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Transcranial Magnetic Stimulation Markers of Antidepressant Treatment in Adolescents With Major Depressive Disorder

Transcranial Magnetic Stimulation Markers of Antidepressant Treatment in Adolescents With Major... Background: The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes. Methods: Fifteen adolescents (age 13–17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9–17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children’s Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment. Results: Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced ( = .01) P in adj depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children’s Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment ( = 0.63; R P = .01). Conclusions: These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression. Keywords: adolescent, cortical inhibition, mood disorders, paired-pulse transcranial magnetic stimulation, short-interval intracortical inhibition Received: September 24, 2018; Revised: April 1, 2019; Accepted: May 14, 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 435 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 436 | International Journal of Neuropsychopharmacology, 2019 Significance Statement This is the first study, to our knowledge, in adolescents showing that improvement in depression severity after antidepres- sant treatment is associated with restored cortical inhibition, as indexed by short-interval cortical inhibition (SICI) measured by transcranial magnetic stimulation (TMS). These findings provide important preliminary data that will inform future studies investigating the neurobiology of adolescent depression and enable the development of better diagnostic methods and individu- alized, biomarker-guided therapeutic approaches in this population. Introduction Major depressive disorder (MDD) is one of the most common et  al., 1992; Siebner et  al., 1998; Stetkarova and Kofler, 2013) psychiatric illnesses for adolescents, with estimated 1-year and are measures of cortical inhibition and are mediated through lifetime prevalence rates of 8% and 11%, respectively. Depression GABAergic function (Ziemann, 1999, 2003). Depending on the in youth is associated with increased psychiatric comorbidities, duration of the interstimulus interval (ISI) and the intensity of suicide risk, and considerable negative impact on quality of life the conditioning stimulus, ICI can be further categorized as SICI and morbidity (Birmaher et al., 1996 P; erou et al., 2013; Avenevoli (ISIs of 2–4 milliseconds) (Hanajima et al., 1996Ziemann et  ; al., et  al., 2015). Despite available treatments, only approximately 1996; Di Lazzaro et al., 1998; Fisher et al., 2002) and long-interval 60% of patients respond to standard treatments, and remission intracortical inhibition (LICI; ISIs of 100–200 milliseconds) (Valls- rates are 30% to 40% (March et  al., 2004Cheung et  ; al., 2005; Solé et  al., 1992; Inghilleri et  al., 1993Nakam ; ura et  al., 1997; Avenevoli et al., 2015). Chen et  al., 1999; Di Lazzaro et  al., 2002), which are thought The neurobiology of depression in children and adoles- to reflect GABA and GABA receptor functioning, respectively A B cents has several potential mechanisms, including aberrant (Hanajima et  al., 1998; Werhahn et  al., 1999; Di Lazzaro et  al., neurocircuitry in the amygdala, hypothalamus, and subgenual 2000, 2002; Ilić et  al., 2002; Hanajima et  al., 2003; Pierantozzi anterior cingulate cortex; genetic and epigenetic factors; and et al., 2004; McDonnell et al., 2006). hypothalamic-pituitary-adrenal hyperactivity (Zalsman et  al., A meta-analysis of TMS studies (Radhu et  al., 2013) 2006; Henje Blom et al., 2016). Current evidence also suggests an showed impaired CSP (a measure of GABA activity) and SICI altered excitatory-inhibitory balance of cortical networks in de- (a measure of GABA activity) in adults with MDD compared pression (Levinson et al., 2010; Croarkin et al., 2011Antice ; vic and with healthy controls. Other studies of adults treated for MDD Murray, 2017). For example, studies using proton magnetic res- found a relationship between the restoration of GABAergic onance spectroscopy have shown that levels of γ-aminobutyric activity measured by TMS and antidepressant treatment acid (GABA), the main inhibitory neurotransmitter in the brain, (Manganotti et  al., 2001Sanacor ; a et  al., 2002; Robol et  al., are reduced in adults and adolescents with depression (Hasler 2004; Minelli et  al., 2010). The few studies that investigated et  al., 2007; Gabbay et  al., 2012, 2017) and that treatment with TMS correlates of depression in children and adolescents antidepressants can restore GABAergic inhibition (Manganotti have reported mixed results. Our group previously reported et al., 2001; Sanacora et al., 2002Robol et  ; al., 2004; Minelli et al., elevated ICF in medication-naïve children and adolescents 2010). In addition to reduced GABAergic inhibition, elevated glu- with depression (Croarkin et al., 2013), an association between tamate levels (Sanacora et al., 2012) and excitatory activity have pretreatment LICI deficits and poor treatment response to flu- also been associated with depression. Indeed, glutamatergic an- oxetine (Croarkin et  al., 2014a), and an inverse relationship tagonism with ketamine has been associated with antidepres- between depression severity and CSP duration (Lewis et  al., sant effects (Dutta et al., 2015). Despite these promising results in 2016). However, the adolescent TMS literature to date has con- understanding the potential role of altered excitatory-inhibitory sisted of cross-sectional studies. balance in the pathophysiology of depression, its implications in In this study, we aimed to investigate TMS correlates of lon- children and adolescents require further investigation because gitudinal treatment outcomes in children and adolescents with of the incomplete maturation of the young brain and develop- MDD. We assessed TMS measures of cortical inhibition and ex- mental shifts in excitatory-inhibitory balance in children and citability in (1) a sample of adolescents with depression who adolescents (Croarkin et al., 2014b; Hameed et al., 2017). received antidepressant pharmacotherapy, and (2) a healthy Single- and paired-pulse transcranial magnetic stimulation control comparator group. Among adolescents with MDD who (TMS) offers a noninvasive way to measure inhibitory and ex- were receiving antidepressants, we further explored pretreat- citatory activity associated with GABAergic and glutamatergic ment and posttreatment changes in TMS measures of cortical pathways, which are impaired in depression (Levinson et  al., inhibition and excitability. On the basis of prior evidence in 2010; Croarkin et  al., 2011; Radhu et  al., 2013). When coupled adults and our previous work, we hypothesized that adoles- with electromyography, TMS can quantify the stimulus effect in cents with depression would have impaired cortical inhibition the motor cortex by measuring motor-evoked potentials (MEPs). and that the improvement in depression severity would be as- TMS-induced effects on MEPs are measured with various para- sociated with enhanced cortical inhibition. digms, including intracortical inhibition (ICI), interhemispheric inhibition, cortical silent period (CSP), intracortical facilitation Materials and Methods (ICF), and motor threshold (Anand and Hotson, 2002). ICF is a measure of cortical excitability (Kujirai et  al., 1993 Hanajima ; All study procedures were approved by the institutional review et  al., 1996; Ziemann et  al., 1996) and is most likely mediated boards of Mayo Clinic and University of Texas Southwestern through N-methyl-d-aspartate glutamatergic receptor activity Medical Center. Informed consent was obtained from the par - (Liepert et al., 1997Ziemann et  ; al., 1998; Schwenkreis et al., 1999, ticipants’ legal guardians or parents, and assent was obtained 2000), whereas ICI and CSP (Day et  al., 1989a, 1989b; Cantello from adolescent participants. Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 437 abductor pollicis brevis (APB). The optimal scalp location for APB Participants stimulation was determined according to a previously published The sample consisted of treatment-seeking participants with method (Daskalakis et al., 2002). The APB location was found by MDD (age 13–17 years ) who were a subset of a sample of adoles- manual movement of the TMS coil while administering single cents recruited from clinical practices as part of a larger study pulses, followed by titration of the magnetic pulse intensity to (ClinicalTrials.gov identifier: NCT02307617). Patients were re- determine the motor threshold. This was conducted in as few cruited at Mayo Clinic (Rochester, MN). Healthy controls (age pulses as possible (maximum of 144, typically fewer than 72), 9–17 years) were recruited as part of a previous trial with iden- with a rest period of 5 minutes or longer to reduce the impact tical TMS methodology (Croarkin et  al., 2013); their data were of these preliminary single pulses on subsequent measures of included in the current analysis. Healthy participants were re- excitability and inhibition. cruited at UT Southwestern Medical Center (Dallas, Texas). Single-pulse paradigms included determination of the Inclusion criteria for depressed participants were as follows: resting motor threshold (RMT), defined as the pulse intensity to (1) MDD that was diagnosed by a clinical and research interview elicit a minimum 50-μV peak-to-peak MEP response on electro- with the Schedule for Affective Disorders and Schizophrenia for myography in 5 of 10 trials. The CSP was obtained via the de- School Age Children–Present and Lifetime Version (K-SADS-PL) livery of a single TMS pulse at 140% of RMT while participants (Kaufman et  al., 1997); (2) a minimum score of 40 on the contracted their contralateral APB at 20% of maximum contrac- Children’s Depression Rating Scale, Revised (CDRS-R) (Poznanski tion strength, as measured by a hand-held dynamometer. CSP et al., 1984; Poznanski and Mokros, 1996) and a score of 4 or more duration was measured from the TMS pulse to the spontaneous on the Clinical Global Impression–Severity (CGI-S) (Guy, 1976) resumption of motor activity on electromyography. Mean CSP consistent with at least moderate