Acute TMS/fMRI response explains offline TMS network effects - An interleaved TMS-fMRI study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an FDA-approved therapeutic option for treatment resistant depression. However, exact mechanisms-of-action are not fully understood and individual responses are variable. Moreover, although previously suggested, the exact network effects underlying TMS' efficacy are poorly understood as of today. Although, it is supposed that DLPFC stimulation indirectly modulates the sgACC, recent evidence is sparse. METHODS: Here, we used concurrent interleaved TMS/fMRI and state-of-the-science purpose-designed MRI head coils to delineate networks and downstream regions activated by DLPFC-TMS. RESULTS: We show that regions of increased acute BOLD signal activation during TMS resemble a resting-state brain network previously shown to be modulated by offline TMS. There was a topographical overlap in wide spread cortical and sub-cortical areas within this specific RSN#17 derived from the 1000 functional connectomes project. CONCLUSION: These data imply a causal relation between DLPFC-TMS and activation of the ACC and a broader network that has been implicated in MDD. In the broader context of our recent work, these data imply a direct relation between initial changes in BOLD activity mediated by connectivity to the DLPFC target site, and later consolidation of connectivity between these regions. These insights advance our understanding of the mechanistic targets of DLPFC-TMS and may provide novel opportunities to characterize and optimize TMS therapy in other neurological and psychiatric disorders.

Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex.

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.

Modulation of the Direction and Magnitude of Hebbian Plasticity in Human Motor Cortex by Stimulus Intensity and Concurrent Inhibition.

BACKGROUND: The mechanisms mediating the efficacy and variability of paired associative stimulation (PAS), thought to be mediated by Hebbian plasticity, remain incompletely understood. The magnitude and direction of Hebbian plasticity may be modulated by the level of neural depolarisation, which is influenced by stimulation intensity and interactions with cortical circuits. HYPOTHESIS: PAS effects would be influenced by the intensity of transcranial magnetic stimulation (TMS) and interaction with other circuits. In particular, PAS would be inhibited by concurrent inhibitory input following median nerve stimulation, known as short latency afferent inhibition (SAI). METHODS: PAS was tested at an interstimulus interval (ISI) 2 ms or 6 ms longer than the N20 peak of the median nerve somatosensory-evoked potential (PASN20+2, PASN20+6). PASN20+2 was tested at three different TMS intensities. Short interval intracortical facilitation and inhibition were tested in the presence of SAI (SICFSAI, SICISAI). RESULTS: The propensity for long term potentiation like effects increased with higher PASN20+2 TMS stimulus intensity, whereas long term depression like effects ensued at subthreshold intensity. Stronger SAI correlated with weaker PAS LTP-like effects across individuals. PASN20+2 (maximal SAI) was less effective than PASN20+6 (weak SAI). SICFSAI or SICISAI did not influence PAS response. CONCLUSION: Inter-individual differences in SAI contribute to the variability in PAS efficacy. The magnitude and direction of PAS effects is modulated by TMS intensity. Together, these findings indicate that the level of neural activity induced by stimulation likely plays a crucial role in determining the direction and magnitude of Hebbian plastic effects evoked by PAS in human cortex.

Evidence for high-fidelity timing-dependent synaptic plasticity of human motor cortex.

A single transcranial magnetic stimulation (TMS) pulse typically evokes a short series of spikes in corticospinal neurons [known as indirect (I)-waves] which are thought to arise from transynaptic input. Delivering a second pulse at inter-pulse intervals (IPIs) corresponding to the timing of these I-waves leads to a facilitation of the response, and if stimulus pairs are delivered repeatedly, a persistent LTP-like increase in excitability can occur. This has been demonstrated at an IPI of 1.5 ms, which corresponds to the first I-wave interval, in an intervention referred to as ITMS (I-wave TMS), and it has been argued that this may have similarities with timing-dependent plasticity models. Consequently, we hypothesized that if the second stimulus is delivered so as not to coincide with I-wave timing, it should lead to LTD. We performed a crossover study in 10 subjects in which TMS doublets were timed to coincide (1.5-ms IPI, ITMS(1.5)) or not coincide (2-ms IPI, ITMS(2)) with I-wave firing. Single pulse motor-evoked potential (MEP) amplitude, resting motor threshold (RMT), and short-interval cortical inhibition (SICI) were measured from the first dorsal interosseous (FDI) muscle. After ITMS(1.5) corticomotor excitability was increased by ~60% for 15 min (P < 0.05) and returned to baseline by 20 min. Increasing the IPI by just 500 µs to 2 ms reversed the aftereffect, and MEP amplitude was significantly reduced (~35%, P < 0.05) for 15 min before returning to baseline. This reduction was not associated with an increase in SICI, suggesting a reduction in excitatory transmission rather than an increase in inhibitory efficacy. RMT also remained unchanged, suggesting that these changes were not due to changes in membrane excitability. Amplitude-matching ITMS(2) did not modulate excitability. The results are consistent with timing-dependent synaptic LTP/D-like effects and suggest that there are plasticity mechanisms operating in the human motor cortex with a temporal resolution of the order of a few hundreds of microseconds.

Electromyographic bursting following the cortical silent period induced by transcranial magnetic stimulation.

