Influence of aging and task-related activation on descending cortical modulation of spinal sensorimotor circuitry

Motor Recovery after Spinal Cord Injury Enhanced by Strengthening Corticospinal Synaptic Transmission

Aspects of cortical area responsibilities while learning a visually cued spatiotemporal motor task.

Sensorimotor control is modulated through complex interactions between descending corticomotor pathways and ascending sensory inputs. Pairing sub-threshold transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS) modulates the Hoffmann’s reflex (H-reflex), providing a neurophysiologic probe into the influence of descending cortical drive on spinal segmental circuits. However, individual variability in the timing and magnitude of H-reflex modulation is poorly understood. Here, we varied the inter-stimulus interval (ISI) between TMS and PNS to systematically manipulate the relative timing of convergence of descending TMS-induced volleys with respect to ascending PNS-induced afferent volleys in the spinal cord to: (1) characterize effective connectivity between the primary motor cortex (M1) and spinal circuits, mediated by both direct, fastest-conducting, and indirect, slower-conducting descending pathways; and (2) compare the effect of individual-specific vs. standard ISIs. Unconditioned and TMS-conditioned H-reflexes (24 different ISIs ranging from −6 to 12 ms) were recorded from the soleus muscle in 10 able-bodied individuals. The magnitude of H-reflex modulation at individualized ISIs (earliest facilitation delay or EFD and individual-specific peak facilitation) was compared with standard ISIs. Our results revealed a significant effect of ISI on H-reflex modulation. ISIs eliciting earliest-onset facilitation (EFD 0 ms) ranged from −3 to −5 ms across individuals. No difference in the magnitude of facilitation was observed at EFD 0 ms vs. a standardized short-interval ISI of −1.5 ms. Peak facilitation occurred at longer ISIs, ranging from +3 to +11 ms. The magnitude of H-reflex facilitation derived using an individual-specific peak facilitation was significantly larger than facilitation observed at a standardized longer-interval ISI of +10 ms. Our results suggest that unique insights can be provided with individual-specific measures of top-down effective connectivity mediated by direct and/or fastest-conducting pathways (indicated by the magnitude of facilitation observed at EFD 0 ms) and other descending pathways that encompass relatively slower and/or indirect connections from M1 to spinal circuits (indicated by peak facilitation and facilitation at longer ISIs). By comprehensively characterizing the temporal profile and inter-individual variability of descending modulation of spinal reflexes, our findings provide methodological guidelines and normative reference values to inform future studies on neurophysiological correlates of the complex array of descending neural connections between M1 and spinal circuits.

Paired associative stimulation (PAS), combining transcranial magnetic stimulation (TMS) with electrical peripheral nerve stimulation (PNS) in pairs with an optimal interstimulus interval (ISI) in between, has been shown to influence the excitability of the motor cortex (MC) in humans. However, the underlying mechanisms remain unclear. This study was designed to explore an optimal protocol of PAS, which can modulate the excitability of MC in rats, and to investigate the underlying mechanisms. The resting motor thresholds (RMTs) of TMS-elicited motor evoked potentials (MEPs) recorded from the gastrocnemius muscle and the latency of P1 component of somatosensory evoked potentials (SEPs) induced by electrical tibial nerve stimulation were determined in male Sprague-Dawley rats (n=10). Sixty rats were then randomly divided into 3 groups: a PAS group (further divided into 10 subgroups at various ISIs calculated by using the latency of P1, n=5, respectively), a TMS (only) group (n=5) and a PNS (only) group (n=5). Ninety repetitions of PAS, TMS and PNS were administered to the rats in the 3 groups, respectively, at the frequency of 0.05 Hz and the intensity of TMS at 120% RMT and that of PNS at 6 mA. RMTs and motor evoked potentials' amplitude (MEPamp) were recorded before and immediately after the interventions. It was found that the MEPamp significantly decreased after PAS at ISI of 5 ms (P<0.05), while the MEPamp significantly increased after PAS at ISI of 15 ms, as compared with those before the intervention (P<0.05). However, the RMT did not change significantly after PAS at ISI of 5 ms or 15 ms (P>0.05). PAS at other ISIs as well as the sole use of TMS and PNS induced no remarkable changes in MEPamp and RMT. In conclusion, PAS can influence motor cortex excitability in rats. Neither TMS alone nor PNS alone shows significant effect.