depressive symptom severity; duration was calculated from 10 trials. and (3) no use of stimulant or benzodiazepine medications on For the paired-pulse SICI and ICF paradigms, the condi- the day of TMS assessments. A  board-certified child and ado- tioning stimulus was set to 80% of each participant’s RMT, while lescent psychiatrist (P.E.C.) completed all clinical interviews, the subsequent test stimulus was delivered at the intensity K-SADS-PL interviews, and clinical rating scales. that resulted in a peak-to-peak MEP amplitude of 1 mV. SICI Potential patients and controls were ineligible for the study was tested using ISIs of 2 or 4 milliseconds, and ICF was tested if they had a contraindication to TMS, as assessed by the TMS using ISIs of 10, 15, or 20 milliseconds. LICI was tested using 2 Adult Safety Screen (Keel et  al., 2001). Contraindications were identical suprathreshold stimuli (both calibrated to evoke 1-mV a history of unprovoked seizures, seizure disorder, history of peak-to-peak amplitude MEPs) separated by ISIs of 100, 150, or febrile seizures, family history of epilepsy, prior neurosurgery, 200 milliseconds. SICI, LICI, and ICF were recorded as the ratio or brain tumor. Potential controls were excluded if they had a of the conditioned MEP amplitude (elicited by the test [second] personal history of psychiatric treatment or psychotropic medi- stimulus) to the mean unconditioned MEP amplitude. A condi- cations, or a family history (first- or second-degree relatives) of tioned/unconditioned MEP amplitude ratio <1.0 indicated net psychiatric illness. inhibition, whereas a ratio >1.0 indicated net facilitation. Twelve trials at each ISI were performed (10 trials for LICI) and averaged. Study Overview and Clinical Measures The CDRS-R, K-SADS-PL, CGI-S, Edinburgh Handedness Statistical Analysis Inventory (Oldfield, 1971), and Columbia Suicide Severity Rating Statistical analyses were performed with Stata/MP 14.1 Scale (Posner et al., 2011) were administered at baseline. Single- pulse and paired-pulse TMS measures were obtained from each (StataCorp, LLC). Continuous variables were described with means and standard deviations. Categorical variables were de- participant. Depressed participants receiving pharmacotherapy were asked to return for a follow-up visit in about 8 weeks. At scribed with frequencies and percentages. Demographic and clinical variables were compared with tests for cate χ gorical follow-up, they again underwent assessment with single- and paired-pulse TMS and clinical measures (CDRS-R, CGI-S, Clinical variables and t tests for continuous variables. Healthy participants and depressed participants were com- Global Impression–Improvement, and Columbia Suicide Severity Rating Scale). pared by using a robust regression model for each TMS measure in which the TMS measure was the dependent variable and The CDRS-R was used to measure baseline and follow-up de- pression severity. The CDRS-R is a clinician-rated 17-item scale “group” was the independent variable, with age and sex in- cluded as covariates. In all of our regression models, we used a that incorporates scores from a parent and the adolescent to de- termine a composite score. All study participants completed the “robust regression” analysis (Stata/MP 14.1, StataCorp, LLC) that allows weighted analysis for outliers based on the residuals. CDRS-R. For the depressed patients who returned for follow-up, the difference between baseline and follow-up scores was calcu- Posthoc correction for multiple comparisons was completed by the Bonferroni method for a total of 9 comparisons. lated to quantify change in depressive symptoms that occurred during the treatment period. For the subgroup of depressed participants who returned for follow-up assessments after treatment with antidepressant medication, the associations between the change in depression TMS severity (ΔCDRS-R) and the change in TMS measures between Magnetic pulses were generated by Magstim 200 magnetic baseline and follow-up visits was tested in a robust regression stimulators connected via a BiStim Module (Magstim Co. Ltd). model. The change in CDRS-R score was the dependent variable TMS measures were obtained from the left primary motor cortex, and the change in each TMS measure was the independent vari- which was stimulated with a 70-mm figure-of-8 electromagnetic able, with age and sex included as covariates. coil placed tangentially over the scalp. Participants remained Given the limited number of covariates we could add in our seated throughout the procedure and wore earplugs. MEPs were regression models, we also ran 2 exploratory sensitivity ana- recorded via surface electromyography of the contralateral lyses to test the possible effects of medications on measures Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 438 | International Journal of Neuropsychopharmacology, 2019 of cortical excitability that had significant results in the main 13% had substance use (cannabis, alcohol) that did not meet analyses. the threshold for a diagnosis of a substance use disorder. We noted significant baseline differences between groups for age (t = −2.63; P = .01), race/ethnicity (χ = 9.9; P = .02), and CDRS-R Results scores (t = −19.88; P < .001). Due to group differences in age and sex, we added these as Participant Characteristics covariates in our regression models. For race/ethnicity, given limited sample size, we did not include it as a covariate but ran Table 1 shows the demographic characteristics of the partici- secondary analyses comparing baseline TMS measures between pants. The depressed group consisted of 15 participants (9 fe- black and white participants within the healthy group, as the male; mean [SD] age, 15.4 [1.2] years; age range, 13–17  years). majority of black participants were in this group (11 of 12). No The mean (SD) length of illness was 1.3 (1.8) years. The healthy differences were found between black and white participants on control group consisted of 22 participants (11 female; mean any of the TMS excitability measures (all P > .05). [SD] age, 13.8 [2.2] years; age range, 9–17 years). Among the de- With regard to medication use, one of the depressed parti- pressed participants, 11 participants were experiencing their cipants was taking fluoxetine at the time of the baseline visit. first episode of depression, and the remaining 4 had recur- Four patients were being treated with stimulant medications, rent depression (range 2–3 episodes). Two of the patients were which were withheld on the day of TMS assessments. Of the previously treated with sertraline. Thirty-three percent of the 10 participants who later returned for follow-up assessment, depressed participants had co-morbid attention-deficit/hyper - 9 were started on antidepressant medications after the base- activity disorder, 13% had generalized anxiety disorder, 13% line visit, and 1 patient who was taking fluoxetine at baseline had posttraumatic stress disorder, 13% had dysthymia, and Table 1. Characteristics of Depressed Participants and Healthy Controls (N = 37) Characteristic Healthy Controls (n = 22) Depressed Participants (n = 15) P Value Age, y Mean (SD) 13.8 (2.2) 15.4 (1.2) .01 Range 9–17 13–17 Male sex, No. (%) 11 (50) 6 (40) .55 Race/ethnicity, No. (%) .02 White 8 (36) 13 (87) Black 11 (50) 1 (7) Hispanic 1 (5) 0 (0) Other 2 (9) 1 (7) Right handedness, No. (%) 20 (91) 13 (87) .68 Comorbid psychiatric diagnoses, No. (%) — — ADHD 5 (33) GAD 2 (13) PTSD 2 (13) Dysthymia 2 (13) Substance use 2 (13) Other 3 (20) Family history of psychiatric illness, No. (%) 0 (0) 14 (93) CDRS-R <.001 Mean (SD) 19.6 (1.6) 53.7 (7.9) Range 17–24 42–66 CGI-S — — Mean (SD) 5.0 (0.8) Range 4–6 Current mood episode duration, y — — Mean (SD) 1.3 (1.8) Range 0.1–7.0 Previous mood episode(s), No. (%) — 4 (27) — Medications after initial assessments (n = 10) — — Fluoxetine 8 (80) Bupropion 1 (10) Escitalopram 1 (10) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CDRS-R, Children’s Depression Rating Scale, Revised; CGI-S, Clinical Global Impression–Severity; DSM-IV- TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision; GAD, generalized anxiety disorder; K-SADS-PL, Schedule for Affective Disorders and Schizophrenia for School Age Children−Present and Lifetime Version; PTSD, posttraumatic stress disorder. a 2 χ or t test. Cannabis use, not meeting DSM-IV-TR diagnostic criteria for cannabis abuse or dependence on K-SADS-PL. Tic disorder (n= 1), prenatal alcohol exposure (n = 1), history of concussions (n= 1). Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 439 had a dose increase after baseline TMS and clinical measures scores, ΔCDRS-R) and change in SICI-2 and SICI-4 (ΔSICI-2; ΔSICI- were obtained. Of these 10 patients, 8 were prescribed fluoxetine 4) in robust regression models controlled for age and sex. Larger (maximum daily dose, 20–60 mg), 1 started treatment with bu- negative numbers for ΔCDRS-R indicated greater improvement propion (maximum daily dose, 150 mg), and 1 started treatment in depressive symptoms, whereas larger negative numbers for with escitalopram (maximum daily dose, 10 mg). ΔSICI-2 and ΔSICI-4 indicated greater improvement in cortical inhibition (ie, greater reduction of the conditioned/uncondi- tioned MEP amplitude ratio). Improvement in CDRS-R positively Baseline Comparison of TMS Measures correlated with improvement in ΔSICI-4 (P = .01; R = 0.63). There Between Groups was no significant relationship with ΔSICI-2 (P = .10; R = 0.33) (Figure 2). Given the variability in follow-up times among par - In the healthy group, SICI data was missing for 1 patient, ICF was ticipants (2–20 weeks), we ran a secondary analysis looking at missing for 1, LICI was missing for 3, and CSP was missing for 4 the relationship between ΔSICI and time elapsed between visits participants. There were no missing data for the patient group. using additional regression models (not age and sex controlled). Baseline comparison of groups with robust regression controlled We found no association between follow-up time and either for age and sex showed significant differences between healthy ΔSICI-2 or ΔSICI-4 (both P > .05) and depressed adolescents in SICI-2 (P = .001, R = 0.30) and SICI-4 (P = .027, R = .15). There were no significant differences between Sensitivity Analyses the healthy control and depressed groups for other TMS meas- ures, including