left M1 in controls and of M1 in the more affected hemisphere in PD patients. SICI was tested at an interstimulus interval (ISI) of 2 ms and SICF at an ISI of 1.5 ms. The interactions between SICI and SICF were evaluated by comparing SICF alone to SICF in the presence of SICI. The latency of the median nerve N20 somatosensory evoked potential plus 2 ms was used as the ISI for SAI. The interactions between SAI and SICI were evaluated by comparing SAI alone to SAI in the presence of SICI and by comparing SICI alone to SICI in the presence of SAI. Repeated measures analyses of variance were applied to test the within-subject effect of condition (circuit A alone; circuit A in the presence of circuit B) and the between-subject factor of group (PD ON; PD OFF; control).
For the comparison between SAI alone and SAI in the presence of SICI, there was a significant effect of condition, but no effect of group. SAI was disinhibited in the presence of SICI. For the comparison between SICI alone and SICI in the presence of SAI, there was a significant effect of condition, but no effect of group. SICI was disinhibited in the presence of SAI. For the comparison between SICF alone and SICF in the presence of SICI, there was no significant effect of condition or group, or interaction between the two. When groups were tested separately, SICF was facilitated in the presence of SICI in controls, but not in PD ON or OFF.
While previous studies showed that individual cortical circuits of SICI and SAI are abnormal in PD, our findings suggest the interactions between these circuits are preserved in PD. Thus, abnormal SICI and SAI cannot be attributed to abnormal interaction among these circuits. Our results suggest that the facilitatory effect of SICI on SICF is diminished in PD and is not affected by dopaminergic medications. Altered interaction between cortical circuits may contribute to the pathophysiology of PD.
Non‐technical summary Motor cortical output is suppressed by two cortical inhibitory systems, short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). SICI ...is decreased in the presence of LICI. However, there is a long‐standing argument whether this is caused by a true interaction between them or is due to simple saturation of the inhibitory effects that occur at common cortical elements which both inhibitory systems target. We addressed this question by recording the descending corticospinal waves in the subjects with implanted epidural electrodes. The results suggest that there are inhibitory interactions between LICI and SICI.
A subthreshold conditioning stimulation (CS) suppresses the motor‐evoked potential (MEP) generated by a test stimulation (TS) at interstimulus intervals (ISIs) of 1–5 ms in a paired‐pulse transcranial magnetic stimulation (TMS) protocol, a phenomenon termed short interval intracortical inhibition (SICI). Intracortical facilitation (ICF) occurs at ISIs of 7–30 ms. Long interval intracortical inhibition (LICI) is elicited with suprathreshold CS preceding the TS at ISIs of 50–200 ms. Previous studies showed that SICI is decreased in the presence of LICI but whether this is due to changes in descending indirect waves (I‐waves) induced by LICI or true inhibitory interactions between LICI and SICI has not been resolved. To address this issue, we recorded I‐waves in two patients with implanted cervical epidural electrodes and investigated how SICI and ICF changed I‐waves in the presence of LICI. SICI alone reduced late I‐waves but in the presence of LICI, neither the I‐waves nor the MEP were further inhibited by SICI. ICF alone increased MEP amplitude but the I‐waves were not facilitated. There was no change of ICF in the presence of LICI compared with ICF alone. We conclude that decreased SICI in the presence of LICI is not due to changes in I‐wave content induced by LICI and is caused by their interactions at the cortical level.
Dual-site transcranial magnetic stimulation to the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) can be used to probe functional connectivity between these regions. The purpose ...of this study was to characterize the effect of DLPFC stimulation on ipsilateral M1 excitability while participants were at rest and contracting the left- and right-hand first dorsal interosseous muscle. Twelve participants were tested in two separate sessions at varying inter-stimulus intervals (ISI: 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20 ms) at two different conditioning stimulus intensities (80% and 120% of resting motor threshold). No significant effect on ipsilateral M1 excitability was found when applying a conditioning stimulus over DLPFC at any specific inter-stimulus interval or intensity in either the left or right hemisphere. Our findings suggest neither causal inhibitory nor faciliatory influences of DLPFC on ipsilateral M1 activity while participants were at rest or when performing an isometric contraction in the target hand muscle.
Various inhibitory pathways exist in the human brain which are crucial in modulating motor cortex output and they can be investigated
non-invasively using transcranial magnetic stimulation. ...Interhemispheric inhibition (IHI) is one form of cortical inhibition.