Normal cortical excitability in Myoclonus-Dystonia — A TMS study

Tactile extinction has been interpreted as an attentional disorder, closely related to hemineglect, due to hyperactivation of the unaffected hemisphere, resulting in an ipsilesional attentional bias. Paired transcranial magnetic stimulation (TMS) techniques, with a subthreshold conditioning stimulus (CS) followed at various interstimulus intervals (ISIs) by a suprathreshold test stimulus (TS), are useful for investigating intracortical inhibition and facilitation in the human motor cortex. In the present work, we investigated the effects of paired TMS over the posterior parietal and frontal cortex of the unaffected hemisphere in a group of eight right-brain-damaged patients with tactile extinction who were carrying out a bimanual tactile discrimination task. The aim of the study was to verify if paired TMS could induce selective inhibition or facilitation of the unaffected hemisphere depending on the ISI, resulting, respectively, in an improvement and a worsening of contralesional extinction. In addition, we wanted to investigate if the effects of parietal and frontal TMS on contralesional extinction appeared at different intervals, suggesting time-dependent activation in the cortical network for the processing of tactile spatial information. Paired TMS stimuli with a CS and a TS, separated by two ISIs of 1 and 10 ms, were applied over the left parietal and frontal cortex after various intervals from the presentation of bimanual cutaneous stimuli. Single-test parietal TMS stimuli improved the patients' performance, whereas paired TMS had distinct effects depending on the ISI: at ISI = 1 ms the improvement in extinction was greater than that induced by single-pulse TMS; at ISI = 10 ms we observed worsening of extinction, with complete reversal of the effects of single-pulse TMS. Compared with TMS delivered over the frontal cortex, parietal TMS improved the extinction rate in a time window that began earlier. These findings shed further light on the mechanism of tactile extinction, suggesting relative hyperexcitability of the parieto-frontal network in the unaffected hemisphere, which is amenable to study and modulation by paired TMS pulses. In addition, the results show time-dependent processing of tactile spatial information in the parietal and frontal cortices, with a bimodal distribution of activity, at least in the attentional network of the unaffected hemisphere.

It has recently been demonstrated that soleus motor-evoked potentials (MEPs) are facilitated prior to the onset of dorsiflexion. The purpose of this study was to examine if this could be explained by removal of spinal inhibition of the descending command to soleus motoneurons. To test this, we investigated how afferent inputs from the tibialis anterior muscle modulate the corticospinal activation of soleus spinal motoneurons at rest, during static contraction and prior to movement. MEPs activated by transcranial magnetic stimulation (TMS) and Hoffmann reflexes (H-reflexes), activated by electrical stimulation of the posterior tibial nerve (PTN), were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning-test (CT) intervals. MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms, and they were facilitated for CT intervals of 50-55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF) and long-latency facilitation (LLF) of the soleus H-reflex induced by a subthreshold TMS pulse at different CT intervals. SLF is known to reflect the excitability of the fastest conducting, corticomotoneuronal cells whereas LLF is believed to be caused by more indirect descending pathways. At CT intervals of 40-45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55 ms) was similar prior to dorsiflexion and at rest, no inhibition could be evoked at the earlier latency (CT interval: 35 ms) prior to onset of dorsiflexion. The observation that the CPN-induced inhibition of soleus MEPs disappears prior to onset of dorsiflexion may explain why soleus MEPs are facilitated prior to onset of dorsiflexion contraction. A possible mechanism involves the removal of inhibition of the descending command to the motoneurons at a spinal interneuronal level because the inhibition was seen in LLF and not in SLF, and the MEP inhibition was not observed in the H-reflex. The data illustrate that spinal interneuronal pathways modify descending commands to human spinal motoneurons and influence the size of MEPs elicited by TMS.

Background: In spinal paired associative stimulation (PAS), orthodromic and antidromic volleys elicited by transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) coincide at corticomotoneuronal synapses at the spinal cord. The interstimulus interval (ISI) between TMS and PNS determines whether PAS leads to motor-evoked potential (MEP) potentiation or depression. PAS applied as a long-term treatment for neurological patients might alter conduction of neural fibers over time. Moreover, measurements of motoneuron conductance for determination of ISIs may be challenging in these patients.Results: We sought to design a PAS protocol to induce MEP potentiation at wide range of ISIs. We tested PAS consisting of high-intensity (100% stimulator output, SO) TMS and high-frequency (50 Hz) PNS in five subjects at five different ISIs. Our protocol induced potentiation of MEP amplitudes in all subjects at all tested intervals. TMS and PNS alone did not result in MEP potentiation. The variant of PAS protocol described here does not require exact adjustment of ISIs in order to achieve effective potentiation of MEPs.Conclusions: This variant of PAS might be feasible as a long-term treatment in rehabilitation of neurological patients.