CSP (P = .62), LICI-100 (P = .83), LICI-150 (P = .16), We performed an exploratory sensitivity analysis comparing LICI-200 (P = .80), ICF-10 (P = .13), ICF-15 (P = .10), and ICF-20 (P = .44). baseline excitability measures between healthy and depressed When corrected for multiple comparisons, only SICI-2 remained groups, excluding participants on stimulants. Results of the ro- significant (P = .01), while SICI-4 was not (P = .24). Figure 1 and bust regression analysis were similar and remained significant adj adj Table 2 show mean values of each measurement for both groups. (SICI-2: P = .007; SICI-4: P = .051), suggesting that stimulant use did not account for the baseline differences between the groups. Of note, stimulants were held on the day of assessments with the Follow-up Assessment of Depressed Participants goal of preventing the possible impact on cortical excitability Ten of the depressed participants who were treated with anti- measures. We also conducted a sensitivity analysis for patients depressant medications returned for a follow-up visit about 8 who were treated with fluoxetine (excluding the patients who weeks later (mean [SD] follow-up time, 7.9 [5.6] weeks; range, were on bupropion and escitalopram) to test the possible effects 2–20 weeks). Four continued to have clinically significant depres- of different medications on cortical excitability. Robust regres- sive symptoms based on their CDRS-R scores (scores remained sion analysis of the correlation between the change in CDRS-R ≥40). Mean (SD) changes in CDRS-R and CGI-S scores were −21.9 scores (ΔCDRS-R) and change in cortical inhibition (ΔSICI-2 and (9.26) and −2.2 (1.14), respectively. ΔSICI-4), controlled for age and sex, showed similar results (SICI- We further tested the association between the change in 2: P = .127; SICI-4: P < .001) even when excluding the patients who CDRS-R scores (the difference between follow-up and baseline were taking medications other than fluoxetine. Figure 1. Baseline transcranial magnetic stimulation (TMS) measures for depressed participants and healthy controls. Error bars represent standard error of means. (A) Comparison of short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). Numbers (e.g., SICI-2) rep- resent the interstimulus intervals in milliseconds. The asterisk indicates a significant group difference after Bonferroni correction for multiple comparisons (P = .001, P = .01). (B) Comparison of cortical silent period (CSP) duration. MEP, motor-evoked potential. adj Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 440 | International Journal of Neuropsychopharmacology, 2019 Table 2. Baseline and Follow-up Transcranial Magnetic Stimulation Measures Depressed Participants a b Measure Healthy Controls, Baseline (n = 22) Baseline (n = 15) Follow-up (n = 10) P Value adj SICI 2 ms 0.45 (0.23) 0.88 (0.39) 1.06 (0.53) .01 4 ms 0.69 (0.35) 0.98 (0.48) 1.15 (0.62) .24 ICF 10 ms 1.47 (0.55) 1.66 (0.53) 1.58 (0.67) >.99 15 ms 1.53 (0.71) 1.81 (0.84) 1.49 (0.51) .87 20 ms 1.43 (0.66) 1.71 (0.74) 1.34 (0.53) >.99 LICI 100 ms 0.20 (0.28) 0.93 (2.27) 0.31 (0.29) >.99 150 ms 0.32 (0.48) 0.76 (1.30) 0.44 (0.42) >.99 200 ms 1.39 (1.18) 1.29 (1.23) 0.60 (0.46) >.99 CSP, s 0.18 (0.04) 0.17 (0.05) 0.16 (0.03) >.99 Abbreviations: CDRS-R, Children’s Depression Rating Scale, Revised; CSP, cortical silent period; ICF, intracortical facilitation; LICI, long-interval intracortical inhibition; SICI, short-interval intracortical inhibition. a Follow-up assessment timeframe: mean [SD] follow-up time, 7.9 [5.6] weeks; range, 2–20 weeks) for a subset of depressed participants treated with antidepressant medication. b Comparison of healthy vs depressed participants at baseline. Bonferroni-corrected P values ( ). P adj c For adolescents in the follow-up group, improvement in CDRS-R positively correlated with improvement in SICI-4 (P =R .01; = 0.63). Figure 2. Scatter plot graphs showing the association between change in Children’s Depression Rating Scale, Revised (CDRS-R) (ΔCDRS-R) and change in short-interval intracortical inhibition (SICI)-2 (ΔSICI-2) and SICI-4 (ΔSICI-4). Greater improvement in CDRS-R (more negative difference) corresponded to greater improvement in - cor tical inhibition (more negative difference). DIFF, difference. studies with depressed adolescents have reported mixed results. Discussion Croarkin and colleagues (Croarkin et al., 2013) previously found To our knowledge, this is the first longitudinal study of TMS that medication-naïve children and adolescents with MDD had measures of cortical inhibition and excitability in adolescents increased ICF compared with healthy controls, but no signifi- with depression. Adolescents with moderate to severe symp- cant differences were observed for cortical inhibition measures, toms of MDD had impaired cortical inhibition compared with including SICI and CSP. However, in a separate posthoc analysis, healthy controls. Improvement in depressive symptom severity depression severity negatively correlated with ICF and CSP, des- with antidepressant treatment was associated with restored pite the absence of group differences (Lewis et al., 2016). In the cortical inhibition, as indexed by improved SICI. current study, we did not find any difference in ICF or identify Our results are consistent with prior TMS studies of adults correlations between baseline depression severity and TMS that showed impaired SICI for patients with depressive dis- measures. However, it is important to note that the group with orders, further supporting the role of impaired GAB-mediated A depression in the aforementioned adolescent studies (Croarkin cortical inhibition in depression (Croarkin et al., 2011). In a meta- et  al., 2013; Lewis et  al., 2016) differed from the sample in the analysis (Radhu et al., 2013) of 3 studies (115 adult patients with current study with regard to previous antidepressant medication MDD and 130 healthy controls), (Bajbouj et al., 2006 Lefauc ; heur history, lower mean age (13.9 vs 15.4 years), shorter disease dur - et al., 2008; Levinson et al., 2010) SICI was markedly impaired in ation (0.9 vs 1.3 years), and exclusion of other comorbid psychi- the MDD group. Results of that meta-analysis also showed short- ened CSP in MDD, suggesting impaired GABA -mediated cortical atric disorders (in the previous study). inhibition. However, we did not find any significant differences in Overall, the results of the current study suggest that older, pre- CSP in the current study. In contrast to adult studies, prior TMS viously treated adolescents with MDD and a longer duration of Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 441 illness might have cortical excitability patterns that are similar with gr eater degrees of treatment resistance would show dif- to those of depressed adults, even though adolescents may not ferent relationships between the change in depressive symp- have adult levels of cortical maturation. An intermediate level of toms and changes in LICI and CSP. maturation in our sample of adolescents with depression could Several mechanisms potentially explain how serotonergic explain some of the differences between our results and those (5-HT) activity and GABAergic activity interact. First, GABAergic of previous adult studies (e.g., shortened CSP, a marker of GABA - neurons inhibit 5-HT neurons in midbrain raphe nuclei (Tao mediated cortical inhibition, which was not present in our de- and Auerbach, 2000). Also, previous research has shown that the pressed group) while supporting other similarities (e.g., impaired serotonergic innervation of the cortex is mediated through the SICI). A  known difference between adults and children is that excitatory effects of 5-HT and 5-HT receptors on GABAergic 2A 3 children have less cortical inhibition (Mall et  al., 2004), which interneurons in the cortex, hippocampus, and amygdala (Freund might have contributed to the lack of CSP findings in our sample. et al., 1990; Jakab and Goldman-Rakic, 2000). Indeed, 5-HT and CSP also can show variability in children and adolescents (Garvey 5-HT agonists increase the activity of GABAergic interneurons and Mall, 2008) and is affected by interhemispheric differences; in these areas (Gellman and Aghajanian, 1993Abi-Saa ; b et  al., these potential confounders were not assessed in this study. 1999). These findings are consistent with aforementioned Moreover, different TMS indices may have differing patterns of studies showing temporary increases in cortical inhibition, age- or maturation-related changes along different time courses, as measured by TMS, after administration of single doses of and little is known about the developmental trajectories of TMS clomipramine (Manganotti et  al., 2001) and citalopram (Robol measures in the setting of psychiatric illness (Croarkin et  al., et  al., 2004). When administered regularly, SSRIs can induce 2014b). For example, prior work suggests that depressed children plasticity within these neural networks (Normann et  al., 2007; and adolescents might have delayed maturation of cortical ex- Liu et al., 2017). Although it is difficult to ascertain whether the citability when compared with age-matched controls (Croarkin modulation of GABAergic activity with SSRIs leads to improve- et  al., 2014b). Additionally, several other psychiatric disorders ment of depressive symptoms or whether improvement in de- in adults (Radhu et  al., 2013), as well as attention-deficit/hyper - pressive symptoms through other mechanisms leads to changes activity disorder in children (Gilbert et  al., 2011), have been as- in inhibitory and excitatory networks, our results suggest that sociated with impaired excitatory-inhibitory balance. In contrast SICI is a potential treatment target in depression because of its to previous adolescent studies, we did not exclude participants potential to index deficits in GABAergic activity. with comorbid psychiatric disorders; thus, the sample from our There are several limitations of this study. First, our sample present study may be more generalizable to adolescents encoun- size for the follow-up group was small and did not allow us to tered in typical clinical settings. control for all potential covariates of interest. We also had a The most notable finding of this study was the positive as- relatively heterogeneous group with regard to age, race/ethni- sociation