Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy

Objectives:  Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve depressive symptoms. We designed and carried out the following left prefrontal rTMS study to determine the safety, feasibility, and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD).
Methods:  We recruited and enrolled 23 depressed BPAD patients (12 BPI depressed state, nine BPII depressed state, two BPI mixed state). Patients were randomly assigned to receive either daily left prefrontal rTMS (5 Hz, 110% motor threshold, 8 sec on, 22 sec off, over 20 min) or placebo each weekday morning for 2 weeks. Motor threshold and subjective rating scales were obtained daily, and blinded Hamilton Rating Scale for Depression (HRSD) and Young Mania Rating Scales (YMRS) were obtained weekly.
Results:  Stimulation was well tolerated with no significant adverse events and with no induction of mania. We failed to find a statistically significant difference between the two groups in the number of antidepressant responders (>50% decline in HRSD or HRSD <10 – 4 active and 4 sham) or the mean HRSD change from baseline over the 2 weeks ( t =−0.22, p=0.83). Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment ( t =1.58, p=0.13). The motor threshold did not significantly change after 2 weeks of active treatment ( t =1.11, p=0.28).
Conclusions:  Daily left prefrontal rTMS appears safe in depressed BPAD subjects, and the risk of inducing mania in BPAD subjects on medications is small. We failed to find statistically significant TMS clinical antidepressant effects greater than sham. Further studies are needed to fully investigate the potential role, if any, of TMS in BPAD depression.     

Slow right prefrontal transcranial magnetic stimulation as a treatment for medication-resistant depression: a double-blind, placebo-controlled study

Over the past decade, efforts have been made to assess the positive therapeutic effects of transcranial magnetic stimulation (TMS) by altering the excitability of the brain. We conducted a double-blind, placebo-controlled study to assess the efficacy of right prefrontal slow repetitive TMS in patients with treatment refractory major depression. This pilot study supports the therapeutic potential of rTMS in the low-frequency range of 1 Hz on right prefrontal cortex for the treatment of refractory major depression. Additional studies will be necessary to assess the efficacy of rTMS with different indices (frequency, intensity, and stimulation site) for major depression and other psychiatric diseases.     

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: A randomized placebo controlled trial

Objectives. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. Methods. Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N = 17, sham coil with the TBS protocol). Results. There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. Conclusions. This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies.     

Comparison of cortical EEG responses to realistic sham versus real TMS of human motor cortex

Background

The analysis of cortical responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) has been successfully applied to study human cortical physiology. However, in addition to the (desired) activation of cortical neurons and fibers, TMS also causes (undesired) indirect brain responses through auditory and somatosensory stimulation, which may contribute significantly to the overall EEG signal and mask the effects of intervention on direct cortical responses.

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5‐day repeated sessions study

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a “build‐up” effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30 min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5 days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day‐to‐day was low in both groups, implying high within‐subject variability of both active and sham iTBS after‐effects. In contrast, we found a high within‐subject repeatability of resting and active motor threshold, and baseline motor‐evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5 days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.     

Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study.

BACKGROUND: Patients with bipolar disorder have been reported to have abnormal cortical function during mania. In this study, we sought to investigate neural activity in the frontal lobe during mania, using functional magnetic resonance imaging (fMRI). Specifically, we sought to evaluate activation in the lateral orbitofrontal cortex, a brain region that is normally activated during activities that require response inhibition. METHODS: Eleven manic subjects and 13 control subjects underwent fMRI while performing the Go-NoGo task, a neuropsychological paradigm known to activate the orbitofrontal cortex in normal subjects. Patterns of whole-brain activation during fMRI scanning were determined with statistical parametric mapping. Contrasts were made for each subject for the NoGo minus Go conditions. Contrasts were used in a second-level analysis with subject as a random factor. RESULTS: Functional MRI data revealed robust activation of the right orbitofrontal cortex (Brodmann's area [BA] 47) in control subjects but not in manic subjects. Random-effects analyses demonstrated significantly less magnitude in signal intensity in the right lateral orbitofrontal cortex (BA 47), right hippocampus, and left cingulate (BA 24) in manic compared with control subjects. CONCLUSIONS: Mania is associated with a significant attenuation of task-related activation of right lateral orbitofrontal function. This lack of activation of a brain region that is usually involved in suppression of responses might account for some of the disinhibition seen in mania. In addition, hippocampal and cingulate activation seem to be decreased. The relationship between this reduced function and the symptoms of mania remain to be further explored.     

