Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation

Transcranial magnetic stimulation has evolved into a powerful neuroscientific tool allowing to interfere transiently with specific brain functions. In addition, repetitive TMS (rTMS) has long-term effects (e.g. on mood), probably mediated by neurochemical alterations. While long-term safety of rTMS with regard to cognitive functioning is well established from trials exploring its therapeutic efficacy, little is known on whether rTMS can induce changes in cognitive functioning in a time window ranging from minutes to hours, a time in which neurochemical effects correlated with stimulation have been demonstrated. This study examined effects of rTMS on three measures of executive function in healthy subjects who received one single rTMS session (40 trains of 2 s duration 20 Hz stimuli) at the left dorsolateral prefrontal cortex (DLPFC). Compared to a sham condition one week apart, divided attention performance was significantly impaired about 30-60 min after rTMS, while Stroop-interference and performance in the Wisconsin Card Sorting Test was unaffected after rTMS. Repetitive TMS of the left DLPFC, at stimulation parameters used in therapeutic studies, does not lead to a clinically relevant impairment of executive function after stimulation. However, the significant effect on divided attention suggests that cognitive effects of rTMS are not limited to the of acute stimulation, and may possibly reflect known neurochemical alterations induced by rTMS. Sensitive cognitive measures may be useful to trace those short-term effects of rTMS non-invasively in humans.     

Frontal Cortex TMS for Tinnitus

Both invasive and non-invasive neuromodulation of the dorsolateral prefrontal cortex (DLPFC) are capable of suppressing tinnitus loudness. Repetitive transcranial magnetic stimulation (rTMS) of the DLPFC has an add-on effect for auditory cortex (AC) rTMS in improving tinnitus-related distress. We aimed to investigate whether TMS and rTMS of the DLPFC is capable of reducing tinnitus loudness and what mechanism might be involved. Two TMS studies targeting the right DLPFC were performed. Study 1 investigated 44 tinnitus patients who underwent either 1 or 10 Hz real or sham TMS (200 pulses at 80% motor threshold). In Study 2 we performed rTMS (10 sessions of 600 pulses) in responders of study 1. Changes on the visual analog scale (VAS) loudness were evaluated. All patients underwent a pre-TMS electroencephalography: differences in functional connectivity between responders and non-responders were evaluated using sLORETA. Only 1 Hz TMS was capable of significantly reducing tinnitus loudness for 11 patients with a mean suppression of 39.23%. RTMS for these 11 patients yielded a 21% improvement in VAS loudness, and in 7 of 11 rTMS was successful, with, a mean suppression of 27.13%. The responders were characterized by a difference in lagged linear connectivity in the theta band among the DLPFC, anterior cingulate cortex (ACC), parahippocampus and AC. In summary, 1 H, TMS and rTMS of the right DLPFC can transiently reduce the perceived tinnitus loudness mediated via functional connections between the DLPFC and a network consisting of the ACC, parahippocampus and AC.     

Effect of repetitive transcranial magnetic stimulation on saccades in depression: a pilot study

Therapeutic repetitive transcranial magnetic stimulation (rTMS) in depression is applied over the prefrontal cortex. This brain region is known to play an important role in the control of saccades. We wanted to investigate whether the fast rTMS procedure affected saccadic activity in depression. Reflexive saccades (RS) and voluntary saccades were studied in 11 patients before and after therapeutic rTMS for depression. Two types of voluntary saccade tasks were used: a voluntary prosaccade (VpS) task and an antisaccade (AS) task. Eye movements were registered by infrared oculography. Latency and directional error rate were analyzed. rTMS was applied over the left dorsolateral prefrontal cortex (DLPFC). RS and VpS parameters were unchanged after 10 sessions of rTMS. However, the latency of antisaccades (AS) was significantly shorter after rTMS than before rTMS. It can be concluded that rTMS over the left DLPFC cortex in depression seems to have no important effect on reflexive saccades, while antisaccade activity is clearly favored by shortening of latency. As voluntary prosaccades were not significantly influenced, our findings may indicate that not merely the voluntary triggering of saccades but the inhibition of unwanted reflexive saccades is influenced by fast rTMS delivered over the DLPFC. These results suggest the intriguing possibility that rTMS might differentially affect specific aspects of saccade behavior.     

Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising relatively non-invasive alternative for the treatment of depression. The purpose of this study was to compare the apparent effectiveness of high frequency (20 Hertz) rTMS applied over the left dorsolateral prefrontal cortex (DLPFC) with that of low frequency (1 Hz) rTMS applied over the right DLPFC METHODS: Twenty-eight antidepressant-free adults with major depressive (n = 25) or bipolar (n = 3) disorder (not on mood stabilizers) in a current major depression (Hamilton Rating Scale for Depression [HAM-D-21] > or = 18; Mean = 24.5, SD = 5.51) were treated (14 right, 14 left) for 4 weeks. RESULTS: Overall paired t-tests revealed a significant reduction in mean HAM-D-21, Beck Depression Inventory (BDI-II), and Clinical Global Impression of Change (CGIC) scores at the end of treatment for both groups (high frequency left DLPFC and low frequency right DLPFC). The treatment response rate found (32%) was typical of other response rates reported in the literature (6,30). One-month follow-up data was obtained from 50% of participants. At 1-month follow-up no significant differences were noted as compared to patients' performance at last treatment visit, indicating moderate robustness of rTMS treatment over time. Furthermore, magnetic stimulation did not substantially alter patient memory over the course of treatment. CONCLUSION: rTMS given at low frequency over the right frontal cortex appears to be as effective treatment of refractory depression as high frequency treatment over the left frontal cortex.     

Acute effects of repetitive transcranial magnetic stimulation on attentional control are related to antidepressant outcomes

Background

Repetitive transcranial magnetic stimulation (rTMS) applied over the dorsolateral prefrontal cortex (DLPFC) is a new treatment procedure that holds promise of more insight into the pathophysiology of depression because the DLPFC may play an important role in the interplay between emotional and attentional information processing. We sought to investigate whether acute neurocognitive effects of rTMS are related to antidepressant outcomes.

Methods

Between January 2005 and May 2007, we examined the effects of a single session compared with 2 weeks of rTMS over the left DLPFC on cognition and mood in therapy-resistant patients with depression. We used a crossover placebo-controlled double-blind design and differentiated rTMS treatment responders and nonresponders. We used a task-switching paradigm to measure cognitive function.

Results

After 2 weeks of high-frequency rTMS over the left DLPFC, depressive symptoms improved in more than half (53%) of our therapy-resistant population. After a single session, mood did not improve but attentional control was increased solely within our group of treatment responders.

Limitations

Our results should be interpreted as preliminary because our sample was small and because the cognitive task we used has not been tested for validity and reliability. In addition, despite minimal stimulation of the DLPFC during sham stimulation, it is possible that the stiumlation was partially active. Finally, benzodiazepines may have had impairing effects on the attentional task.

Conclusion

Cognitive reactivity after a single session of rTMS may hold promise as a predictor of beneficial treatment outcomes. Moreover, within the group of responders, attentional control appears to play an important role in the progress of mood disorders.     

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.     

Brain stimulation‐induced neuroplasticity underlying therapeutic response in phantom sounds

Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state‐of‐the‐art voxel‐based morphometry (VBM) to investigate whether transcranial magnetic stimulation‐induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole‐brain analyses (P < 0.05, FWE corrected), we assessed longitudinal gray matter changes as well as structural connectivity between the ensuing regions. We observed longitudinal mesoscopic gray matter changes of left dorsolateral prefontal (DLPFC), left operculo‐insular, and right inferior temporal cortex (ITC) in responders (N = 22) but not nonresponders (N = 38), as indicated by a group × time interaction and post‐hoc tests. These results were neither influenced by age, sex, hearing loss nor by tinnitus laterality, duration, and severity at baseline. Furthermore, we found robust DLPFC–insula and insula–ITC connectivity in responders, while only relatively weak DLPFC–insula connectivity and no insula–ITC connectivity could be demonstrated in nonresponders. Our results reinforce the implication of nonauditory brain regions in phantom sounds and suggest the dependence of therapeutic response on their neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554–562, 2018. © 2017 Wiley Periodicals, Inc.     

