Impaired Modulation of Corticospinal Excitability in Drug-Free Patients With Major Depressive Disorder: A Theta-Burst Stimulation Study

Transcranial Magnetic Stimulation (TMS) is a growing therapy for a variety of psychiatric and neurological disorders that arise from or are modulated by cortical regions of the brain represented by singular 3D target points. These target points are often determined manually with assistance from a pre-operative T1-weighted MRI, although there is growing interest in automatic target point localisation using an atlas. However, both approaches can be time-consuming which has an effect on the clinical workflow and the latter does not take into account patient variability such as the varying number of cortical gyri where these targets are located. Methods: This paper proposes a multi-resolution convolutional neural network for point localisation in MR images for a priori defined points in increasingly finely resolved versions of the input image. This approach is both fast and highly memory efficient, allowing it to run in high-throughput centres, and has the capability of distinguishing between patients with high levels of anatomical variability. Results: Preliminary experiments have found the accuracy of this network to be 7.26 ± 5.30 mm, compared to 9.39 ± 4.63 mm for deformable registration and 6.94 ± 5.10 mm for a human expert. For most treatment points, the human expert and proposed CNN statistically significantly outperform registration, but neither statistically significantly outperforms the other, suggesting that the proposed network has human-level performance. Conclusions: The

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“…This registration method has previously been used in research studies performed using the same centre's technology. [4,7,18]…”

Section: Comparative Methodsmentioning

confidence: 99%

Automatic cortical target point localisation in MRI for transcranial magnetic stimulation via a multi-resolution convolutional neural network

et al. 2021

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“…We achieved our a priori sample size estimations (30) based on data from previous studies. To detect a medium to large-sized effect for cortical plasticity (η 2 = 0.12) with a power of 80% and a significance level of 0.025 (Bonferroni corrected), we needed a sample size of minimal 7 subjects per group (patient and control groups) (7,8). To detect a large-sized effect for cortical inhibition (SICI: η 2 = 0.22; CSP: d = 1.02) with a power of 80% and a significance level of 0.025, we needed a sample size of minimal 7 and 17 subjects per group, respectively (18).…”

Section: Subjectsmentioning

confidence: 99%

“…In addition, due to its shorter duration and low stimulus intensity, the iTBS paradigm is less demanding than PAS and therefore more suitable to use in severely depressed patients. Vignaud et al (8) showed impaired cortical plasticity upon iTBS in MDD treatmentresistant patients, although they observed high variability in the response to iTBS. There are only a few studies of cortical plasticity in MDD patients, in which the effect of psychoactive drug use and the variation in depression severity has remained unclear.…”

Section: Introductionmentioning

confidence: 99%

“…A previous study reported significant performance impairment in three learning tasks in MDD patients (5). Based on neurophysiological findings, previous studies hypothesized that cortical plasticity is impaired in patients with MDD (6)(7)(8)(9). These studies made use of Transcranial Magnetic Stimulation (TMS), a neurophysiologic technique to assess inhibitory and excitatory neurotransmission in the motor cortex via single-pulse stimulations, as well as the modulation of cortical excitability via TMS paradigms (10).…”

Section: Introductionmentioning

confidence: 99%

“…Reduced cortical plasticity was shown in 23 and 27 MDD patients, taking psychotropic drugs at the time of measurement, in response to the paradigm of paired associative stimulation (PAS) (6,7). Recently, one study investigated cortical plasticity in 11 drug-free MDD patients with the intermittent theta-burst stimulation (iTBS) paradigm (8). The iTBS paradigm bears a strong resemblance with the methodology used in ex vivo preclinical studies to measure LTP (11).…”

Section: Introductionmentioning

confidence: 99%

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Cortical Inhibition and Plasticity in Major Depressive Disorder

et al. 2022

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BackgroundMajor depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls.MethodsWe measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls.ResultsThe overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group (t(17) = −2.8, p = 0.01), whereas no potentiation was observed in patients.ConclusionsPotentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size.SignificanceThese findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients.

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Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder

et al. 2022

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ImportanceThe antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)–receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD.ObjectiveTo test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD.Design, Setting, and ParticipantsThis was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level).InterventionsParticipants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4.Main Outcomes and MeasuresThe primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores.ResultsA total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, −6.15; 95% CI, −2.43 to −9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred.Conclusions and RelevanceFindings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation.Trial RegistrationClinicalTrials.gov Identifier: NCT03937596

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Impaired Modulation of Corticospinal Excitability in Drug-Free Patients With Major Depressive Disorder: A Theta-Burst Stimulation Study

Cited by 10 publications

References 40 publications

Automatic cortical target point localisation in MRI for transcranial magnetic stimulation via a multi-resolution convolutional neural network

Automatic cortical target point localisation in MRI for transcranial magnetic stimulation via a multi-resolution convolutional neural network

Cortical Inhibition and Plasticity in Major Depressive Disorder

Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder

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