On-line flexibility of the cognitive tuning of corticospinal excitability: a TMS study in human gait

Human subjects have been found to be able to cognitively prepare themselves to resist to a TMS-induced central perturbation by selectively modulating the corticospinal excitability (CS). The aim of this study was to investigate the on-line adaptability of this cognitive tuning of CS excitability during human gait. Transcranial magnetic stimulation (TMS) was used both as a central perturbation evoking a movement and as a tool for quantifying the CS excitability before the movement was evoked. TMS was applied at mid-stance (evoking additional hip extension) or at the beginning of the swing (evoking hip flexion) with a random phase, thus evoking unpredictable flexion or extension movement. This was compared to a condition of fixed phase, in which the subjects knew in advance the direction of the evoked movement. In both conditions, we compared the amplitude of the TMS-evoked movement and the motor-evoked potentials (MEPs) of the muscles acting at the hip joint (RF/BF) according to two opposite instructions, either to cognitively prepare to "let go", or to cognitively prepare to "compensate" for the evoked movements. The results showed that the subjects were able to compensate for random TMS-evoked movements, but with a lower performance level in comparison to the fixed TMS-evoked movements. When they succeeded in the random-phase condition, the subjects used the same preparation strategy as in the fixed-phase condition; preparing to compensate resulted in a selective increase in the CS excitability to those muscles which would be involved in counteracting the possible central perturbation. This requires continuous change in the tuning of CS excitability within the stride and thus reveals the high flexibility of the cognitive tuning of CS excitability during gait.     

Cortical and subcortical brain effects of transcranial magnetic stimulation (TMS)-induced movement: an interleaved TMS/functional magnetic resonance imaging study.

BACKGROUND: To date, interleaved transcranial magnetic stimulation and functional magnetic resonance imaging (TMS/fMRI) studies of motor activation have not recorded whole brain patterns. We hypothesized that TMS would activate known motor circuitry with some additional regions plus some areas dropping out. METHODS: We used interleaved TMS/fMRI (11 subjects, three scans each) to elucidate whole brain activation patterns from 1-Hz TMS over left primary motor cortex. RESULTS: Both TMS (110% motor threshold) and volitional movement of the same muscles excited by TMS caused blood oxygen level-dependent (BOLD) patterns encompassing known motor circuitry. Additional activation was observed bilaterally in superior temporal auditory areas. Decreases in BOLD signal with unexpected post-task "rebounds" were observed for both tasks in the right motor area, right superior parietal lobe, and in occipital regions. Paired t test of parametric contrast maps failed to detect significant differences between TMS- and volition-induced effects. Differences were detectable, however, in primary data time-intensity profiles. CONCLUSIONS: Using this interleaved TMS/fMRI technique, TMS over primary motor cortex produces a whole brain pattern of BOLD activation similar to known motor circuitry, without detectable differences from mimicked volitional movement. Some differences may exist between time courses of BOLD intensity during TMS circuit activation and volitional circuit activation.     

TMS in depression. A treatment whose time has come?

Garcia-Toro M, Romera M, Andrés J, Echevarría M. TMS in depression. A treatment whose time has come? Bipolar Disord 2002: 4(Suppl. 1): 100. © Blackwell Munksgaard, 2002     

Posterior medial frontal cortex and threat-enhanced religious belief: a replication and extension

Research indicates that the posterior medial frontal cortex (pMFC) functions as a ‘neural alarm’ complex broadly involved in registering threats and helping to muster relevant responses. Holbrook and colleagues investigated whether pMFC similarly mediates ideological threat responses, finding that downregulating pMFC via transcranial magnetic stimulation (TMS) caused (i) less avowed religious belief despite being reminded of death and (ii) less group bias despite encountering a sharp critique of the national in-group. While suggestive, these findings were limited by the absence of a non-threat comparison condition and reliance on sham rather than control TMS. Here, in a pre-registered replication and extension, we downregulated pMFC or a control region (MT/V5) and then primed participants with either a reminder of death or a threat-neutral topic. As mentioned previously, participants reminded of death reported less religious belief when pMFC was downregulated. No such effect of pMFC downregulation was observed in the neutral condition, consistent with construing pMFC as monitoring for salient threats (e.g. death) and helping to recruit ideological responses (e.g. enhanced religious belief). However, no effect of downregulating pMFC on group bias was observed, possibly due to reliance on a collegiate in-group framing rather than a national framing as in the prior study.     