Promoting endogenous associative plasticity in human primary motor cortex

A novel variant of paired-associative stimulation (PAS) consisting of high-frequency peripheral nerve stimulation (PNS) and high-intensity transcranial magnetic stimulation (TMS) above the motor cortex, called high-PAS, can lead to improved motor function in patients with incomplete spinal cord injury. In PAS, the interstimulus interval (ISI) between the PNS and TMS pulses plays a significant role in the location of the intended effect of the induced plastic changes. While conventional PAS protocols (single TMS pulse often applied with intensity close to resting motor threshold, and single PNS pulse) usually require precisely defined ISIs, high-PAS can induce plasticity at a wide range of ISIs and also in spite of small ISI errors, which is helpful in clinical settings where precise ISI determination can be challenging. However, this also makes the determination of high-PAS level of plasticity induction more challenging and calls for more research on the mechanism of action of high-PAS. We sought to determine if the TMS-induced orthodromic activation in upper motor neurons and PNS-induced antidromic activation in lower motor neurons arriving simultaneously to the intervening synapses at the spinal cord level can be shown to induce acute changes at the targeted location, unlike an otherwise identical but cortically targeted equivalent. Ten healthy subjects participated in two separate sessions, where high-PAS induced activation was set to target spinal (SPINAL) or cortical (CORTICAL) levels with ISI manipulation between otherwise identically applied TMS and PNS pulses. The outcomes were assessed with motor-evoked potentials (MEPs) and Hoffmann (H)-reflex before (PRE), immediately after, and 30 and 60 min after (POST, POST30, POST60) the intervention. MEPs were significantly enhanced in both interventions. In the SPINAL but not in the CORTICAL session, maximal H-reflex amplitudes significantly increased at two timepoints, indicating an increase in spinal excitability. The H/M ratio (maximal H-reflex normalized to maximal M-wave) also showed a significant increase from PRE to POST30 timepoint in the SPINAL session when compared with the CORTICAL equivalent. These results confirm that spinally targeted high-PAS with individualized ISIs indeed has an effect at the spinal level in the sensorimotor system. High-PAS is a novel PAS variant that has shown promising results in motor rehabilitation of individuals with SCI and these new findings contribute to the understanding of its mechanism of action. This provides further evidence for high-PAS as an option for clinical settings to target plasticity at different levels of the corticospinal tract.

