Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interhemispheric interactions between the right angular gyrus and the left motor cortex: a transcranial magnetic stimulation study.

The interconnection of the angular gyrus of right posterior parietal cortex (PPC) and the left motor cortex (LM1) is essential for goal-directed hand movements. Previous work with transcranial magnetic stimulation (TMS) showed that right PPC stimulation increases LM1 excitability, but right PPC followed by left PPC-LM1 stimulation (LPPC-LM1) inhibits LM1 corticospinal output compared with LPPC-LM1 alone. It is not clear if right PPC-mediated inhibition of LPPC-LM1 is due to inhibition of left PPC or to combined effects of right and left PPC stimulation on LM1 excitability. We used paired-pulse TMS to study the extent to which combined right and left PPC stimulation, targeting the angular gyri, influences LM1 excitability. We tested 16 healthy subjects in five paired-pulsed TMS experiments using MRI-guided neuronavigation to target the angular gyri within PPC. We tested the effects of different right angular gyrus (RAG) and LM1 stimulation intensities on the influence of RAG on LM1 and on influence of left angular gyrus (LAG) on LM1 (LAG-LM1). We then tested the effects of RAG and LAG stimulation on LM1 short-interval intracortical facilitation (SICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI). The results revealed that RAG facilitated LM1, inhibited SICF, and inhibited LAG-LM1. Combined RAG-LAG stimulation did not affect SICI but increased LICI. These experiments suggest that RAG-mediated inhibition of LAG-LM1 is related to inhibition of early indirect (I)-wave activity and enhancement of GABAB receptor-mediated inhibition in LM1. The influence of RAG on LM1 likely involves ipsilateral connections from LAG to LM1 and heterotopic connections from RAG to LM1.NEW & NOTEWORTHY Goal-directed hand movements rely on the right and left angular gyri (RAG and LAG) and motor cortex (M1), yet how these brain areas functionally interact is unclear. Here, we show that RAG stimulation facilitated right hand motor output from the left M1 but inhibited indirect (I)-waves in M1. Combined RAG and LAG stimulation increased GABAB, but not GABAA, receptor-mediated inhibition in left M1. These findings highlight unique brain interactions between the RAG and left M1.

Rubber hand illusion modulates the influences of somatosensory and parietal inputs to the motor cortex.

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.

Pallidal deep brain stimulation modulates cortical excitability and plasticity.

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.

Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease.

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼ 3 and ∼ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼ 3 ms) and medium (∼ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity. SIGNIFICANCE STATEMENT: We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼ 3 ms) and medium (∼ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.

Heterosynaptic modulation of motor cortical plasticity in human.

Inductions of long-term potentiation (LTP) and depression (LTD) are modulated if they are preceded by a priming protocol, in a manner consistent with metaplasticity. Depotentiation refers to reversal of LTP by a subsequent protocol that has no effect by itself. Paired associative stimulation (PAS) at interstimulus interval of 25 ms (PAS25) and 10 ms (PAS10) produces spike timing-dependent LTP-like and LTD-like effects in human primary motor cortex. Continuous theta burst stimulation (cTBS) with 600 pulses produces an LTD-like effect, whereas cTBS with 150 pulses (cTBS150) has no effect by itself. We investigated whether cortical plasticity induced by PAS can be modulated by heterosynaptic inputs of cTBS150. PAS25 and PAS10 primed and followed by cTBS150 were compared withPAS25 and PAS10 alone. Motor evoked potential (MEP) amplitude, recruitment curve, and intracortical circuits including short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), intracortical facilitation, and short-latency afferent inhibition were measured before and after the interventions. After PAS25 alone, MEP amplitude increased while intracortical circuits did not change. A priming cTBS150 enhanced the effects of PAS25 with further increase in MEP amplitude and led to reduction in SICI and LICI. PAS25 followed by cTBS150 led to reduced MEP amplitude and increased LICI and SICI. Both priming and following cTBS150 reversed the LTD-like effect produced by PAS10 with little change in intracortical circuits. We conclude that cortical plasticity induced by PAS and cTBS interacts in a heterosynaptic and bidirectional manner. The order of the interventions determines whether the underlying mechanisms are related to metaplasticity or depotentiation.

The influence of sensory afferent input on local motor cortical excitatory circuitry in humans.

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.

Effects of short-latency afferent inhibition on short-interval intracortical inhibition.