between the improvement in depression severity and city, current medications, and history of prior antidepressant improvement in SICI after antidepressant therapy. Given that use. With regard to the potential impact of race or ethnicity, we SICI indirectly reflects GABA activity (Hanajima et  al., 1998; are not aware of any previous studies comparing cortical excit- Di Lazzaro et  al., 2000, 2005; Ilić et  al., 2002; Hanajima et  al., ability measures between black and white participant groups; 2003), this result suggests that restored GABAergic inhibition however, one small study showed cortical excitability differ - is associated with improved depression severity in the set- ences between Han Chinese and Caucasians (Yi et  al., 2014). ting of antidepressant treatment. Prior research in adults has On the other hand, comparisons of TMS measures, including shown restored GABAergic activity with therapeutic interven- our main findings (SICI-2, SICI-4), between black and white par- tions such as electroconvulsive therapy (Sanacora et al., 2003), ticipants within the healthy group did not show any signifi- repetitive TMS (rTMS) (Daskalakis et  al., 2006), and selective cant differences between these groups. In terms of medication serotonin reuptake inhibitors (SSRIs) (Sanacora et  al., 2002). use, our sensitivity analysis showed similar results when we Daskalakis and colleagues (Daskalakis et al., 2006) found state- excluded participants taking medications other than fluox- dependent effects of rTMS on SICI in healthy participants and etine. Although the mean age of the healthy participants was showed that those with less cortical inhibition at baseline lower than that of the depressed participants, we did control (higher SICI ratios) showed more improvement in SICI after for age in the statistical analyses. Further, younger partici- rTMS. They also showed potentiation of CSP with high- and pants would be expected to have greater SICI-2 impairment low-frequency rTMS. In a proton magnetic resonance spec- (Mall et al., 2004). Despite this age difference in our study, the troscopy study of patients with MDD, Sanacora and colleagues older depressed sample had greater SICI-2 impairment. Finally, (Sanacora et  al., 2002) showed that occipital GABA levels in- TMS testing of the motor cortex employed manual localiza- creased after treatment with SSRIs. Other studies also showed tion of the APB “hotspot.” This could introduce bias into MEP increased SICI (greater inhibition) in patients with MDD and findings based on the variability of pulses among subjects and healthy controls after administration of SSRIs (Manganotti between sessions, with potential resultant changes in cortical et  al., 2001; Robol et  al., 2004). Even though no study has as- inhibition. While our methodology attempted to mitigate the sessed longitudinal changes in TMS measures in adolescents, potential bias that this could have introduced among MEP another study of depressed adolescents from our group has measures, future studies should utilize position tracking de- shown an association between pretreatment LICI impair - vices, conventional measurement (e.g., 10–20 EEG system), or ment (which reflects GABA -mediated activity) and poor treat- neuro-navigation (Ahdab et  al., 2010). The major strength of ment response to fluoxetine, suggesting that deficits in GABA our study was being the first study, to our knowledge, to com- functioning may be associated with treatment nonresponse pare longitudinal changes in TMS measures associated with (Croarkin et  al., 2014a). In our study, almost all patients had adolescent depression before and after treatment. This study some degree of improvement in their total CDRS-R scores adds important preliminary data to the existing literature to- (range, −3 to −38), which may explain the lack of differences in ward developing target biomarkers of depression and anti- these GABA measures. It is possible that adolescent samples depressant treatment. B Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 442 | International Journal of Neuropsychopharmacology, 2019 the Centre for Addiction and Mental Health (CAMH) Foundation Conclusion and the Campbell Institute. A.I.S., A.L.N., and M.A.G.  have no In this naturalistic, longitudinal study investigating TMS financial disclosures. markers in adolescents with MDD, we showed that cortical in- hibition was impaired, with patterns somewhat similar to those References reported for adults with depression. Moreover, we showed that improvement in depression severity after antidepressant treat- Abi-Saab  WM, Bubser  M, Roth  RH, Deutch  AY (1999) 5-HT2 re- ment is associated with restored cortical inhibition, as indexed ceptor regulation of extracellular GABA levels in the pre- by SICI. This was the first study to our knowledge to investigate frontal cortex. Neuropsychopharmacology 20:92–96. longitudinal changes in TMS measures of cortical inhibition as- Ahdab R, Ayache SS, Brugières P, Goujon C, Lefaucheur JP (2010) sociated with antidepressant treatment in an adolescent popu- Comparison of “standard” and “navigated” procedures of TMS lation. These findings provide important preliminary data that coil positioning over motor, premotor and prefrontal targets will inform future studies investigating the neurobiology of in patients with chronic pain and depression. Neurophysiol adolescent depression and enable the development of better Clin 40:27–36. diagnostic methods and individualized, biomarker-guided Anand  S, Hotson  J (2002) Transcranial magnetic stimulation: therapeutic approaches in this population. neurophysiological applications and safety. Brain Cogn 50:366–386. Anticevic  A, Murray  JD (2017) Rebalancing altered computa- Funding tions: considering the role of neural excitation and inhib- This research was supported by grants from the Brain and ition balance across the psychiatric spectrum. Biol Psychiatry Behavior Research Foundation (Young Investigator Award 81:816–817. 20883), the National Institute of Mental Health (K23 MH100266 Avenevoli S, Swendsen J, He J-P, Burstein M, Merikangas KR (2015) and R01MH113700). This publication was also made possible Major depression in the National Comorbidity Survey–Ado- by the Mayo Clinic Clinical Translational Science Award (CTSA) lescent Supplement: prevalence, correlates, and treatment. J through grant number UL1TR002377 from the National Center Am Acad Child Adolesc Psychiatry 54:37–44.e32. for Advancing Translational Sciences (NCATS), a component of Bajbouj  M, Lisanby  SH, Lang  UE, Danker-Hopfe  H, Heuser  I, the National Institutes of Health (NIH). The content is solely the Neu  P (2006) Evidence for impaired cortical inhibition in responsibility of the authors and does not necessarily represent patients with unipolar major depression. Biol Psychiatry the official views of the National Institutes of Health. 59:395–400. Birmaher  B, Ryan  ND, Williamson  DE, Brent  DA, Kaufman  J, Dahl  RE, Perel  J, Nelson  B (1996) Childhood and adolescent Acknowledgments depression: a review of the past 10  years. Part I. J Am Acad The sponsors had no role in study design; in the collection, ana- Child Adolesc Psychiatry 35:1427–1439. lysis and interpretation of data; in the writing of the report; and Cantello R, Gianelli M, Civardi C, Mutani R (1992) Magnetic brain in the decision to submit the article for publication. stimulation: the silent period after the motor evoked poten- Editing, proofreading, and reference verification were provided tial. Neurology 42:1951–1959. by Scientific Publications, Mayo Clinic. Chen  R, Lozano  AM, Ashby  P (1999) Mechanism of the silent period following transcranial magnetic stimulation. Evidence from epidural recordings. Exp Brain Res 128:539–542. Statement of Interest Cheung  AH, Emslie  GJ, Mayes  TL (2005) Review of the efficacy D.D.C. receives research support from the Mayo Clinic Foundation and safety of antidepressants in youth depression. J Child Departmental Small Grant Program. C.P.L. receives research sup- Psychol Psychiatry 46:735–754. port from the Brain and Behavior Research Foundation and the Croarkin  PE, Levinson  AJ, Daskalakis  ZJ (2011) Evidence for Mayo Clinic Foundation Departmental Small Grant Program gabaergic inhibitory deficits in major depressive disorder. and is a site investigator for a multicenter studies funded by Neurosci Biobehav Rev 35:818–825. Neuronetics, Inc and NeoSync, Inc. Croarkin PE, Nakonezny PA, Husain MM, Melton T, Buyukdura JS, P.E.C.  has received research grant support from Pfizer, Kennard  BD, Emslie  GJ, Kozel  FA, Daskalakis  ZJ (2013) Evi- Inc, NIMH (K23 MH100266 and R01MH113700), the Brain and dence for increased glutamatergic cortical facilitation in chil- Behavior Research Foundation, and the Mayo Clinic Foundation. dren and adolescents with major depressive disorder. JAMA He has served as a site subprincipal or principal investigator Psychiatry 70:291–299. (without additional compensation) for Eli Lilly and Co, Forest Croarkin  PE, Nakonezny  PA, Husain  MM, Port  JD, Melton  T, Laboratories, Inc, Merck & Co, Inc, and Pfizer, Inc; has received Kennard  BD, Emslie  GJ, Kozel  FA, Daskalakis  ZJ (2014a) Evi- equipment support from Neuronetics, Inc; and receives sup- dence for pretreatment LICI deficits among depressed chil- plies and genotyping services from Assurex Health, Inc for dren and adolescents with nonresponse to fluoxetine. Brain an investigator-initiated study. He is the primary investigator Stimul 7:243–251. for a multicenter study funded by Neuronetics, Inc. He is a Croarkin PE, Nakonezny PA, Lewis CP, Zaccariello MJ, Huxsahl JE, site primary investigator for a study funded by NeoSync, Inc. Husain MM, Kennard BD, Emslie GJ, Daskalakis ZJ (2014b) De- He has consulted for Procter and Gamble. In the last 5  years, velopmental aspects of cortical excitability and inhibition Z.J.D.  has received research and equipment in-kind support in depressed and healthy youth: an exploratory study. Front for an investigator-initiated study through Brainsway, Inc. Hum Neurosci 8:669. and Magventure, Inc. 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Transcranial Magnetic Stimulation Markers of Antidepressant Treatment in Adolescents With Major Depressive Disorder

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Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.