We thank Pompéia and colleagues for their insightful comments on our recent paper (Di Lazzaro et al. 2005b) in which we demonstrate that measures of transcranial magnetic stimulation (TMS) provide an opportunity to segregate physiologically relevant differences of benzodiazepine action in the intact human brain. By using paired pulse TMS protocols, or by coupling of peripheral nerve stimulation with TMS of the contralateral motor cortex, it is possible to recruit specific neuronal circuits of the human brain and to evaluate in vivo the effects of drugs on several neurotransmitter systems (Ziemann, 2004). The short latency inhibitory effect produced by peripheral nerve stimulation on the excitability of the contralateral motor cortex is known as short latency afferent inhibition (SAI). SAI tests an inhibitory circuit in motor cortex (Tokimura et al. 2000) that is controlled by central cholinergic activity: SAI is decreased by the muscarinic receptor antagonist scopolamine in normal subjects (Di Lazzaro et al. 2000b), is significantly reduced in Alzheimer's disease patients and, in these patients, can be increased by acetylcholinesterase inhibitors (Di Lazzaro et al. 2005a). A particular paired pulse TMS protocol (Kujirai et al. 1993) elicits short latency intracortical inhibition (SICI). SICI tests an inhibitory circuit in motor cortex in which neurotransmission through the GABAA receptor is involved (Ziemann et al. 1996; Di Lazzaro et al. 2000a; Ilic et al. 2002) while, in contrast to SAI, this measure is not modified by scopolamine (Di Lazzaro et al. 2000b), and decreased by an acetylcholinesterase inhibitor (Korchounov et al. 2005). Thus, evaluation of the effects of benzodiazepines on SAI and SICI provides a novel and fascinating opportunity to evaluate their effects on distinct inhibitory circuits in human motor cortex. In our recent study (Di Lazzaro et al. 2005b), we provide evidence, for the first time, for a dissociation of lorazepam and a ‘classical benzodiazepine’ (diazepam) on these measures. While both drugs enhance SICI, lorazepam decreases SAI and diazepam increases it. This dissociation may contribute to our understanding of why these two benzodiazepines impair memory function differently. What makes lorazepam different from other benzodiazepines remains unknown though Pompéia and colleagues suggest in their letter that a possible explanation for the atypical effects of lorazepam might be that it has a unique binding profile, possibly to as yet uncharacterized benzodiazepine receptors. This idea bears much similarity with our as yet unproven proposal that lorazepam and diazepam differ in their affinity to subtypes of the GABAA receptor bearing different alpha-units (Di Lazzaro et al. 2005b). If we conceive SAI as a GABAergic cortical inhibition positively controlled by acetylcholine, then the dissociation between lorazepam and diazepam on SAI may be caused by the GABAA receptor that mediates inhibition in the GABAergic motor cortical SAI circuit, or the GABAA receptor that controls release of acetylcholine at brainstem or intracortical levels (Giorgetti et al. 2000). According to the first scenario, which we speculated upon in our recent paper (Di Lazzaro et al. 2005b), lorazepam and diazepam both reduce acetylcholine release to a similar extent, therefore exerting a similar depression on SAI, but diazepam is significantly more effective than lorazepam in enhancing inhibition in the GABAergic motor cortical SAI circuit. This could explain the observed net effect of increased SAI under diazepam but decreased SAI under lorazepam (Di Lazzaro et al. 2005b). The second scenario, which is equally possible, is that lorazepam decreases acetylcholine release more effectively than diazepam while both drugs have similar effects on inhibition in the GABAergic SAI circuit, again resulting in the same dissociating net effects on SAI as above. If true, this would indicate that measures of TMS can be applied to probe cortical inhibition at the level of different subtypes of GABAA receptors. This would be a major advance, not only in comparison to psychophysical studies and less specific electrophysiological studies (Itil et al. 1989; Pompéia et al. 2003), as quoted by Pompéia and colleagues in their letter to the editor, but also in comparison to all previous TMS drug studies (Ziemann, 2004). The significance of this research lies in the fact that cortical GABAergic interneurones are highly diverse and operate with a corresponding diversity of GABAA receptor subtypes in controlling developmental plasticity and behaviour (Fagiolini et al. 2004; Möhler et al. 2004). We agree with Pompéia and colleagues that much more needs to be done, including dose–response curves and testing of other atypical benzodiazepines, to corroborate the view that TMS can distinguish non-invasively and at the systems level of human cerebral cortex between neuronal circuits bearing different GABAA receptor subtypes. However, it appears that a first step towards this important goal has been achieved.

For clinical application of transcranial static magnetic stimulation (tSMS), it is important to achieve a focal target cortical stimulation. Previous study suggested that the associative stimulation combining non-invasive stimulation of the motor cortex (M1) and the peripheral nerve stimulation (PNS) may be useful to produce cortical excitability change. To test this hypothesis, we measured the M1 excitability and intracortical circuits by using transcranial magnetic stimulation (TMS) before and after the tSMS of short duration (5 min) combined with PNS. Thirty-three normal volunteers were participated; tSMS+PNS (n = 11), sham+PNS (n = 11), and tSMS alone (n = 11). We found the transient suppression of the motor-evoked potential (MEP) of the right abductor pollicis brevis (APB) muscle, but not of the abductor digiti minimi (ADM) muscle, when combining tSMS with PNS over median nerve at the wrist. The lack of suppressive effect on APB in tSMS alone with short duration is in accord with the previous observation. In addition, the tendency of transient enhancement of the short-latency intracortical inhibition was observed immediately after intervention in the tSMS±PNS group. These findings show that the combination of tSMS and PNS can induce the cortical excitability change in target cortical motor area and potentiate the suppression effect.

The use of F-response in defining interstimulus intervals appropriate for LTP-like plasticity induction in lower limb spinal paired associative stimulation.