Peripheral nerve stimulation inhibits the motor cortex, and the process has been termed short-latency afferent inhibition (SAI) at interstimulus intervals (ISIs) of ∼20 ms. The objective of the present study was to test how SAI interacts with short-interval intracortical inhibition (SICI) under different stimulation conditions. We studied 20 healthy volunteers. Surface electromyogram was recorded from the first dorsal interosseous muscle. Using paired- and triple-pulse paradigms, we investigated how SAI interacts with SICI under these different conditions. The effects of different conditioning stimulus (CS) intensities (0.6-0.9 active motor threshold), SAI latencies (23 and 25 ms), and ISIs (2 and 3 ms) for SICI were examined in rest and active conditions. SAI had inhibitory interactions with SICI at different CS intensities for rest or active SICI, at SAI latencies of 23 and 25 ms. This interaction occurred at weak CS intensities for SICI when there was no inhibition, and SICI became facilitatory in the presence of SAI. This can be explained by SICI inhibiting SAI and not by saturation of inhibition. The interaction between SAI and SICI was greater for SICI at ISI of 3 ms than for ISI of 2 ms, suggesting that different circuits may be activated at these ISIs. We conclude that SAI and SICI have inhibitory interactions that are influenced by factors such as ISI and muscle activities, which should be considered in design and interpretation of cortical interaction studies.

Dose-response curve of associative plasticity in human motor cortex and interactions with motor practice.

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.

Short- and long-latency interhemispheric inhibitions are additive in human motor cortex.

Transcranial magnetic stimulation (TMS) of the human primary motor cortex (M1) at suprathreshold strength results in inhibition of M1 in the opposite hemisphere, a process termed interhemispheric inhibition (IHI). Two phases of IHI, termed short-latency interhemispheric inhibition (SIHI) and long-latency interhemispheric inhibition (LIHI), involving separate neural circuits, have been identified. In this study we evaluated how these two inhibitory processes interact with each other. We studied 10 healthy right-handed subjects. A test stimulus (TS) was delivered to the left M1, and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous (FDI) muscle. Contralateral conditioning stimuli (CCS) were applied to the right M1 either 10 ms or 50 ms prior to the TS, inducing SIHI and LIHI, respectively, in the left M1. The effects of SIHI and LIHI alone, and SIHI and LIHI delivered together, were compared. The TS was adjusted to produce 1-mV or 0.5-mV MEPs when applied alone or after CCS. SIHI and LIHI were found to be additive when delivered together, irrespective of the strength of the TS. The interactions were affected neither by varying the strength of the conditioning stimulus producing SIHI nor by altering the current direction of the TS. Small or opposing interactions, however, may not have been detected. These results support previous findings suggesting that SIHI and LIHI act through different neural circuits. Such inhibitory processes may be used individually or additively during motor tasks and should be studied as separate processes in functional studies.

Long-term subthalamic nucleus stimulation improves sensorimotor integration and proprioception.

OBJECTIVE: Sensorimotor integration is impaired in patients with Parkinson's disease (PD). Short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) measured with transcranial magnetic stimulation (TMS) can be used to measure sensorimotor integration. Subthalamic nucleus (STN) deep brain stimulation (DBS) has been found to restore these abnormalities, but the time course of these changes is not known. We prospectively evaluated the short-term and long-term effects of STN DBS on SAI, LAI and proprioception. We hypothesised plasticity changes induced by chronic stimulation are necessary to normalise sensorimotor integration and proprioception. METHODS: Patients with PD were studied preoperatively, at 1 month and more than 6 months postoperatively. SAI was tested with median nerve stimulation to the wrist preceding TMS pulse to motor cortex by ~20 ms and LAI by 200 ms. Proprioception (distance and spatial errors) in the arm was quantitatively assessed. For postoperative assessments, patients were studied in the medication-off/stimulator-off, medication-off/stimulator-on, medication-on/stimulator-off and medication-on/stimulator-on conditions. RESULTS: 11 patients with PD and 10 controls were enrolled. Preoperatively, SAI and proprioception was abnormal during the medication-on conditions and LAI was reduced regardless of the medication status. STN DBS had no significant effect on SAI, LAI and proprioception at 1 month. However, at 6 months SAI, LAI and distance errors were normalised in the medication-on/stimulator-on condition. Spatial error was normalised with DBS on and off. CONCLUSIONS: Chronic STN DBS in PD normalises sensorimotor integration and proprioception, likely through long-term plastic changes in the basal ganglia thalamocortical circuit.

Short-interval intracortical inhibition blocks long-term potentiation induced by paired associative stimulation.