Neurophysiological effects of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant depression

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) is effective for treatment resistant depression (TRD), but little is known about rTMS’ effects on neurophysiological markers. We previously identified neurophysiological markers in depression (N45 and N100) of GABA receptor mediated inhibition. Here, we indexed TMS-electroencephalographic (TMS-EEG) effects of rTMS.MethodsTMS-EEG data was analyzed from a double blind 2:1 randomized active (10 Hz left/bilateral):sham rTMS TRD trial. Participants underwent TMS-EEG over left dorsolateral prefrontal cortex (DLPFC) before and after 6 weeks of rTMS. 30 had useable datasets. TMS-evoked potentials (TEP) and components (N45, N100, P60) were examined with global mean field analysis (GMFA) and locally in DLPFC regions of interest.ResultsThe N45 amplitude differed between active and sham groups over time, N100 amplitude did not. N45 (t = 2.975, p = 0.007) and N100 amplitudes (t = 2.177, p = 0.042) decreased after active rTMS, demonstrating alterations in cortical inhibition. TEP amplitudes decreased after active rTMS in left (t = 4.887, p < 0.001) and right DLPFC (t = 4.403, p < 0.001) not sham rTMS, demonstrating alterations in cortical excitability.ConclusionsOur results provide important new knowledge regarding rTMS effects on TMS-EEG measures in TRD, suggesting rTMS reduces neurophysiological markers of inhibition and excitability.SignificanceThese findings uncover potentially important neurophysiological mechanisms of rTMS action.     

Left versus right repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomised controlled trials

Although the majority of randomised controlled trials suggest that major depressive disorder (MDD, major depression) and treatment-resistant depression can be effectively treated by applying either high- (HF) or low-frequency (LF) repetitive transcranial magnetic stimulation (rTMS) to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, it is not clear which rTMS approach is more effective or safer. This systematic review and meta-analysis was conducted on randomised controlled trials on HF and LF rTMS applied to the left and right DLPFC, respectively, for the treatment of MDD. Eight randomised controlled trials composed of 249 patients were selected to compare the effects of LF (≤1 Hz) rTMS over the right DLPFC to HF (10–20 Hz) rTMS over the left DLPFC. The therapeutic effects of both approaches were similar (odds ratio (OR) = 1.15; 95% confidence interval = 0.65–2.03). Dropout analysis based on only two studies was insufficient to draw a conclusion on the tolerability of LF rTMS. The pooled examination demonstrated that both rTMS methods were equally effective therapies for MDD. However, considering that LF right-sided rTMS produces fewer side effects and is more protective against seizures, its clinical applicability shows greater promise and should be explored further.     

Antidepressant effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebo-controlled trial

Repetitive transcranial magnetic stimulation (rTMS) has antidepressant effects in patients with major depressive disorder. The mechanisms of action and optimal stimulation parameters remain unclear. To test the hypothesis that rTMS exerts antidepressant effects either by enhancing left dorsolateral prefrontal cortex (DLPFC) excitability or by decreasing right DLPFC excitability, the authors studied 45 patients with unipolar recurrent major depressive disorder in a double-blind, randomized, parallel group, sham-controlled trial. Patients were randomized to receive 1 Hz or 10 Hz rTMS to the left DLPFC, 1 Hz to the right DLPFC or sham TMS. Left 10 Hz and right 1 Hz rTMS showed similar significant antidepressant effects. Other parameters led to no significant antidepressant effects.     