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study

BackgroundIntermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly.ObjectiveWe compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS.Methods208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments.ResultsHRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups.ConclusionsThese results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD.Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792)     

Brain oscillation-synchronized stimulation of the left dorsolateral prefrontal cortex in depression using real-time EEG-triggered TMS

BackgroundRepetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity.ObjectiveTo study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD.MethodsUsing real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition.ResultsTriggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels.ConclusionsAlpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.     

Effectiveness of a second deep TMS in depression: a brief report

Objectives

Deep transcranial magnetic stimulation (DTMS) is an emerging and promising treatment for major depression. In our study, we explored the effectiveness of a second antidepressant course of deep TMS in major depression. We enrolled eight patients who had previously responded well to DTMS but relapsed within 1 year in order to evaluate whether a second course of DTMS would still be effective.

Methods

Eight depressive patients who relapsed after a previous successful deep TMS course expressed their wish to be treated again. Upon their request, they were recruited and treated with 20 daily sessions of DTMS at 20 Hz using the Brainsway's H1 coil. The Hamilton depression rating scale (HDRS), Hamilton anxiety rating scale (HARS) and the Beck depression inventory (BDI) were used weekly to evaluate the response to treatment.

Results

Similar to the results obtained in the first course of treatment, the second course of treatment (after relapse) induced significant reductions in HDRS, HARS and BDI scores, compared to the ratings measured prior to treatment. The magnitude of response in the second course was smaller relative to that obtained in the first course of treatment.

Conclusions

Our results suggest that depressive patients who previously responded well to deep TMS treatment are likely to respond again. However, the slight reduction in the magnitude of the response in the second treatment raises the question of whether tolerance or resistance to this treatment may eventually develop.     

Lack of prefrontal repetitive transcranial magnetic stimulation effects in time production processing

The aim of the present study was to determine the effects of high frequency repetitive transcranial magnetic stimulation (rTMS) over different neuroanatomical areas [left and right doroslateral prefrontal cortex (DLPFC) and right cerebellar hemisphere] on time production task. The study was performed in 16 healthy right-handed men with a cross-over, within subject repeated measures design. There were four rTMS conditions: baseline without stimulation, high frequency rTMS over right, left DLPFC and over right cerebellum. The volunteers were asked to produce a 3-min interval by internal counting. The rTMS was applied during the task. No significantly differences were observed in absolute error scores in time estimation task with any rTMS condition. This preliminary study does not support the role of the prefrontal lobe in time production processes.     

经颅磁刺激结合阿戈美拉丁治疗难治性抑郁症的临床研究

目的:探讨经颅磁刺激(TMS)结合阿戈美拉丁治疗难治性抑郁症的临床疗效.方法:选取2013年10月～2015年10月在本院门诊及住院诊治的137例难治性抑郁症患者,分为试验组:采用TMS结合阿戈美拉丁治疗67例;对照组:只进行TMS治疗70例.试验组应用高频(10 Hz以上)、低强度(运动阈值的95％)TMS治疗,持续时间15s,每次治疗刺激25次,每次间隔2 min,每日1次治疗,连续治疗5d为1个疗程,疗程之间间隔3d,共治疗2个月,同时给予阿戈美拉丁治疗,20 mg/d.对照组只用TMS治疗,疗程与试验组一致.采用SPSS 20.0进行统计学分析.结果:①试验组与对照组中,治疗后的汉密尔顿抑郁量表(HAMD)评分都低于治疗前(P＜0.05);治疗后,试验组的HAMD评分显著低于对照组(P＜0.01);②试验组与对照组中,治疗后的血浆去甲肾上腺素(NE)含量都高于治疗前(P＜0.05);治疗后,试验组的血浆NE含量显著高于对照组(P＜0.01);③试验组与对照组中,治疗后的平均巴氏指数(BI)都高于治疗前(P＜0.05);治疗后,试验组的平均BI显著高于对照组(P＜0.01);④试验组的治愈、显效和有效比例显著高于对照组(P＜0.01),试验组的无显效的比例显著低于对照组(P＜0.01).结论:TMS结合阿戈美拉丁治疗能明显改善抑郁症患者症状,治疗效果优于只应用TMS治疗的患者.     