In subjects performing voluntary background contraction, transcranial magnetic stimulation (TMS) induces an interruption of electromyographic (EMG) activity known as the silent period (SP). This is thought to be mediated through the action of inhibitory cortical neurons, in particular involving γ-aminobutyric acid type B (GABA(B)) receptors. In some studies of the SP, a post-SP increase in EMG activity has been reported but not described in detail. In the present study we have sought to determine the presence and persistence of late EMG bursting associated with the return of voluntary drive after the SP, and to characterize the relationship to background contraction level, stimulus intensity, and SP duration. TMS was delivered at 3 levels of intensity (120, 140 and 160% of active motor threshold) and during 3 levels of voluntary contraction of the first dorsal interosseous muscle (10, 30 and 50% of maximum contraction) in a pseudo-randomized order in 11 healthy participants. The SP was followed by a brief (~60 ms) burst of EMG up to 290±42% of the pre-stimulus EMG level. Both SP duration and the amplitude of the EMG burst increased with TMS intensity (p<0.001). Burst amplitude correlated with SP duration (r2=0.750; p=0.003). We conclude that post-SP EMG bursting is a quantifiable phenomenon that depends on the strength of TMS and the duration of the SP. This bursting may correspond with the post inhibitory period of disinhibition that has recently been identified in human motor cortex.

Inhibitory and disinhibitory effects on I-wave facilitation in motor cortex.

A suprathreshold pulse of transcranial magnetic stimulation (TMS) delivered to human motor cortex results in a period of long-interval intracortical inhibition (LICI) followed by a briefer period of disinhibition (late cortical disinhibition [LCD]). Short-interval intracortical facilitation (SICF) is mediated by excitatory networks in the motor cortex responsible for the generation of the indirect (I-) wave volleys that are evoked by TMS at a periodicity of about 1.5 ms. Because the excitatory synaptic network responsible for SICF undergoes inhibitory regulation, we hypothesized that SICF will be modulated during periods of inhibition and disinhibition. In particular we were interested to know whether SICF was up-regulated during disinhibition, implying an increase in excitatory synaptic efficacy. We measured SICF, at a paired-pulse interval of 1.5 ms, at various times (100-300 ms) after a suprathreshold priming stimulus (PS) of sufficient strength to evoke LICI and LCD. We found that the strength of SICF was normal during LICI, but was increased during LCD by an average of 64%. SICF onset latency was reduced by one I-wave interval during LCD and was delayed by one I-wave interval during LICI. We conclude that disinhibition, rather than inhibition, modulates the excitatory neuronal networks that underlie SICF, whereas the I-wave targeted is modified by the presence of both inhibition and disinhibition and that there is therefore a dissociation between the strength and site of SICF interaction. The increase in SICF during disinhibition further indicates that this is a promising period to investigate or modulate excitatory synaptic networks while they are less constrained by ongoing levels of inhibition.

Late cortical disinhibition in human motor cortex: a triple-pulse transcranial magnetic stimulation study.

In human motor cortex transcranial magnetic stimulation (TMS) has been used to identify short-interval intracortical inhibition (SICI) corresponding to gamma-aminobutyric acid type A (GABA(A)) effects and long-interval intracortical inhibition (LICI) and the cortical silent period (SP) corresponding to postsynaptic GABA(B) effects. Presynaptic GABA(B) effects, corresponding to disinhibition, can also be identified with TMS and have been shown to be acting during LICI by measuring SICI after a suprathreshold priming stimulus (PS). The duration of disinhibition is not certain and, guided by studies in experimental preparations, we hypothesized that it may be longer-lasting than postsynaptic inhibition, leading to a period of late cortical disinhibition and consequently a net increase in corticospinal excitability. We tested this first by measuring the motor-evoked potential (MEP) to a test stimulus (TS), delivered after a PS at interpulse intervals (IPIs) < or =300 ms that encompassed the period of PS-induced LICI and its aftermath. MEP amplitude was initially decreased, but then increased at IPIs of 190-210 ms, reaching 160 +/- 17% of baseline 200 ms after PS (P < 0.05). SP duration was 181 +/- 5 ms. A second experiment established that the onset of the later period of increased excitability correlated with PS intensity (r(2) = 0.99) and with the duration of the SP (r(2) = 0.99). The third and main experiment demonstrated that SICI was significantly reduced in strength at all IPIs < or =220 ms after PS. We conclude that TMS-induced LICI is associated with a period of disinhibition that is at first masked by LICI, but that outlasts LICI and gives rise to a period during which disinhibition predominates and net excitability is raised. Identification of this late period of disinhibition in human motor cortex may provide an opportunity to explore or modulate the behavior of excitatory networks at a time when inhibitory effects are restrained.

Neuromodulation by paired-pulse TMS at an I-wave interval facilitates multiple I-waves.

Corticospinal excitability can be increased by a transcranial magnetic stimulation (TMS) intervention that delivers repeated paired TMS pulses at an I (indirect)-wave interval of 1.5 ms. This is thought to target excitatory synaptic events by reinforcing facilitatory I-wave interaction, however, it remains to be determined what effect this intervention has on the various I-wave components. In the present study we compared I-wave facilitation curves over a range of inter-pulse intervals (IPIs) encompassing the first three I-waves, before and after 15 min of a paired-pulse TMS intervention with an IPI of 1.5 ms. The three peaks in the I-wave facilitation curves occurred at the same IPIs pre- and post-intervention (1.3, 2.5 and 4.3 ms). The facilitation curves were increased in amplitude for all three I-wave peaks post-intervention (mean increase 33%), and the mean increase across all IPIs correlated with the post-intervention increase in single-pulse MEP amplitude (r = 0.77). Modelling showed that the changes in the post-intervention curves were consistent with an increase in amplitude and broadening of the individual I-wave peaks. We conclude that an iTMS intervention with an IPI of 1.5 ms is able to target multiple I-waves. The findings are consistent with existing models of I-wave generation and suggest that the intervention increases the efficacy of synaptic events associated with the generation of descending I-wave volleys.