Exploring stimulus-response characteristics of late cortical silent period in major depressive disorder

Dear Editor, The cortical silent period (cSP) measures central motor inhibition, primarily mediated by inhibitory gamma-aminobutyric acid (GABA) B interneurons, with some contribution from GABA-A and dopaminergic systems.[1,2] It is measured using single-pulse transcranial magnetic stimulation (TMS) on the motor hotspot of the contralateral muscle during voluntary contraction.[1,3] The cSP is useful for investigating cortical inhibitory mechanisms, which are often abnormal in neuropsychiatric disorders.[4] Some studies have reported the interruption of cSP by a burst of muscle activity, resulting in an additional silent period called the late cSP, which may be a component of the primary cSP.[5] However, a study in healthy volunteers identified a distinct stimulus-response relationship for late cSP, suggesting it might arise from independent mechanisms.[6] In this study, we describe the stimulus-response characteristics of late cSP observed in a patient with major depressive disorder (MDD) and comorbid psychogenic vomiting. METHODS During a TMS-based assessment of motor cortical plasticity, we observed a secondary silent period in a 20-year-old right-handed female participant enrolled in a clinical trial for treatment-resistant MDD.[7] Given the novelty of this observation in our neuromodulation center, we aimed to investigate this phenomenon further using a previously employed methodology.[6] We explained the procedure to the participant and obtained written informed consent. The safety of the TMS procedure was assessed using the TMS Adult Safety Screen. During the experiment, the participant sat comfortably with her arms resting on her thighs. Electromyography recordings were obtained from the bilateral first dorsal interossei (FDI) muscles using silver chloride electrodes in a belly tendon montage (CED 1902-11/2 electrode adapter). FDI muscle hotspots were identified bilaterally using the method recommended by Groppa et al.[1] A Cool-B70 figure-of-eight coil from the MagPro X100 (MagVenture) machine was positioned at the hotspot at a 45-degree angle, with the coil handle directed posteriorly. Resting motor thresholds (RMTs) were estimated bilaterally using the modified Rossini-Rothwell method.[1] Once RMTs were determined, the cSP experiment was conducted first on the left motor cortex, with stimulus intensities (SIs) ranging from 60% to 150% of RMT.[6] The participant squeezed a smiley ball bilaterally at ~50% of their maximum strength, starting 3 seconds before the stimulus and continuing for 2 sec afterward. Ten cSP recordings were collected at each SI, with an inter-pulse interval of 5 sec, and each experimental set was separated by a 1-min interval. The same procedure was repeated on the right motor cortex, resulting in ten recordings from both sides. The entire experiment took 45 min to complete. The waveform average function of the Signal CED software version 7.07 was used to average the cSP recordings at each SI. The cSP, late cSP, and burst pulse duration were calculated following the methodology outlined in the previous study.[6] RESULTS The RMT was estimated to be 60% and 55% of the maximum stimulator output (MSO) for the right and left FDI muscles, respectively. Figure 1 displays the primary cSP, late cSP, and burst pulse durations at different SIs for both the right and left FDI muscles. The peak-to-peak motor-evoked potential (MEP) amplitudes at different SIs are also depicted. In our experiment, the cSP appeared at 80% of RMT for the right FDI and 90% of RMT for the left FDI. The cSP duration gradually increased with increasing SI, stabilizing at 140% of RMT [Figure 2]. The late cSP appeared at an SI of 110% of RMT (equivalent to 66% and 60% of MSO for the right and left FDI, respectively), persisting at this level and gradually extending to the right FDI. On the left FDI, the peak late cSP occurred at 120% of RMT, then decreased but remained stable within the 130%–150% RMT range. The burst pulse duration also increased gradually with SI. MEP amplitudes at higher SI (above 70%–90%) were relatively stable.Figure 1: Stimulus-response relationship of cSP, late cSP, burst pulse duration, and peak-to-peak MEP amplitude at different stimulus intensities (SIs) in (a) left and (b) right first dorsal interosseus (FDI) muscleFigure 2: EMG recording from right FDI at different stimulus intensities (SIs), showing the appearance of late cSP at higher SI (represented as % of resting motor threshold, RMT)DISCUSSION Our study found that the late cSP initiated at 110% of RMT (66% MSO for the right FDI and 60% MSO for the left FDI) and persisted up to 150% of RMT in both FDI muscles. This aligns with previous research showing late cSP within the 60%–80% MSO range.[8,9] Notably, the stimulus-response relationship of late cSP in our study resembled that of primary cSP but only emerged during suprathreshold stimulation. In contrast, a study on healthy volunteers found that late cSP on FDI muscles appeared within and around RMT (90%–100%) and disappeared at higher SIs, indicating a different stimulus-response relationship for primary cSP and late cSP.[6] The burst pulse duration was higher and showed a linear relationship with SI in our case, in contrast to the lower mean duration of 34–48 ms observed in healthy participants.[6] The neurophysiological basis and implications of the late cSP remain incompletely understood. While late cSP has been observed in healthy volunteers, it was absent in patients with cerebellar ataxia.[10] In contrast, a study reported a significantly higher occurrence of late cSP in the dominant hand of patients with schizophrenia compared to healthy volunteers.[8] The same group also noted multiple late cSPs in patients with restless leg syndrome compared to healthy volunteers.[9] The stimulus-response characteristics of late cSP may differ in MDD compared to other neuropsychiatric disorders. A dysfunctional behavioral activation system is associated with depression,[11] and studying cSP in depression can help elucidate motor and behavioral control in this condition. Our current study revealed the presence of late cSP in patients with MDD, persisting at suprathreshold SI, contrary to prior findings. Limitation includes observations in a single case study in MDD. Further research is warranted to elucidate the mechanisms and stimulus-response relationships of late cSP in a larger sample of various neuropsychiatric disorders. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.