Aerobic exercise, including graded exercise testing (GXT), may cause neurophysiological changes of circuits in the primary motor cortex (M1) related to mechanisms of fatigue and/or plasticity. Investigating M1 inhibitory circuit changes over time in exercising compared to non-exercising muscles after GXT of the upper limbs (UL) and lower limbs (LL) may distinguish between different post-exercise mechanisms. PURPOSE: To evaluate M1 inhibitory circuit changes resulting from UL and LL GXT and determine their associations with fitness. METHODS: Six healthy subjects (30 ± 6 yrs) participated. Transcranial Magnetic Stimulation (TMS), Peripheral Nerve Stimulation (PNS), and Electromyography (EMG) were used for neurophysiological testing. Gas analysis was performed to evaluate VO2max (UL: 24.2 ± 4.8, LL: 35.1 ± 5.9 mL/kg/min) during GXTs. Surface electrodes were placed over the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. Measures of M1 and M1-related afferent inhibition included cortical silent period (CSP) and short-latency afferent inhibition (SAI), respectively. SAI inter-stimulus intervals (ISI) between PNS and TMS stimulations were 21-23ms (UL), and 32-35ms (LL). TMS coil orientation (CO) was altered between posterior-anterior (PA) and anterior-posterior (AP) for both measures of CSP and SAI. CSP and SAI were taken 0-45 min (POST1) and 45-90 min (POST2) post-exercise and compared to pre-exercise. Repeated measures ANOVAs were performed to evaluate effects of exercise type, CO, time, and ISI. RESULTS: CSP decreased at POST1 and increased at POST2 in FDI (97.9 ± 1.2% vs. 104.5 ± 2.5%, p < 0.05) with a trend toward significance in TA (99.3 ± 2.5% vs. 103.5 ± 4.9%, p = 0.19). Although SAI was found for the TA at 32ms (p<0.05) and FDI at 21-23ms (p < 0.05), the interaction of exercise type, CO, and ISI did not reach significance after Huynh-Feldt correction (FDI: p = 0.10, TA: p = 0.10). Univariate linear regression of VO2max and SAI revealed a potential relationship reliant on exercise type and CO (UL: R2 = 0.91, LL: R2 = 0.68). CONCLUSIONS: Changes in CSP suggest that exercise may cause early disinhibition followed by greater inhibition in M1 while changes in SAI may be influenced by fitness levels. Collectively, the results support UL and LL GXTs cause measurable M1 neurophysiological changes.

Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) are noninvasive techniques used to induce muscle contraction, aiding motor function restoration in individuals with neurological disorders. Understanding sensory inputs from PNS and MPS is crucial for facilitating neuroplasticity and restoring impaired motor function. Although previous studies suggest that MPS could induce Ia-sensory inputs less than PNS, experimental evidence supporting this claim is insufficient. Here, we implemented a conditioning paradigm combining transcutaneous spinal cord stimulation (tSCS) with PNS or MPS to investigate their Ia-sensory inputs. This paradigm induces postactivation depression of spinal reflexes associated with transient decreases in neurotransmitter release from Ia-afferent terminals, allowing us to examine the Ia-sensory input amount from PNS and MPS based on the depression degree. We hypothesized that MPS would induce less postactivation depression than PNS. Thirteen individuals underwent MPS and PNS on the soleus muscle as conditioning stimuli, with tSCS applied to the skin between the spinous processes (L1-L2) as test stimuli. PNS- and MPS-conditioned spinal reflexes were recorded at five interstimulus intervals (ISIs) and four intensities. Results revealed that all PNS conditioning showed significant decreases in spinal reflex amplitudes, indicating postactivation depression. Furthermore, PNS conditioning exhibited greater depression for shorter ISIs and higher conditioning intensities. In contrast, MPS conditioning demonstrated intensity-dependent depression, but without all-conditioning depression and clear ISI dependency as seen in PNS conditioning. In addition, PNS induced significantly greater depression than MPS across most conditions. Our findings provide experimental evidence supporting the conclusion that MPS activates Ia-sensory nerves less than PNS.NEW & NOTEWORTHY Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) induce neuroplasticity, but differences in their effects on Ia-sensory inputs are unclear. We investigated their Ia-sensory inputs using a conditioning paradigm with spinal reflexes. Results showed that PNS conditioning significantly inhibited spinal reflexes than MPS conditioning, indicating greater postactivation depression due to Ia-sensory nerve activation. These findings provide experimental evidence that MPS activates Ia-sensory nerves to a lesser extent than PNS, enhancing our understanding of neuroplasticity.