ISSN
1461-1457
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1469-5111
DOI
10.1093/ijnp/pyz021
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Abstract

Background: The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes. Methods: Fifteen adolescents (age 13–17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9–17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children’s Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment. Results: Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced ( = .01) P in adj depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children’s Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment ( = 0.63; R P = .01). Conclusions: These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression. Keywords: adolescent, cortical inhibition, mood disorders, paired-pulse transcranial magnetic stimulation, short-interval intracortical inhibition Received: September 24, 2018; Revised: April 1, 2019; Accepted: May 14, 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 435 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 436 | International Journal of Neuropsychopharmacology, 2019 Significance Statement This is the first study, to our knowledge, in adolescents showing that improvement in depression severity after antidepres- sant treatment is associated with restored cortical inhibition, as indexed by short-interval cortical inhibition (SICI) measured by transcranial magnetic stimulation (TMS). These findings provide important preliminary data that will inform future studies investigating the neurobiology of adolescent depression and enable the development of better diagnostic methods and individu- alized, biomarker-guided therapeutic approaches in this population. Introduction Major depressive disorder (MDD) is one of the most common et  al., 1992; Siebner et  al., 1998; Stetkarova and Kofler, 2013) psychiatric illnesses for adolescents, with estimated 1-year and are measures of cortical inhibition and are mediated through lifetime prevalence rates of 8% and 11%, respectively. Depression GABAergic function (Ziemann, 1999, 2003). Depending on the in youth is associated with increased psychiatric comorbidities, duration of the interstimulus interval (ISI) and the intensity of suicide risk, and considerable negative impact on quality of life the conditioning stimulus, ICI can be further categorized as SICI and morbidity (Birmaher et al., 1996 P; erou et al., 2013; Avenevoli (ISIs of 2–4 milliseconds) (Hanajima et al., 1996Ziemann et  ; al., et  al., 2015). Despite available treatments, only approximately 1996; Di Lazzaro et al., 1998; Fisher et al., 2002) and long-interval 60% of patients respond to standard treatments, and remission intracortical inhibition (LICI; ISIs of 100–200 milliseconds) (Valls- rates are 30% to 40% (March et  al., 2004Cheung et  ; al., 2005; Solé et  al., 1992; Inghilleri et  al., 1993Nakam ; ura et  al., 1997; Avenevoli et al., 2015). Chen et  al., 1999; Di Lazzaro et  al., 2002), which are thought The neurobiology of depression in children and adoles- to reflect GABA and GABA receptor functioning, respectively A B cents has several potential mechanisms, including aberrant (Hanajima et  al., 1998; Werhahn et  al., 1999; Di Lazzaro et  al., neurocircuitry in the amygdala, hypothalamus, and subgenual 2000, 2002; Ilić et  al., 2002; Hanajima et  al., 2003; Pierantozzi anterior cingulate cortex; genetic and epigenetic factors; and et al., 2004; McDonnell et al., 2006). hypothalamic-pituitary-adrenal hyperactivity (Zalsman et  al., A meta-analysis of TMS studies (Radhu et  al., 2013) 2006; Henje Blom et al., 2016). Current evidence also suggests an showed impaired CSP (a measure of GABA activity) and SICI altered excitatory-inhibitory balance of cortical networks in de- (a measure of GABA activity) in adults with MDD compared pression (Levinson et al., 2010; Croarkin et al., 2011Antice ; vic and with healthy controls. Other studies of adults treated for MDD Murray, 2017). For example, studies using proton magnetic res- found a relationship between the restoration of GABAergic onance spectroscopy have shown that levels of γ-aminobutyric activity measured by TMS and antidepressant treatment acid (GABA), the main inhibitory neurotransmitter in the brain, (Manganotti et  al., 2001Sanacor ; a et  al., 2002; Robol et  al., are reduced in adults and adolescents with depression (Hasler 2004; Minelli et  al., 2010). The few studies that investigated et  al., 2007; Gabbay et  al., 2012, 2017) and that treatment with TMS correlates of depression in children and adolescents antidepressants can restore GABAergic inhibition (Manganotti have reported mixed results. Our group previously reported et al., 2001; Sanacora et al., 2002Robol et  ; al., 2004; Minelli et al., elevated ICF in medication-naïve children and adolescents 2010). In addition to reduced GABAergic inhibition, elevated glu- with depression (Croarkin et al., 2013), an association between tamate levels (Sanacora et al., 2012) and excitatory activity have pretreatment LICI deficits and poor treatment response to flu- also been associated with depression. Indeed, glutamatergic an- oxetine (Croarkin et  al., 2014a), and an inverse relationship tagonism with ketamine has been associated with antidepres- between depression severity and CSP duration (Lewis et  al., sant effects (Dutta et al., 2015). Despite these promising results in 2016). However, the adolescent TMS literature to date has con- understanding the potential role of altered excitatory-inhibitory sisted of cross-sectional studies. balance in the pathophysiology of depression, its implications in In this study, we aimed to investigate TMS correlates of lon- children and adolescents require further investigation because gitudinal treatment outcomes in children and adolescents with of the incomplete maturation of the young brain and develop- MDD. We assessed TMS measures of cortical inhibition and ex- mental shifts in excitatory-inhibitory balance in children and citability in (1) a sample of adolescents with depression who adolescents (Croarkin et al., 2014b; Hameed et al., 2017). received antidepressant pharmacotherapy, and (2) a healthy Single- and paired-pulse transcranial magnetic stimulation control comparator group. Among adolescents with MDD who (TMS) offers a noninvasive way to measure inhibitory and ex- were receiving antidepressants, we further explored pretreat- citatory activity associated with GABAergic and glutamatergic ment and posttreatment changes in TMS measures of cortical pathways, which are impaired in depression (Levinson et  al., inhibition and excitability. On the basis of prior evidence in 2010; Croarkin et  al., 2011; Radhu et  al., 2013). When coupled adults and our previous work, we hypothesized that adoles- with electromyography, TMS can quantify the stimulus effect in cents with depression would have impaired cortical inhibition the motor cortex by measuring motor-evoked potentials (MEPs). and that the improvement in depression severity would be as- TMS-induced effects on MEPs are measured with various para- sociated with enhanced cortical inhibition. digms, including intracortical inhibition (ICI), interhemispheric inhibition, cortical silent period (CSP), intracortical facilitation Materials and Methods (ICF), and motor threshold (Anand and Hotson, 2002). ICF is a measure of cortical excitability (Kujirai et  al., 1993 Hanajima ; All study procedures were approved by the institutional review et  al., 1996; Ziemann et  al., 1996) and is most likely mediated boards of Mayo Clinic and University of Texas Southwestern through N-methyl-d-aspartate glutamatergic receptor activity Medical Center. Informed consent was obtained from the par - (Liepert et al., 1997Ziemann et  ; al., 1998; Schwenkreis et al., 1999, ticipants’ legal guardians or parents, and assent was obtained 2000), whereas ICI and CSP (Day et  al., 1989a, 1989b; Cantello from adolescent participants. Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 437 abductor pollicis brevis (APB). The optimal scalp location for APB Participants stimulation was determined according to a previously published The sample consisted of treatment-seeking participants with method (Daskalakis et al., 2002). The APB location was found by MDD (age 13–17 years ) who were a subset of a sample of adoles- manual movement of the TMS coil while administering single cents recruited from clinical practices as part of a larger study pulses, followed by titration of the magnetic pulse intensity to (ClinicalTrials.gov identifier: NCT02307617). Patients were re- determine the motor threshold. This was conducted in as few cruited at Mayo Clinic (Rochester, MN). Healthy controls (age pulses as possible (maximum of 144, typically fewer than 72), 9–17 years) were recruited as part of a previous trial with iden- with a rest period of 5 minutes or longer to reduce the impact tical TMS methodology (Croarkin et  al., 2013); their data were of these preliminary single pulses on subsequent measures of included in the current analysis. Healthy participants were re- excitability and inhibition. cruited at UT Southwestern Medical Center (Dallas, Texas). Single-pulse paradigms included determination of the Inclusion criteria for depressed participants were as follows: resting motor threshold (RMT), defined as the pulse intensity to (1) MDD that was diagnosed by a clinical and research interview elicit a minimum 50-μV peak-to-peak MEP response on electro- with the Schedule for Affective Disorders and Schizophrenia for myography in 5 of 10 trials. The CSP was obtained via the de- School Age Children–Present and Lifetime Version (K-SADS-PL) livery of a single TMS pulse at 140% of RMT while participants (Kaufman et  al., 1997); (2) a minimum score of 40 on the contracted their contralateral APB at 20% of maximum contrac- Children’s Depression Rating Scale, Revised (CDRS-R) (Poznanski tion strength, as measured by a hand-held dynamometer. CSP et al., 1984; Poznanski and Mokros, 1996) and a score of 4 or more duration was measured from the TMS pulse to the spontaneous on the Clinical Global Impression–Severity (CGI-S) (Guy, 1976) resumption of motor activity on electromyography. Mean CSP consistent with at least moderate depressive symptom severity; duration was calculated from 10 trials. and (3) no use of stimulant or benzodiazepine medications on For the paired-pulse SICI and ICF paradigms, the condi- the day of TMS assessments. A  board-certified child and ado- tioning stimulus was set to 80% of each participant’s RMT, while lescent psychiatrist (P.E.C.) completed all clinical interviews, the subsequent test stimulus was delivered at the intensity K-SADS-PL interviews, and clinical rating scales. that resulted in a peak-to-peak MEP amplitude of 1 mV. SICI Potential patients and controls were ineligible for the study was tested using ISIs of 2 or 4 milliseconds, and ICF was tested if they had a contraindication to TMS, as assessed by the TMS using ISIs of 10, 15, or 20 milliseconds. LICI was tested using 2 Adult Safety Screen (Keel et  al., 2001). Contraindications were identical suprathreshold stimuli (both calibrated to evoke 1-mV a history of unprovoked seizures, seizure disorder, history of peak-to-peak amplitude MEPs) separated by ISIs of 100, 150, or febrile seizures, family history of epilepsy, prior neurosurgery, 200 milliseconds. SICI, LICI, and ICF were recorded as the ratio or brain tumor. Potential controls were excluded if they had a of the conditioned MEP amplitude (elicited by the test [second] personal history of psychiatric treatment or psychotropic medi- stimulus) to the mean unconditioned MEP amplitude. A condi- cations, or a family history (first- or second-degree relatives) of tioned/unconditioned MEP amplitude ratio <1.0 indicated net psychiatric illness. inhibition, whereas a ratio >1.0 indicated net facilitation. Twelve trials at each ISI were performed (10 trials for LICI) and averaged. Study Overview and Clinical Measures The CDRS-R, K-SADS-PL, CGI-S, Edinburgh Handedness Statistical Analysis Inventory (Oldfield, 1971), and Columbia Suicide Severity Rating Statistical analyses were performed with Stata/MP 14.1 Scale (Posner et al., 2011) were administered at baseline. Single- pulse and paired-pulse TMS measures were obtained from each (StataCorp, LLC). Continuous variables were described with means and standard deviations. Categorical variables were de- participant. Depressed participants receiving pharmacotherapy were asked to return for a follow-up visit in about 8 weeks. At scribed with frequencies and percentages. Demographic and clinical variables were compared with tests for cate χ gorical follow-up, they again underwent assessment with single- and paired-pulse TMS and clinical measures (CDRS-R, CGI-S, Clinical variables and t tests for continuous variables. Healthy participants and depressed participants were com- Global Impression–Improvement, and Columbia Suicide Severity Rating Scale). pared by using a robust regression model for each TMS measure in which the TMS measure was the dependent variable and The CDRS-R was used to measure baseline and follow-up de- pression severity. The CDRS-R is a clinician-rated 17-item scale “group” was the independent variable, with age and sex in- cluded as covariates. In all of our regression models, we used a that incorporates scores from a parent and the adolescent to de- termine a composite score. All study participants completed the “robust regression” analysis (Stata/MP 14.1, StataCorp, LLC) that allows weighted analysis for outliers based on the residuals. CDRS-R. For the depressed patients who returned for follow-up, the difference between baseline and follow-up scores was calcu- Posthoc correction for multiple comparisons was completed by the Bonferroni method for a total of 9 comparisons. lated to quantify change in depressive symptoms that occurred during the treatment period. For the subgroup of depressed participants who returned for follow-up assessments after treatment with antidepressant medication, the associations between the change in depression TMS severity (ΔCDRS-R) and the change in TMS measures between Magnetic pulses were generated by Magstim 200 magnetic baseline and follow-up visits was tested in a robust regression stimulators connected via a BiStim Module (Magstim Co. Ltd). model. The change in CDRS-R score was the dependent variable TMS measures were obtained from the left primary motor cortex, and the change in each TMS measure was the independent vari- which was stimulated with a 70-mm figure-of-8 electromagnetic able, with age and sex included as covariates. coil placed tangentially over the scalp. Participants remained Given the limited number of covariates we could add in our seated throughout the procedure and wore earplugs. MEPs were regression models, we also ran 2 exploratory sensitivity ana- recorded via surface electromyography of the contralateral lyses to test the possible effects of medications on measures Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 438 | International Journal of Neuropsychopharmacology, 2019 of cortical excitability that had significant results in the main 13% had substance use (cannabis, alcohol) that did not meet analyses. the threshold for a diagnosis of a substance use disorder. We noted significant baseline differences between groups for age (t = −2.63; P = .01), race/ethnicity (χ = 9.9; P = .02), and CDRS-R Results scores (t = −19.88; P < .001). Due to group differences in age and sex, we added these as Participant Characteristics covariates in our regression models. For race/ethnicity, given limited sample size, we did not include it as a covariate but ran Table 1 shows the demographic characteristics of the partici- secondary analyses comparing baseline TMS measures between pants. The depressed group consisted of 15 participants (9 fe- black and white participants within the healthy group, as the male; mean [SD] age, 15.4 [1.2] years; age range, 13–17  years). majority of black participants were in this group (11 of 12). No The mean (SD) length of illness was 1.3 (1.8) years. The healthy differences were found between black and white participants on control group consisted of 22 participants (11 female; mean any of the TMS excitability measures (all P > .05). [SD] age, 13.8 [2.2] years; age range, 9–17 years). Among the de- With regard to medication use, one of the depressed parti- pressed participants, 11 participants were experiencing their cipants was taking fluoxetine at the time of the baseline visit. first episode of depression, and the remaining 4 had recur- Four patients were being treated with stimulant medications, rent depression (range 2–3 episodes). Two of the patients were which were withheld on the day of TMS assessments. Of the previously treated with sertraline. Thirty-three percent of the 10 participants who later returned for follow-up assessment, depressed participants had co-morbid attention-deficit/hyper - 9 were started on antidepressant medications after the base- activity disorder, 13% had generalized anxiety disorder, 13% line visit, and 1 patient who was taking fluoxetine at baseline had posttraumatic stress disorder, 13% had dysthymia, and Table 1. Characteristics of Depressed Participants and Healthy Controls (N = 37) Characteristic Healthy Controls (n = 22) Depressed Participants (n = 15) P Value Age, y Mean (SD) 13.8 (2.2) 15.4 (1.2) .01 Range 9–17 13–17 Male sex, No. (%) 11 (50) 6 (40) .55 Race/ethnicity, No. (%) .02 White 8 (36) 13 (87) Black 11 (50) 1 (7) Hispanic 1 (5) 0 (0) Other 2 (9) 1 (7) Right handedness, No. (%) 20 (91) 13 (87) .68 Comorbid psychiatric diagnoses, No. (%) — — ADHD 5 (33) GAD 2 (13) PTSD 2 (13) Dysthymia 2 (13) Substance use 2 (13) Other 3 (20) Family history of psychiatric illness, No. (%) 0 (0) 14 (93) CDRS-R <.001 Mean (SD) 19.6 (1.6) 53.7 (7.9) Range 17–24 42–66 CGI-S — — Mean (SD) 5.0 (0.8) Range 4–6 Current mood episode duration, y — — Mean (SD) 1.3 (1.8) Range 0.1–7.0 Previous mood episode(s), No. (%) — 4 (27) — Medications after initial assessments (n = 10) — — Fluoxetine 8 (80) Bupropion 1 (10) Escitalopram 1 (10) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CDRS-R, Children’s Depression Rating Scale, Revised; CGI-S, Clinical Global Impression–Severity; DSM-IV- TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision; GAD, generalized anxiety disorder; K-SADS-PL, Schedule for Affective Disorders and Schizophrenia for School Age Children−Present and Lifetime Version; PTSD, posttraumatic stress disorder. a 2 χ or t test. Cannabis use, not meeting DSM-IV-TR diagnostic criteria for cannabis abuse or dependence on K-SADS-PL. Tic disorder (n= 1), prenatal alcohol exposure (n = 1), history of concussions (n= 1). Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 439 had a dose increase after baseline TMS and clinical measures scores, ΔCDRS-R) and change in SICI-2 and SICI-4 (ΔSICI-2; ΔSICI- were obtained. Of these 10 patients, 8 were prescribed fluoxetine 4) in robust regression models controlled for age and sex. Larger (maximum daily dose, 20–60 mg), 1 started treatment with bu- negative numbers for ΔCDRS-R indicated greater improvement propion (maximum daily dose, 150 mg), and 1 started treatment in depressive symptoms, whereas larger negative numbers for with escitalopram (maximum daily dose, 10 mg). ΔSICI-2 and ΔSICI-4 indicated greater improvement in cortical inhibition (ie, greater reduction of the conditioned/uncondi- tioned MEP amplitude ratio). Improvement in CDRS-R positively Baseline Comparison of TMS Measures correlated with improvement in ΔSICI-4 (P = .01; R = 0.63). There Between Groups was no significant relationship with ΔSICI-2 (P = .10; R = 0.33) (Figure 2). Given the variability in follow-up times among par - In the healthy group, SICI data was missing for 1 patient, ICF was ticipants (2–20 weeks), we ran a secondary analysis looking at missing for 1, LICI was missing for 3, and CSP was missing for 4 the relationship between ΔSICI and time elapsed between visits participants. There were no missing data for the patient group. using additional regression models (not age and sex controlled). Baseline comparison of groups with robust regression controlled We found no association between follow-up time and either for age and sex showed significant differences between healthy ΔSICI-2 or ΔSICI-4 (both P > .05) and depressed adolescents in SICI-2 (P = .001, R = 0.30) and SICI-4 (P = .027, R = .15). There were no significant differences between Sensitivity Analyses the healthy control and depressed groups for other TMS meas- ures, including CSP (P = .62), LICI-100 (P = .83), LICI-150 (P = .16), We performed an exploratory sensitivity analysis comparing LICI-200 (P = .80), ICF-10 (P = .13), ICF-15 (P = .10), and ICF-20 (P = .44). baseline excitability measures between healthy and depressed When corrected for multiple comparisons, only SICI-2 remained groups, excluding participants on stimulants. Results of the ro- significant (P = .01), while SICI-4 was not (P = .24). Figure 1 and bust regression analysis were similar and remained significant adj adj Table 2 show mean values of each measurement for both groups. (SICI-2: P = .007; SICI-4: P = .051), suggesting that stimulant use did not account for the baseline differences between the groups. Of note, stimulants were held on the day of assessments with the Follow-up Assessment of Depressed Participants goal of preventing the possible impact on cortical excitability Ten of the depressed participants who were treated with anti- measures. We also conducted a sensitivity analysis for patients depressant medications returned for a follow-up visit about 8 who were treated with fluoxetine (excluding the patients who weeks later (mean [SD] follow-up time, 7.9 [5.6] weeks; range, were on bupropion and escitalopram) to test the possible effects 2–20 weeks). Four continued to have clinically significant depres- of different medications on cortical excitability. Robust regres- sive symptoms based on their CDRS-R scores (scores remained sion analysis of the correlation between the change in CDRS-R ≥40). Mean (SD) changes in CDRS-R and CGI-S scores were −21.9 scores (ΔCDRS-R) and change in cortical inhibition (ΔSICI-2 and (9.26) and −2.2 (1.14), respectively. ΔSICI-4), controlled for age and sex, showed similar results (SICI- We further tested the association between the change in 2: P = .127; SICI-4: P < .001) even when excluding the patients who CDRS-R scores (the difference between follow-up and baseline were taking medications other than fluoxetine. Figure 1. Baseline transcranial magnetic stimulation (TMS) measures for depressed participants and healthy controls. Error bars represent standard error of means. (A) Comparison of short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). Numbers (e.g., SICI-2) rep- resent the interstimulus intervals in milliseconds. The asterisk indicates a significant group difference after Bonferroni correction for multiple comparisons (P = .001, P = .01). (B) Comparison of cortical silent period (CSP) duration. MEP, motor-evoked potential. adj Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 440 | International Journal of Neuropsychopharmacology, 2019 Table 2. Baseline and Follow-up Transcranial Magnetic Stimulation Measures Depressed Participants a b Measure Healthy Controls, Baseline (n = 22) Baseline (n = 15) Follow-up (n = 10) P Value adj SICI 2 ms 0.45 (0.23) 0.88 (0.39) 1.06 (0.53) .01 4 ms 0.69 (0.35) 0.98 (0.48) 1.15 (0.62) .24 ICF 10 ms 1.47 (0.55) 1.66 (0.53) 1.58 (0.67) >.99 15 ms 1.53 (0.71) 1.81 (0.84) 1.49 (0.51) .87 20 ms 1.43 (0.66) 1.71 (0.74) 1.34 (0.53) >.99 LICI 100 ms 0.20 (0.28) 0.93 (2.27) 0.31 (0.29) >.99 150 ms 0.32 (0.48) 0.76 (1.30) 0.44 (0.42) >.99 200 ms 1.39 (1.18) 1.29 (1.23) 0.60 (0.46) >.99 CSP, s 0.18 (0.04) 0.17 (0.05) 0.16 (0.03) >.99 Abbreviations: CDRS-R, Children’s Depression Rating Scale, Revised; CSP, cortical silent period; ICF, intracortical facilitation; LICI, long-interval intracortical inhibition; SICI, short-interval intracortical inhibition. a Follow-up assessment timeframe: mean [SD] follow-up time, 7.9 [5.6] weeks; range, 2–20 weeks) for a subset of depressed participants treated with antidepressant medication. b Comparison of healthy vs depressed participants at baseline. Bonferroni-corrected P values ( ). P adj c For adolescents in the follow-up group, improvement in CDRS-R positively correlated with improvement in SICI-4 (P =R .01; = 0.63). Figure 2. Scatter plot graphs showing the association between change in Children’s Depression Rating Scale, Revised (CDRS-R) (ΔCDRS-R) and change in short-interval intracortical inhibition (SICI)-2 (ΔSICI-2) and SICI-4 (ΔSICI-4). Greater improvement in CDRS-R (more negative difference) corresponded to greater improvement in - cor tical inhibition (more negative difference). DIFF, difference. studies with depressed adolescents have reported mixed results. Discussion Croarkin and colleagues (Croarkin et al., 2013) previously found To our knowledge, this is the first longitudinal study of TMS that medication-naïve children and adolescents with MDD had measures of cortical inhibition and excitability in adolescents increased ICF compared with healthy controls, but no signifi- with depression. Adolescents with moderate to severe symp- cant differences were observed for cortical inhibition measures, toms of MDD had impaired cortical inhibition compared with including SICI and CSP. However, in a separate posthoc analysis, healthy controls. Improvement in depressive symptom severity depression severity negatively correlated with ICF and CSP, des- with antidepressant treatment was associated with restored pite the absence of group differences (Lewis et al., 2016). In the cortical inhibition, as indexed by improved SICI. current study, we did not find any difference in ICF or identify Our results are consistent with prior TMS studies of adults correlations between baseline depression severity and TMS that showed impaired SICI for patients with depressive dis- measures. However, it is important to note that the group with orders, further supporting the role of impaired GAB-mediated A depression in the aforementioned adolescent studies (Croarkin cortical inhibition in depression (Croarkin et al., 2011). In a meta- et  al., 2013; Lewis et  al., 2016) differed from the sample in the analysis (Radhu et al., 2013) of 3 studies (115 adult patients with current study with regard to previous antidepressant medication MDD and 130 healthy controls), (Bajbouj et al., 2006 Lefauc ; heur history, lower mean age (13.9 vs 15.4 years), shorter disease dur - et al., 2008; Levinson et al., 2010) SICI was markedly impaired in ation (0.9 vs 1.3 years), and exclusion of other comorbid psychi- the MDD group. Results of that meta-analysis also showed short- ened CSP in MDD, suggesting impaired GABA -mediated cortical atric disorders (in the previous study). inhibition. However, we did not find any significant differences in Overall, the results of the current study suggest that older, pre- CSP in the current study. In contrast to adult studies, prior TMS viously treated adolescents with MDD and a longer duration of Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 Copyedited by: oup Camsari et al. | 441 illness might have cortical excitability patterns that are similar with gr eater degrees of treatment resistance would show dif- to those of depressed adults, even though adolescents may not ferent relationships between the change in depressive symp- have adult levels of cortical maturation. An intermediate level of toms and changes in LICI and CSP. maturation in our sample of adolescents with depression could Several mechanisms potentially explain how serotonergic explain some of the differences between our results and those (5-HT) activity and GABAergic activity interact. First, GABAergic of previous adult studies (e.g., shortened CSP, a marker of GABA - neurons inhibit 5-HT neurons in midbrain raphe nuclei (Tao mediated cortical inhibition, which was not present in our de- and Auerbach, 2000). Also, previous research has shown that the pressed group) while supporting other similarities (e.g., impaired serotonergic innervation of the cortex is mediated through the SICI). A  known difference between adults and children is that excitatory effects of 5-HT and 5-HT receptors on GABAergic 2A 3 children have less cortical inhibition (Mall et  al., 2004), which interneurons in the cortex, hippocampus, and amygdala (Freund might have contributed to the lack of CSP findings in our sample. et al., 1990; Jakab and Goldman-Rakic, 2000). Indeed, 5-HT and CSP also can show variability in children and adolescents (Garvey 5-HT agonists increase the activity of GABAergic interneurons and Mall, 2008) and is affected by interhemispheric differences; in these areas (Gellman and Aghajanian, 1993Abi-Saa ; b et  al., these potential confounders were not assessed in this study. 1999). These findings are consistent with aforementioned Moreover, different TMS indices may have differing patterns of studies showing temporary increases in cortical inhibition, age- or maturation-related changes along different time courses, as measured by TMS, after administration of single doses of and little is known about the developmental trajectories of TMS clomipramine (Manganotti et  al., 2001) and citalopram (Robol measures in the setting of psychiatric illness (Croarkin et  al., et  al., 2004). When administered regularly, SSRIs can induce 2014b). For example, prior work suggests that depressed children plasticity within these neural networks (Normann et  al., 2007; and adolescents might have delayed maturation of cortical ex- Liu et al., 2017). Although it is difficult to ascertain whether the citability when compared with age-matched controls (Croarkin modulation of GABAergic activity with SSRIs leads to improve- et  al., 2014b). Additionally, several other psychiatric disorders ment of depressive symptoms or whether improvement in de- in adults (Radhu et  al., 2013), as well as attention-deficit/hyper - pressive symptoms through other mechanisms leads to changes activity disorder in children (Gilbert et  al., 2011), have been as- in inhibitory and excitatory networks, our results suggest that sociated with impaired excitatory-inhibitory balance. In contrast SICI is a potential treatment target in depression because of its to previous adolescent studies, we did not exclude participants potential to index deficits in GABAergic activity. with comorbid psychiatric disorders; thus, the sample from our There are several limitations of this study. First, our sample present study may be more generalizable to adolescents encoun- size for the follow-up group was small and did not allow us to tered in typical clinical settings. control for all potential covariates of interest. We also had a The most notable finding of this study was the positive as- relatively heterogeneous