It can be elicited by stimulation of the opposite motor cortex at interstimulus intervals (ISIs) of 10 ms (IHI10) or 40 ms
(IHI40) and inhibitions at these intervals are probably mediated by different mechanisms. Peripheral sensory stimulation can
also inhibit the motor cortex. Median nerve stimulation produces long latency afferent inhibition (LAI) at ISI 200 ms. LAI
inhibits another form of cortical inhibition known as long interval intracortical inhibition (LICI) and a study that examined
the interaction between IHI10 and LICI hypothesized that they are mediated by an overlapping population of inhibitory neurones.
We tested this hypothesis by examining the interaction between IHI10, IHI40 and LAI. With increasing test MEP amplitude LAI,
IHI10 and IHI40 all decreased. There was no correlation between the strength of LAI, IHI10 and IHI40. In the presence of LAI,
IHI10 was slightly but significantly reduced compared to IHI10 alone. There was no correlation between the reduction in IHI10
in the presence of LAI and the strength of LAI or IHI10. In the presence of LAI, IHI40 was significantly reduced compared
to IHI40 alone. LAI produced a greater decrease in IHI40 than in IHI10. The decrease in IHI40 in the presence of LAI strongly
correlated with the strength of LAI but not with the strength of IHI40. Reducing the strength of LAI, IHI10 and IHI40 still
resulted in similar interaction between IHI10 and LAI but markedly decreased the effect of LAI on IHI40. We conclude that
LAI and IHI10 do not directly inhibit each other but LAI probably inhibits IHI40. LICI is more likely to be related to IHI40
than to IHI10.
Paired-pulse transcranial magnetic stimulation (TMS) can be used to non-invasively evaluate human motor cortical inhibitory circuits such as short interval intracortical inhibition (SICI) and long ...interval intracortical inhibition (LICI). Pharmacological studies suggested that SICI is mediated by GABA
A
receptors while LICI is probably mediated by GABA
B
receptors. A previous study also showed that SICI and LICI are mediated by separate neuronal populations and that LICI inhibits SICI, possibly through presynaptic GABA
B
receptors. The aim of this study was to examine whether the time course of motor-evoked potentials (MEP) inhibition by LICI, likely mediated through postsynaptic GABA
B
receptors, is different from SICI inhibition by LICI, likely mediated through presynaptic GABA
B
receptors. Nine healthy volunteers were studied and MEP were recorded from the first dorsal interosseous muscle. A triple-stimulus TMS paradigm was used to evaluate the effect of LICI at ISIs of 100 and 150 ms on SICI. LICI at 100 and 150 ms caused a similar degree of MEP inhibition. LICI at 100 ms led to a significant reduction of SICI but LICI at 150 ms had no effect on SICI. Repeated measures ANOVA revealed a significant interaction between the LICI mediated inhibition of SICI and ISI (
P
= 0.0072). These findings suggest that the time courses of presynaptic and postsynaptic GABA
B
receptors mediated inhibition are different in the human motor cortex.
The posterior parietal cortices (PPCs) engage in motor processing during reach and grasp. Yet, the neural substrates behind their connections to the motor cortex (M1) are still unknown. It has been ...postulated that right PPC (rPPC) acts directly on left PPC (lPPC), which then acts on left M1 (lM1). Alternately, rPPC may act on lM1 circuits at the same time as lPPC. Here, we used triple-site transcranial magnetic stimulation (TMS) to test this hypothesis. Previous studies showed that rPPC or lPPC stimulation alone facilitates motor evoked potentials (MEPs), whereas rPPC and lPPC stimulation together inhibits the facilitated MEPs. To consider their interaction at M1, we tested two M1 circuits: short interval intracortical facilitation (SICF) and short interval intracortical inhibition (SICI). SICF is elicited by two suprathreshold pulses to M1 delivered in ∼1.5 ms intervals which facilitate M1 output. SICI inhibits M1 output and is elicited by a subthreshold conditioning stimulus delivered 1–6 ms prior to a suprathreshold pulse. We hypothesized that if rPPC and lPPC inhibit MEPs by acting on SICF or SICI in M1, a correlation would emerge.