Paired associative stimulation (PAS) of the motor cortex leads to increased motor evoked potential (MEP) amplitudes in the stimulated hand muscles. We hypothesized that evoking GABA(A) receptor-mediated short-interval intracortical inhibition (SICI) simultaneously with excitatory PAS would depress long-term potentiation plasticity in motor cortex. Four different PAS paradigms were tested, standard PAS (PAS25) and three conditioned PAS protocols (CS2-PAS25, CS2-PAS25adj, and CS10-PAS25adj). A subthreshold conditioning stimulus 2 ms (CS2) or 10 ms (CS10) before the test stimuli was added to the conditioned PAS protocols. Since CS2 has inhibitory and CS10 has facilitatory effect on cortical excitability, in the CS2-PAS25adj and CS10-PAS25adj protocols, TS intensity was adjusted to produce a 1-mV MEP in the presence of CS2 or CS10 to control for the degree of corticospinal excitation. As expected, MEP amplitudes after PAS25 were higher compared with that at baseline, but importantly, MEP amplitudes did not change after PAS was induced in the presence of SICI in either the CS2-PAS25 or CS2-PAS25adj condition. Furthermore, the CS10-PAS25adj protocol showed significantly increased MEP amplitude at 60 min after PAS compared with baseline. These results show that SICI blocked the induction of long-term potentiation-like plasticity in the motor cortex, indicating that GABAergic circuits play an important role in the regulation of cortical plasticity. The study demonstrates a noninvasive and nonpharmacological way to achieve focal modulation of plasticity.

Direct demonstration of inhibitory interactions between long interval intracortical inhibition and short interval intracortical inhibition.

A subthreshold conditioning stimulation (CS) suppresses the motor-evoked potential (MEP) generated by a test stimulation (TS) at interstimulus intervals (ISIs) of 1­5ms in a paired-pulse transcranial magnetic stimulation (TMS) protocol, a phenomenon termed short interval intracortical inhibition (SICI). Intracortical facilitation (ICF) occurs at ISIs of 7­30ms. Long interval intracortical inhibition (LICI) is elicited with suprathreshold CS preceding the TS at ISIs of 50­200 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.

Transcranial magnetic stimulation in different current directions activates separate cortical circuits.

Transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) produces a series of corticospinal descending waves, with a direct (D) wave followed by several indirect (I) waves. TMS inducing posterior-anterior (PA) current in the brain predominantly recruits the early I1-wave, whereas anterior-posterior (AP) directed current preferentially recruits the late I3-wave. However, it is not known whether I-waves elicited by different current directions are mediated by the same neuronal populations. We studied the neuronal mechanisms mediating I-waves by examining the influence of short-latency afferent inhibition (SAI) on various I-waves. SAI was tested with electrical median nerve stimulation at the wrist followed by TMS to the contralateral M1 at different current directions. Surface electromyograms and single motor units were recorded from the first dorsal interosseous muscle. SAI was weaker for the AP compared with that for the PA current direction. With increasing median nerve stimulation intensities, SAI increased for the PA direction but showed a U-shaped relationship for the AP direction. SAI produced more inhibition of late I-waves generated by PA than those generated by AP current direction. We conclude that late I-waves generated by PA and AP current directions are mediated by different neuronal mechanisms.

The nature and time course of cortical activation following subthalamic stimulation in Parkinson's disease.

We studied the time course and nature of interactions between the subthalamic nucleus (STN) and the motor cortex in 8 Parkinson disease (PD) patients with chronically implanted STN deep-brain stimulation (DBS) electrodes. We first identified the cortical evoked potentials following STN stimulation. The most consistent potential was positive wave with peak latency of 22.2 +/- 1.2 ms from stimulation of clinically effective contacts. We then stimulated the motor cortex with transcranial magnetic stimulation (TMS) at 2-15 ms and at the latency of the evoked potential ( approximately 23 ms) following STN DBS. TMS induced currents in 3 directions: lateral-medial (LM) direction activated corticospinal axons directly, posterior-anterior (PA), and anterior-posterior (AP) directions activated corticospinal neurons transynaptically. Motor-evoked potentials (MEP) elicited by AP and PA TMS were facilitated at short (2-4 ms) and medium latencies (21-24 ms). However, MEPs elicited by LM TMS were not modified by STN DBS. Short-latency antidromic stimulation of the corticosubthalamic projections and medium latency transmission likely through the basal ganglia-thalamocortical circuit led to cortical evoked potentials and increased motor cortex excitability at specific intervals following STN stimulation at clinically effective contacts. Cortical activation may be related to the clinical effects of STN DBS in PD.

Impaired motor cortical facilitatory-inhibitory circuit interaction in Parkinson's disease.

OBJECTIVE: Motor cortical (M1) inhibition and facilitation can be studied with short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). These circuits are altered in Parkinson's disease (PD). The sensorimotor measure short latency afferent inhibition (SAI) is possibly altered in PD. The aim was to determine if the manner in which these circuits interact with each other is abnormal in PD. METHODS: Fifteen PD patients were studied at rest in ON and OFF medication states, and were compared to 16 age-matched controls. A triple-stimulus transcranial magnetic stimulation paradigm was used to elicit a circuit of interest in the presence of another circuit. RESULTS: SICF was increased in PD OFF and PD ON conditions compared to controls. SICI facilitated SICF in controls and PD ON, but not in PD OFF. SICF in the presence of SICI negatively correlated with UPDRS-III scores in OFF and ON medication conditions. SAI showed similar inhibition of SICI in controls, PD OFF and PD ON conditions. CONCLUSIONS: The facilitatory effect of SICI on SICF is absent in PD OFF, but is restored with dopaminergic medication. SIGNIFICANCE: Impaired interaction between M1 circuits is a pathophysiological feature of PD.