Region-specific glutamate changes in patients with unipolar depression

The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.     

Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up

Background and objectiveRepetitive transcranial magnetic stimulation (rTMS) is a first-line treatment for treatment-resistant depression (TRD). The mechanisms of action of rTMS are not fully understood, and no biomarkers are available to assist in clinical practice to predict response to rTMS. This study aimed to demonstrate that after-rTMS clinical improvement is associated with functional connectivity (FC) changes of the subgenual cingulate cortex (sgACC) and rostral anterior cingulate (rACC), and FC of sgACC and rACC might serve as potential predictors for treatment response.MethodsResting-state functional magnetic resonance imaging (rs-fMRI) data were collected within 1 week before rTMS initiation in 50 TRD patients to predict subsequent response to rTMS on the left dorsolateral prefrontal cortex (DLPFC). Follow-up rs-fMRI was obtained 12 weeks after completion of rTMS and neural correlates of rTMS in sgACC- and rACC-related FC patterns were compared to before rTMS data and with rs-fMRI from healthy participants.ResultsTreatment response was associated with lower FC of sgACC to right DLPFC and higher FC of rACC to left lateral parietal cortex (IPL) measured at baseline. Using sgACC-DLPFC and rACC-IPL connectivity as features, responder-nonresponder classification accuracies of 84% and 76% (end-of-treatment), 88% and 81% (3-month follow-up), respectively were achieved. Longitudinal rs-fMRI data analyses revealed that the hyperconnectivity between sgACC and visual cortex was normalized to a level which was comparable to that of healthy participants.ConclusionsBrain activity patterns in depression are predictive of treatment response to rTMS, and longitudinal change of brain activity in relevant brain circuits after rTMS is associated with treatment response in depression. Target engagement paradigms may offer opportunities to increase the efficacy of rTMS in TRD by optimal selection of patients for treatment.Trial registrationClinicalTrials.gov Identifiers: NCT01887782 and NCT02800226.     

Neurometabolite effects of response to quetiapine and placebo in adolescents with bipolar depression

Abstract Objective: Mood stabilizers have been reported to affect brain concentrations of myo-inositol (mI) and N-acetylaspartate (NAA). We examined the effects of quetiapine (QUET), an atypical antipsychotic, on these neurochemicals, and potential predictors of response to QUET in adolescents with bipolar depression. Methods: Twenty-six adolescents with bipolar depression participated in an 8-week placebo-controlled trial of QUET monotherapy. Subjects were scanned at baseline and after 8 weeks with proton magnetic resonance spectroscopy (1H-MRS) at 3T and 4T at two sites, with 8?cm(3) voxels placed in the right and left dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). LCModel was used to calculate absolute concentrations of NAA and mI. Results: Twenty-six subjects had pre- and posttreatment scans (mean age=15.6 years, 9 boys). Of these subjects, 5 out of 16 subjects receiving QUET and 5 out of 10 receiving placebo (PBO) were responders (50% decrease in Children's Depression Rating Scale [CDRS] score). Although baseline ACC mI did not predict responder status, responders had significantly lower posttreatment ACC mI values than did nonresponders (3.27±.71 vs. 4.23±.70; p=0.004). There were no significant differences in the changes in ACC and DLPFC NAA levels in the QUET group compared with the PBO group (ACC: -0.55±1.3 vs.+0.25±1.5, p=0.23; right-DLPFC: -0.55±1.3 vs. 0.33±0.89, p=0.13; left-DLPFC: -0.04±0.91 vs.+0.29±0.61, p=0.41). Conclusion: We found that posttreatment, not baseline, ACC mI levels were associated with response to QUET in adolescents with bipolar depression. There were no differences in NAA concentration changes between the QUET and PBO groups. Larger studies including different brain regions would help to clarify the effects of QUET on neurochemistry in patients with bipolar disorder.     