16 healthy adults participated (9 females, 22–64 years, 35.4 ± 14.6 years old). MRI-navigated TMS was delivered by 3 small coils over rPPC, lPPC and lM1. MEPs were recorded from the right first dorsal interosseous muscle. Exp 1 tested PPC-lM1 circuits and their interactions at several rPPC and lPPC stimuli intensities, including 90 and ∼108% RMT over lPPC and 30 to 130% RMT over rPPC. Exp 2 tested PPC-lM1 circuits and their interaction at different test MEP amplitudes of ∼0.2 mV, 1 mV, and 4 mV. Exp 3 tested the effect of rPPC on SICF. Exp 4 tested the effect of SICI on lPPC-lM1 and rPPC-lPPC-lM1 interactions.
Exp 1: The interaction of rPPC and lPPC inhibited MEPs. This effect occurred when the rPPC was stimulated at 70% and 90% RMT, and the lPPC was stimulated at ∼108% RMT. rPPC-to-lM1 connectivity correlated with this interaction, whereas lPPC-to-lM1 connectivity did not. Exp 2: Compared to higher intensities, low intensity M1 stimulation at ∼0.2 mV showed facilitated rPPC-to-lM1 connectivity and increased the inhibitory effects of rPPC and lPPC interaction. Exp 3: rPPC inhibited SICF at 1.4 ± 0.1 ms, and this inhibition correlated with rPPC and lPPC inhibition. Exp 4: SICI abolished the facilitatory effect of lPPC-lM1 and the inhibitory effect of rPPC-to-lPPC-lM1 connection. SICI in the presence of lPPC-lM1 correlated with rPPC in the presence of lPPC-lM1.
We showed that the rPPC and lPPC inhibit the lM1, which is more prominent when tested at low M1 stimulation intensity. rPPC-to-lM1 connectivity correlated with this interaction. The effect of PPC on M1 may be mediated in part by cortical circuits SICF and SICI. We conclude that the effects of rPPC and lPPC likely interact at lM1.
Associative plasticity is hypothesized to be an important neurophysiological correlate of memory formation and learning with potentials for applications in neurorehabilitation and for the development ...of new electrophysiological measures to study disorders of cortical plasticity. We hypothesized that the magnitude of the paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like effect depends on the number of pairs in the PAS protocol. We also hypothesized that homeostatic interaction of PAS with subsequent motor learning is related to the magnitude of the PAS-induced LTP-like effect. We studied 10 healthy subjects. In experiment 1a, subjects received 90 (PAS90), 180 (PAS180), or 270 (PAS270) pairs of stimuli, followed by a dynamic motor practice (DMP) 1 h after the end of the PAS protocols. In experiment 1b, the DMP preceded the PAS protocol. In experiment 2, the time course of PAS270 was studied. We found that PAS270 resulted in greater increase in motor evoked potential (MEP) amplitude compared with protocols with fewer pairs of stimuli. Moreover, the interaction between PAS protocols with motor learning differed depending on the number of stimulus pairs used to induce PAS. While DMP alone increased MEP amplitudes, DMP during the LTP-like effects induced by PAS270 led to a long-term depression (LTD)-like effect (homeostatic interaction). This homeostatic interaction did not occur after PAS90 and PAS180. In conclusion, we found a dose-dependent effect of the number of stimulus pairs used in the PAS protocol on cortical plasticity. Homeostatic interaction between PAS and DMP was observed only after PAS270.
Deep brain stimulation improves motor symptoms in Parkinson's disease and changes primary motor cortex excitability, but how subthalamic nucleus stimulation affects premotor-motor cortical ...connectivity remains unclear.
We investigated 10 Parkinson patients in whom single subthalamic nucleus stimulation was time-locked to transcranial magnetic dual-coil, paired-pulse stimulation of the dorsal premotor and primary motor cortex. Premotor-motor interaction with deep brain stimulation switched off was compared to 10 controls.
Parkinson patients showed abnormally facilitated premotor-motor interaction with deep brain stimulation switched off compared to controls. This abnormal premotor-motor facilitation was abolished during subthalamic nucleus stimulation at 3 Hz.
In Parkinson's disease, aberrant signals from the basal ganglia leading to a loss of physiological premotor-motor inhibition can be normalized by subthalamic deep brain stimulation. This effect is likely mediated by activation of subthalamic-pallidal-thalamic projection to the premotor cortex.
•Parkinson patients exhibited abnormal premotor-motor facilitation with DBS switched off.•Premotor-motor transcranial magnetic stimulation was paired with 3 Hz DBS at different times.•3 Hz DBS reduced the abnormal premotor-motor interaction independent of pairing intervals.
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