Dorsomedial prefrontal cortex and cerebellar contribution to in‐group attitudes: a transcranial magnetic stimulation study

We tend to express more positive judgments and behaviors toward individuals belonging to our own group compared to other (out‐) groups. In this study, we assessed the role of the cerebellum and of the dorsomedial prefrontal cortex (dmPFC) – two regions critically implicated in social cognition processes – in mediating implicit valenced attitudes toward in‐group and out‐group individuals. To this aim, we used transcranial magnetic stimulation (TMS) in combination with a standard attitude priming task, in which Caucasian participants had to categorize the valence of a series of adjectives primed by either an in‐group or an out‐group face. In two behavioral experiments, we found an in‐group bias (i.e. faster categorization of positive adjectives when preceded by in‐group faces) but no evidence of an out‐group bias. Interestingly, TMS over both the dmPFC and over the (right) cerebellum significantly interfered with the modulation exerted by group membership on adjective valence classification, abolishing the in‐group bias observed at baseline. Overall, our data suggest that both the dmPFC and the cerebellum play a causal role in mediating implicit social attitudes.     

Critical role of rhythms in prefrontal transcranial magnetic stimulation for depression: A randomized sham‐controlled study

Repetitive transcranial magnetic stimulation (rTMS) is an alternative treatment for depression, but the neural correlates of the treatment are currently inconclusive, which might be a limit of conventional analytical methods. The present study aimed to investigate the neurophysiological evidence and potential biomarkers for rTMS and intermittent theta burst stimulation (iTBS) treatment. A total of 61 treatment‐resistant depression patients were randomly assigned to receive prolonged iTBS (piTBS; N = 19), 10 Hz rTMS (N = 20), or sham stimulation (N = 22). Each participant went through a treatment phase with resting state electroencephalography (EEG) recordings before and after the treatment phase. The aftereffects of stimulation showed that theta‐alpha amplitude modulation frequency (f _am) was associated with piTBS_Responder, which involves repetitive bursts delivered in the theta frequency range, whereas alpha carrier frequency (f _c) was related to 10 Hz rTMS, which uses alpha rhythmic stimulation. In addition, theta‐alpha amplitude modulation frequency was positively correlated with piTBS antidepressant efficacy, whereas the alpha frequency was not associated with the 10 Hz rTMS clinical outcome. The present study showed that TMS stimulation effects might be lasting, with changes of brain oscillations associated with the delivered frequency. Additionally, theta‐alpha amplitude modulation frequency may be as a function of the degree of recovery in TRD with piTBS treatment and also a potential EEG‐based predictor of antidepressant efficacy of piTBS in the early treatment stage, that is, first 2 weeks.     

Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS–EEG study

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.     

Intracortical inhibition and facilitation are impaired in patients with early Parkinson''s disease: a paired TMS study

Twelve patients with early Parkinson's disease (PD), none of whom had received any previous L-DOPA treatment, but using other antiparkinsonian drugs, were studied using transcranial magnetic stimulation (TMS). Contralateral and ipsilateral hemispheres were examined, with a focus on the more pronounced parkinsonian symptoms. The conditioning-test TMS paradigm (with a subthreshold conditioning stimulus and a suprathreshold test stimulus) was used through a stimulating round coil. Paired stimuli of short (3, 5 and 7 ms), medium (10, 15 and 20 ms), and long (100, 150, 200 and 250 ms) interstimulus intervals (ISI) were pseudo-randomly mixed with a single stimulus. The first interosseus muscle was used for the motor-evoked potential recordings. Ten healthy subjects (age and sex matched) were studied in the same manner to obtain normative data. When both groups were compared, the significant difference (reduction of the intracortical inhibition and facilitation) between the PD patients and the control group was found at the short and the medium ISI (3, 5, 7, 10, 15 and 20 ms) in both hemispheres (P < 0.05). The longer ISI produced non-significant differences between the two groups in intracortical excitability. There was a non-significant difference in the motor threshold. In conclusion, it can be supposed that both intracortical inhibition and facilitation are impaired in patients with early PD using other antiparkinsonian treatments than L-DOPA or dopamine agonists.