Effect of long interval interhemispheric inhibition on intracortical inhibitory and facilitatory circuits.

Stimulation of the primary motor cortex (M1) of one hemisphere of the brain inhibits the opposite M1, a process known as interhemispheric inhibition (IHI). An early phase of IHI peaks at about approximately 10 ms after stimulation of the opposite hemisphere and is termed short latency interhemispheric inhibition (SIHI). A later phase peaks at about 40 ms and has been termed long latency interhemispheric inhibition (LIHI). The objective of the present study is to test how LIHI interacts with cortical inhibitory and facilitatory circuits, including short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long interval intracortical inhibition (LICI). We studied 10 healthy volunteers. LIHI from right to left hemisphere was elicited by stimulating the right M1 at an interstimulus interval (ISI) of 40 ms before stimulation of the left M1. Conditioning and test stimuli to elicit SICI, ICF and LICI were given to left M1. The effects of different sizes of test motor-evoked potential (MEP amplitudes; 0.2, 1 and 2 mV) were examined for SICI, ICF, LICI and LIHI. Using paired-pulse and triple-pulse protocols, how LIHI interacts with SICI, ICF and LICI were investigated. We found SICI increased, while LICI and LIHI decreased with increasing test MEP amplitude. The presence of LIHI did not change the degree of SICI and intracortical facilitation (ICF), and their effects of these circuits were additive. On the other hand, LICI and LIHI were reduced in the presence of each other. We conclude that different sets of cortical neurons mediate LIHI, SICI, ICF and LICI. GABA(B)-mediated LICI and LIHI have inhibitory interactions with each other while LIHI has an additive effect with GABA(A)-mediated SICI.

Reversal of cortical reorganization in human primary motor cortex following thumb reconstruction.

Deafferentation such as the amputation of a body part causes cortical reorganization in the primary motor cortex (M1). We investigated whether this reorganization is reversible after reconstruction of the lost body part. We tested two patients who had long-standing thumb amputations followed by thumb reconstruction with toe-to-thumb transfer 9 to 10 mo later and one patient who underwent thumb replantation immediately following traumatic amputation. Using transcranial magnetic stimulation, we measured the motor evoked potential (MEP) threshold, latency, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) at different time points in the course of recovery in abductor pollicis brevis muscle. For the two patients who underwent late toe-to-thumb transfer, the rest motor threshold was lower on the injured side than that on the intact side before surgery and it increased with time after reconstruction, whereas the active motor threshold remained unchanged. The rest and active MEP latencies were similar on the injured side before and < or =15 wk after surgery and followed by restoration of expected latency differences. SICI was reduced before surgery and progressively normalized with the time after surgery. ICF did not change with time. These physiological measures correlated with the recovery of motor and sensory functions. All the measurements on the intact side of the toe-to-thumb transfer patients and in the patient with thumb replantation immediately following traumatic amputation remained stable over time. We conclude that chronic reorganization occurring in the M1 after amputation can be reversed by reconstruction of the lost body part.

Two phases of interhemispheric inhibition between motor related cortical areas and the primary motor cortex in human.

Interhemispheric inhibition (IHI) refers to the neurophysiological mechanism in which one hemisphere of the brain inhibits the opposite hemisphere. IHI can be studied by transcranial magnetic stimulation using a conditioning-test paradigm. We investigated IHI from 5 motor related cortical areas in the right hemisphere to the left primary motor cortex (M1). These areas are hand and face representations of M1, dorsal premotor cortex, somatosensory cortex, and dorsolateral prefrontal cortex. Test stimulus was delivered to the left M1 and conditioning stimulus (CS) was delivered to one of 5 motor related cortical areas in the right hemisphere. The time course of IHI, effects of different CS intensities and current directions on IHI were tested. Maximum IHI was found at interstimulus intervals of approximately 10 ms (short latency IHI, SIHI) and approximately 50 ms (long latency IHI, LIHI) for the motor related areas tested. LIHI could be elicited over a wide range of CS intensities, whereas SIHI required higher CS intensities. We conclude that there are 2 distinct phases of IHI from motor related cortical areas to the opposite M1 through the corpus callosum, and they are mediated by different neuronal populations.

Effects of short interval intracortical inhibition and intracortical facilitation on short interval intracortical facilitation in human primary motor cortex.

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.