Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Croarkin, Paul E.; Nakonezny, Paul A.; Wall, Christopher A.; Murphy, Lauren; Sampson, Shirlene; Frye, Mark A.; Port, John D.

doi:10.1016/j.pscychresns.2015.11.005

Cited by 55 publications

(85 citation statements)

References 45 publications

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“…Levkovitz et al (2009) studied different deep TMS settings in 65 adults with MDD and found that high intensity (120% of MT) but not low-intensity (110% of MT) deep TMS for 4 weeks was an effective treatment (and no participants in the study experienced seizures) (Levkovitz et al 2009). Although one of the initial pilot studies in adolescents with depression (using a standard, figure-8 coil) used lower intensity (Mayer et al 2012), the other work has used 120% intensity with no reported seizures to date (Wall et al 2011;Croarkin et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Seizure Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression

Cullen

Jasberg

Nelson

et al. 2016

Journal of Child and Adolescent Psychopharmacology

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Objective: Deep transcranial magnetic stimulation (TMS) with an H-1 coil was recently approved by the U.S. Food and Drug Administration (U.S. FDA) for treatment-resistant depression (TRD) in adults. Studies assessing the safety and effectiveness of deep TMS in adolescent TRD are lacking. The purpose of this brief report is to provide a case history of an adolescent enrolled in an investigational deep TMS protocol. Methods: A case history is described of the first participant of a sham-controlled clinical trial who had a seizure in the course of deep TMS with parameter settings extrapolated from the adult studies that led to US FDA approval (H-1 coil, 120% target stimulation intensity, 18 Hz, 55 trains of 2-second duration, total 1980 pulses). Results: The participant was a 17-year-old unmedicated female, with no significant medical history and no history of seizures or of drug or alcohol use. Brain magnetic resonance imaging showed no structural abnormalities. She initially received sham, which was well tolerated. During active treatment sessions, titration began at 85% of motor threshold (MT) and increased by 5% per day. Her weekly MT measurements were stable. On her first day of 120% MT (8th active treatment), during the 48th train, the participant had a generalized, tonic-clonic seizure that lasted 90 seconds and resolved spontaneously. She had an emergency medicine evaluation and was discharged home without anticonvulsant medications. There were no further seizures reported at a 6-month follow-up. Conclusions: We report a deep TMS-induced generalized tonic-clonic seizure in an adolescent with TRD participating in a clinical trial. Given the demonstrated benefits of deep TMS for adult TRD, research investigating its use in adolescents with TRD is an important area. However, in light of this experience, additional precautions for adolescents should be considered. We propose that further dose-finding investigations are needed to refine adolescent-specific parameters that may be safe and effective for treating adolescents with TRD with deep TMS.

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Section: Discussionmentioning

confidence: 99%

Seizure Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression

Cullen

Jasberg

Nelson

et al. 2016

Journal of Child and Adolescent Psychopharmacology

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“…Several studies have used 1 H-MRS in this context (Croarkin et al, 2016; Dubin et al, 2016; Godlewska et al, 2015; Grimm et al, 2012; Jarnum et al, 2011; Luborzewski et al, 2007; Merkl et al, 2011; Michael et al, 2003; Njau et al, 2016; Pfleiderer et al, 2003; Taylor et al, 2012; Yang et al, 2014; Zhang et al, 2013), but are characterized by important methodological limitations. First, many of these studies measured Glx – a composite measure containing both glutamate and glutamine – making them difficult to interpret.…”

Section: Introductionmentioning

confidence: 99%

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

Brennan

Admon

Perriello

et al. 2017

Psychiatry Research: Neuroimaging

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Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (1H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired 1H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD.

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“…Participants underwent structural MRI and TE-optimized proton MRS using a method similar to that published previously (Croarkin et al, 2016). Briefly, scans were obtained using a General Electric 3 T Discovery MRI scanner (GE Medical Systems, Inc., Waukesha, WI, USA) equipped with an 8-channel head coil.…”

Section: Methodsmentioning

confidence: 99%

“…This region encompassed the hand knob of the precentral gyrus (Brodmann area 4) that was presumably interrogated with TMS. The ACC voxel was positioned as previously described (Croarkin et al, 2016), encompassing the pregenual ACC of both hemispheres (Brodmann areas 24a, 24b and 32). A TE-optimized PRESS sequence (PROBE-P, TR = 2000 ms, TE = 80 ms, 128 acquisitions, 5000 Hz bandwidth, 2048 points) was used to obtain spectroscopic data for both voxel locations.…”

Section: Methodsmentioning

confidence: 99%

“…By contrast, Tremblay et al (2013) found a positive correlation between motor cortex [Glx] and CSP duration (which persisted when controlling for GABA concentration), but the authors found no correlation between 1 H-MRS-measured [GABA] and CSP, SICI, or LICI. Few studies have utilized combined TMS-MRS methods in psychiatric populations, and those that have done so typically examined treatment-induced changes in excitatory and inhibitory neurochemistry following repetitive transcranial magnetic stimulation (rTMS) for depression (Croarkin et al, 2016; Dubin et al, 2016). To our knowledge, no prior studies, either adult or pediatric, have examined the associations between TMS measures of excitatory and inhibitory neurophysiology and MRS-measured glutamatergic neurochemistry in depressed individuals.…”

Section: Introductionmentioning

confidence: 99%

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An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents

Lewis

Port

Frye

et al. 2016

Front. Neural Circuits

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Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents.Methods: Twenty-four adolescents (aged 11–18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx].Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs).Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

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Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents

Cited by 55 publications

References 45 publications

Seizure Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression

Seizure Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents

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