Predictive value of dorso-lateral prefrontal connectivity for rTMS response in treatment-resistant depression: A brain perfusion SPECT study

Background

Previous clinical trials have suggested that repetitive transcranial magnetic stimulation (rTMS) has a significant antidepressant effect in patients with treatment resistant depression (TRD). However, results remain heterogeneous with many patients without effective response.

Impaired interhemispheric interactions in patients with major depression

Previous studies have shown that patients with major depression have an interhemispheric imbalance between right and left prefrontal and motor cortex. We aimed to investigate the interhemispheric interactions in patients with major depression using repetitive transcranial magnetic stimulation (rTMS). Thirteen patients with major depression and 14 age-matched healthy subjects participated in this study. Corticospinal excitability before and after 1 Hz rTMS (applied to the left primary motor cortex) was assessed in the left and right motor cortex and these results were compared with those in healthy subjects. There was a significant difference in the interhemispheric effects between patients with depression and healthy subjects. In healthy subjects, 1 Hz rTMS significantly decreased corticospinal excitability in the stimulated, left hemisphere and increased it in the contralateral, right hemisphere. In depressed subjects, 1 Hz rTMS also decreased corticospinal excitability in the left hemisphere; however, it induced no significant changes in corticospinal excitability in the contralateral, right hemisphere. In addition, there was a significant correlation between the degree of interhemispheric modulation and the severity of the depression as indexed by the Beck Depression Inventory scores. Our findings showing a decreased interhemispheric modulation in patients with major depression are consistent with the notion that mood disorders are associated with slow interhemispheric switching mechanisms.     

rTMS for the Treatment of Depression: a Comprehensive Review of Effective Protocols on Right DLPFC

Major depressive disorders (MDDs) are the most common and debilitating diseases worldwide. Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative or adjunctive treatment for different types of depression disorders, including drug-resistant major depressions. Despite controversial findings on the therapeutic outcomes of this technique, the general consent is developing this technique as an alternative treatment for depression disorders. Notwithstanding one protocol of rTMS has been approved by FDA for the acute treatment of major depression, studies are ongoing for finding more efficient protocols. This study aimed to comprehensively overview the effective rTMS protocols applied on left dorsolateral prefrontal cortex DLPFC for MDDs. The databases of PubMed (1985–2015), Web of Sciences (1985–2015), and Google Scholar (1980–2015) were searched using the set terms. The obtained results were screened for the relevant contents by two authors, and the appropriate studies were selected for further review. The most widely used protocols for depression are 1Hz for right and 10Hz for left DLPFC. In addition, the main parameters of these protocols and the main neurophysiological mechanisms of two common frequencies of 1 and 10 Hz are summarized. Different protocols of rTMS, particularly low versus high frequencies, result in significantly different electrophysiological and neurocognitive changes in the subject. Low frequency rTMS modulates frontal alpha power asymmetry and high frequency protocols influence more broader regions and wider electrophysiological characteristics of the brain.     

The dorsolateral prefrontal cortex in idiom interpretation: an rTMS study

Neuropsychological studies have suggested that a prefrontal lesion can impair idiom comprehension. We tested the role of the dorsolateral prefrontal cortex (DLPFC) in idiom processing by using repetitive transcranial magnetic stimulation (rTMS) in normal participants. Each subject was presented with a written (idiomatic or literal) sentence followed by four pictures. rTMS was applied over left or right DLPFC or in a sham condition after picture presentation. Reaction times (RTs) decreased for the two types of sentence during rTMS, but accuracy was affected only in the case of idioms. The results show that both left and right DLPFC are involved in monitoring the idiomatic response, thus complementing neuropsychological studies.     