group with regard to age, race/ethni- sociation between the improvement in depression severity and city, current medications, and history of prior antidepressant improvement in SICI after antidepressant therapy. Given that use. With regard to the potential impact of race or ethnicity, we SICI indirectly reflects GABA activity (Hanajima et  al., 1998; are not aware of any previous studies comparing cortical excit- Di Lazzaro et  al., 2000, 2005; Ilić et  al., 2002; Hanajima et  al., ability measures between black and white participant groups; 2003), this result suggests that restored GABAergic inhibition however, one small study showed cortical excitability differ - is associated with improved depression severity in the set- ences between Han Chinese and Caucasians (Yi et  al., 2014). ting of antidepressant treatment. Prior research in adults has On the other hand, comparisons of TMS measures, including shown restored GABAergic activity with therapeutic interven- our main findings (SICI-2, SICI-4), between black and white par- tions such as electroconvulsive therapy (Sanacora et al., 2003), ticipants within the healthy group did not show any signifi- repetitive TMS (rTMS) (Daskalakis et  al., 2006), and selective cant differences between these groups. In terms of medication serotonin reuptake inhibitors (SSRIs) (Sanacora et  al., 2002). use, our sensitivity analysis showed similar results when we Daskalakis and colleagues (Daskalakis et al., 2006) found state- excluded participants taking medications other than fluox- dependent effects of rTMS on SICI in healthy participants and etine. Although the mean age of the healthy participants was showed that those with less cortical inhibition at baseline lower than that of the depressed participants, we did control (higher SICI ratios) showed more improvement in SICI after for age in the statistical analyses. Further, younger partici- rTMS. They also showed potentiation of CSP with high- and pants would be expected to have greater SICI-2 impairment low-frequency rTMS. In a proton magnetic resonance spec- (Mall et al., 2004). Despite this age difference in our study, the troscopy study of patients with MDD, Sanacora and colleagues older depressed sample had greater SICI-2 impairment. Finally, (Sanacora et  al., 2002) showed that occipital GABA levels in- TMS testing of the motor cortex employed manual localiza- creased after treatment with SSRIs. Other studies also showed tion of the APB “hotspot.” This could introduce bias into MEP increased SICI (greater inhibition) in patients with MDD and findings based on the variability of pulses among subjects and healthy controls after administration of SSRIs (Manganotti between sessions, with potential resultant changes in cortical et  al., 2001; Robol et  al., 2004). Even though no study has as- inhibition. While our methodology attempted to mitigate the sessed longitudinal changes in TMS measures in adolescents, potential bias that this could have introduced among MEP another study of depressed adolescents from our group has measures, future studies should utilize position tracking de- shown an association between pretreatment LICI impair - vices, conventional measurement (e.g., 10–20 EEG system), or ment (which reflects GABA -mediated activity) and poor treat- neuro-navigation (Ahdab et  al., 2010). The major strength of ment response to fluoxetine, suggesting that deficits in GABA our study was being the first study, to our knowledge, to com- functioning may be associated with treatment nonresponse pare longitudinal changes in TMS measures associated with (Croarkin et  al., 2014a). In our study, almost all patients had adolescent depression before and after treatment. This study some degree of improvement in their total CDRS-R scores adds important preliminary data to the existing literature to- (range, −3 to −38), which may explain the lack of differences in ward developing target biomarkers of depression and anti- these GABA measures. It is possible that adolescent samples depressant treatment. B Downloaded from https://academic.oup.com/ijnp/article-abstract/22/7/435/5490612 by Ed 'DeepDyve' Gillespie user on 02 July 2019 442 | International Journal of Neuropsychopharmacology, 2019 the Centre for Addiction and Mental Health (CAMH) Foundation Conclusion and the Campbell Institute. A.I.S., A.L.N., and M.A.G.  have no In this naturalistic, longitudinal study investigating TMS financial disclosures. markers in adolescents with MDD, we showed that cortical in- hibition was impaired, with patterns somewhat similar to those References reported for adults with depression. Moreover, we showed that improvement in depression severity after antidepressant treat- Abi-Saab  WM, Bubser  M, Roth  RH, Deutch  AY (1999) 5-HT2 re- ment is associated with restored cortical inhibition, as indexed ceptor regulation of extracellular GABA levels in the pre- by SICI. This was the first study to our knowledge to investigate frontal cortex. Neuropsychopharmacology 20:92–96. longitudinal changes in TMS measures of cortical inhibition as- Ahdab R, Ayache SS, Brugières P, Goujon C, Lefaucheur JP (2010) sociated with antidepressant treatment in an adolescent popu- Comparison of “standard” and “navigated” procedures of TMS lation. These findings provide important preliminary data that coil positioning over motor, premotor and prefrontal targets will inform future studies investigating the neurobiology of in patients with chronic pain and depression. Neurophysiol adolescent depression and enable the development of better Clin 40:27–36. diagnostic methods and individualized, biomarker-guided Anand  S, Hotson  J (2002) Transcranial magnetic stimulation: therapeutic approaches in this population. neurophysiological applications and safety. Brain Cogn 50:366–386. Anticevic  A, Murray  JD (2017) Rebalancing altered computa- Funding tions: considering the role of neural excitation and inhib- This research was supported by grants from the Brain and ition balance across the psychiatric spectrum. Biol Psychiatry Behavior Research Foundation (Young Investigator Award 81:816–817. 20883), the National Institute of Mental Health (K23 MH100266 Avenevoli S, Swendsen J, He J-P, Burstein M, Merikangas KR (2015) and R01MH113700). This publication was also made possible Major depression in the National Comorbidity Survey–Ado- by the Mayo Clinic Clinical Translational Science Award (CTSA) lescent Supplement: prevalence, correlates, and treatment. J through grant number UL1TR002377 from the National Center Am Acad Child Adolesc Psychiatry 54:37–44.e32. for Advancing Translational Sciences (NCATS), a component of Bajbouj  M, Lisanby  SH, Lang  UE, Danker-Hopfe  H, Heuser  I, the National Institutes of Health (NIH). The content is solely the Neu  P (2006) Evidence for impaired cortical inhibition in responsibility of the authors and does not necessarily represent patients with unipolar major depression. Biol Psychiatry the official views of the National Institutes of Health. 59:395–400. Birmaher  B, Ryan  ND, Williamson  DE, Brent  DA, Kaufman  J, Dahl  RE, Perel  J, Nelson  B (1996) Childhood and adolescent Acknowledgments depression: a review of the past 10  years. Part I. J Am Acad The sponsors had no role in study design; in the collection, ana- Child Adolesc Psychiatry 35:1427–1439. lysis and interpretation of data; in the writing of the report; and Cantello R, Gianelli M, Civardi C, Mutani R (1992) Magnetic brain in the decision to submit the article for publication. stimulation: the silent period after the motor evoked poten- Editing, proofreading, and reference verification were provided tial. Neurology 42:1951–1959. by Scientific Publications, Mayo Clinic. Chen  R, Lozano  AM, Ashby  P (1999) Mechanism of the silent period following transcranial magnetic stimulation. Evidence from epidural recordings. Exp Brain Res 128:539–542. Statement of Interest Cheung  AH, Emslie  GJ, Mayes  TL (2005) Review of the efficacy D.D.C. receives research support from the Mayo Clinic Foundation and safety of antidepressants in youth depression. J Child Departmental Small Grant Program. C.P.L. receives research sup- Psychol Psychiatry 46:735–754. port from the Brain and Behavior Research Foundation and the Croarkin  PE, Levinson  AJ, Daskalakis  ZJ (2011) Evidence for Mayo Clinic Foundation Departmental Small Grant Program gabaergic inhibitory deficits in major depressive disorder. and is a site investigator for a multicenter studies funded by Neurosci Biobehav Rev 35:818–825. Neuronetics, Inc and NeoSync, Inc. Croarkin PE, Nakonezny PA, Husain MM, Melton T, Buyukdura JS, P.E.C.  has received research grant support from Pfizer, Kennard  BD, Emslie  GJ, Kozel  FA, Daskalakis  ZJ (2013) Evi- Inc, NIMH (K23 MH100266 and R01MH113700), the Brain and dence for increased glutamatergic cortical facilitation in chil- Behavior Research Foundation, and the Mayo Clinic Foundation. dren and adolescents with major depressive disorder. JAMA He has served as a site subprincipal or principal investigator Psychiatry 70:291–299. (without additional compensation) for Eli Lilly and Co, Forest Croarkin  PE, Nakonezny  PA, Husain  MM, Port  JD, Melton  T, Laboratories, Inc, Merck & Co, Inc, and Pfizer, Inc; has received Kennard  BD, Emslie  GJ, Kozel  FA, Daskalakis  ZJ (2014a) Evi- equipment support from Neuronetics, Inc; and receives sup- dence for pretreatment LICI deficits among depressed chil- plies and genotyping services from Assurex Health, Inc for dren and adolescents with nonresponse to fluoxetine. Brain an investigator-initiated study. He is the primary investigator Stimul 7:243–251. for a multicenter study funded by Neuronetics, Inc. He is a Croarkin PE, Nakonezny PA, Lewis CP, Zaccariello MJ, Huxsahl JE, site primary investigator for a study funded by NeoSync, Inc. Husain MM, Kennard BD, Emslie GJ, Daskalakis ZJ (2014b) De- He has consulted for Procter and Gamble. In the last 5  years, velopmental aspects of cortical excitability and inhibition Z.J.D.  has received research and equipment in-kind support in depressed and healthy youth: an exploratory study. Front for an investigator-initiated study through Brainsway, Inc. Hum Neurosci 8:669. and Magventure, Inc. 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Published: Jul 1, 2019

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