An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression

Repetitive transcranial magnetic stimulation (rTMS) is currently undergoing active investigation for use in the treatment of major depression. Recent research has indicated that current methods used to localize the site of stimulation in dorsolateral prefrontal cortex (DLPFC) are significantly inaccurate. However, little information is available on which to base a choice of stimulation site. The aim of the current study was to systematically examine imaging studies in depression to attempt to identify whether there is a pattern of imaging results that suggests an optimal site of stimulation localization. We analysed all imaging studies published prior to 2005 that examined patients with major depression. Studies reporting activation in DLPFC were identified. The DLPFC regions identified in these studies were analysed using the Talairach and Rajkowska-Goldman-Rakic coordinate systems. In addition, we conducted a quantitative meta-analysis of resting studies and studies of serotonin reuptake inhibitor antidepressant treatment. There was considerable heterogeneity in the results between studies. Changes in Brodmann area 9 were relatively consistently identified in resting, cognitive activation and treatment studies included in the meta-analysis. However, there was little consistency in the direction of these changes or the hemisphere in which they were identified. At this stage, the results of imaging studies published to date have limited capacity to inform the choice of optimal prefrontal cortical region for the use in rTMS treatment studies.     

Intermittent theta-burst stimulation moderates interaction between increment of N-Acetyl-Aspartate in anterior cingulate and improvement of unipolar depression

BackgroundIntermittent theta-burst stimulation (iTBS), a novel repetitive transcranial magnetic stimulation (rTMS) technique, appears to have antidepressant effects when applied over left dorsolateral prefrontal cortex (DLPFC). However, its underlying neurobiological mechanisms are unclear. Proton magnetic resonance spectroscopy (¹H-MRS) provides in vivo measurements of cerebral metabolites altered in major depressive disorder (MDD) like N-acetyl-aspartate (NAA) and choline-containing compounds (Cho). We used MRS to analyse effects of iTBS on the associations between the shifts in the NAA and Cho levels during therapy and MDD improvement.MethodsIn-patients with unipolar MDD (N = 57), in addition to treatment as usual, were randomized to receive 20 iTBS or sham stimulations applied over left DLPFC over four weeks. Single-voxel ¹H-MRS of the anterior cingulate cortex (ACC) was performed at baseline and follow-up. Increments of concentrations, as well as MDD improvement, were defined as endpoints. We tested a moderated mediation model of effects using the PROCESS macro (an observed variable ordinary least squares and logistic regression path analysis modeling tool) for SPSS.ResultsImprovement of depressive symptoms was significantly associated with decrease of Cho/NAA ratio, mediated by NAA. iTBS had a significant moderating effect enhancing the relationship between NAA change and depression improvement.ConclusionsOur findings suggest a potential neurochemical pathway and mechanisms of antidepressant action of iTBS, which may moderate the improvement of metabolic markers of neuronal viability. iTBS might increase neuroplasticity, thus facilitating normalization of neuronal circuit function.     

Accelerated HF-rTMS in treatment-resistant unipolar depression: Insights from subgenual anterior cingulate functional connectivity

Objectives. Intensified repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) may result in fast clinical responses in treatment resistant depression (TRD). In these kinds of patients, subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) seems to be consistently disturbed. So far, no de novo data on the relationship between sgACC FC changes and clinical efficacy of accelerated rTMS were available. Methods. Twenty unipolar TRD patients, all at least stage III treatment resistant, were recruited in a randomized sham-controlled crossover high-frequency (HF)-rTMS treatment study. Resting-state (rs) functional MRI scans were collected at baseline and at the end of treatment. Results. HF-rTMS responders showed significantly stronger resting-state functional connectivity (rsFC) anti-correlation between the sgACC and parts of the left superior medial prefrontal cortex. After successful treatment an inverted relative strength of the anti-correlations was observed in the perigenual prefrontal cortex (pgPFC). No effects on sgACC rsFC were observed in non-responders. Conclusions. Strong rsFC anti-correlation between the sgACC and parts of the left prefrontal cortex could be indicative of a beneficial outcome. Accelerated HF-rTMS treatment designs have the potential to acutely adjust deregulated sgACC neuronal networks in TRD patients.