Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is being investigated as a potential treatment for depression. Few studies have addressed the neurocognitive effects of a course of rTMS in severely depressed patients. We evaluated neurocognitive effects of a 1-4 week course (mean 3 weeks) of rTMS using an aggressive set of parameters, in 15 severely depressed subjects. METHODS: A battery of neurocognitive tests relevant to attention, working memory-executive function, objective memory and motor speed were administered to 15 subjects with treatment-resistant major depression (unipolar and bipolar), before and after a course of rTMS. Mean z scores were computed for each of 4 cognitive domains and analyzed using repeated measures multivariate analysis of covariance. Significant interactions were further clarified using univariate analysis of variance. RESULTS: There was no worsening of performance on any of the cognitive domains over the baseline-post rTMS period. On the contrary, evidence of modest but statistically significant improvement in performance was noted in working memory-executive function, objective memory and fine motor speed domains over the rTMS treatment period. CONCLUSIONS: There was no evidence of adverse neurocognitive changes over the baseline-post rTMS period in 15 treatment-resistant depressed subjects undergoing a 3 week (mean) trial of rTMS. Significant improvements in several domains observed over the rTMS treatment period could not be explained by improved mood. Practice effects as well as other factors potentially contributing to these findings are discussed. SIGNIFICANCE: rTMS is being increasingly studied as a neurophysiological probe as well as for its potential antidepressive effects. The effects on neuronal function raise appropriate questions of safety of its use at varying stimulus parameters and durations. This study contributes to the small body of evidence of the cognitive effects of rTMS in severely depressed patients.     

Physiological effects of electroconvulsive therapy and transcranial magnetic stimulation in major depression

Major depressive episodes are associated with dysregulation of various physiologic systems. Antidepressant medications alter regulation of the hormonal and sleep systems. A thorough understanding of these changes may elucidate the pathophysiologic basis of the disorder [Amsterdam et al., 1989: Psychoneuroendocrinology 14:43-62], and interventions targeted directly at these systems are being increasingly recognized as possible treatments for depression [Wong et al., 2000: Proc Natl Acad Sci USA 97:325-330; Szuba et al., 1996: Proc Am Coll Neuropsychopharmacol Ann Meet]. These physiologic systems are regulated by the major neurotransmitters implicated in the etiology of mood disorders--norepinephrine, serotonin, and dopamine. Many of the hormones of import for this article also act as neurotransmitters and thus alter cerebral activity themselves [Owens and Nemeroff, 1993: Ciba Found Symp 172:296-308; Weitzner, 1998: Psychother Psychosom 67:125-132]. Parenteral infusion of hydrocortisone [DeBattista, 2000: Am J Psychiatry 157:1334-1337] and thyrotropin-releasing hormone (TRH) [Prange et al., 1972: Lancet 2:999-1002; Marangell et al., 1997: Arch Gen Psychiatry 54:214-222; Szuba, 1996: Proc Am Coll Neuropsychopharmacol Ann Meet.] produce acute antidepressant effects. Antagonists to corticotropin-releasing hormone and repeated parenteral infusion of TRH may have antidepressant activity when given during several weeks [Wong, 2000: Proc Natl Acad Sci USA 97:325-330; Arborelius et al., 1999: J Endocrinol 160:1-12; Callahan et al., 1997: Biol Psychiatry 41:264-272]. Manipulations of the sleep system through sleep deprivation can ameliorate depression [Szuba et al., 1994: Psychiatry Res 51:283-295; see Wirz-Justice et al., 1999: Biol Psychiatry 46:445-453 for review]. Sleep deprivation has been shown in more than three dozen studies published in the last three decades to produce marked, acute antidepressant effects in the majority of depressed individuals [Wirz-Justice, et al., 1999: Biol Psychiatry 46:445-453]. Thus, examination of the effects the two nonpharmacologic treatments, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), produce in these physiologic systems may help elucidate their mechanisms of action, while enhancing understanding of the neurobiology of depressive illness. We will review these physiologic changes associated with depression, the effects that manipulations of these systems can have on depressive disorders, and then describe the effects the two techniques that can stimulate the human brain in vivo, ECT and TMS, exert on these systems.     

A controlled study of repetitive transcranial magnetic stimulation in medication-resistant major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) as a treatment for depression has shown statistically significant effects, but the clinical significance of these effects has been questioned. METHODS: Patients with medication-resistant depression were randomized to receive 15 sessions of active or sham repetitive TMS delivered to the left dorsolateral prefrontal cortex at 110% the estimated prefrontal cortex threshold. Each session consisted of 32 trains of 10 Hz repetitive TMS delivered in 5-second trains. The primary end point was treatment response defined as a >or=50% decrease in Hamilton Depression Rating Scale (HDRS) score at both 1 and 2 weeks following the final repetitive TMS treatment. Remission was defined as a HDRS score < 8. RESULTS: The response rate for the TMS group was 30.6% (11/35), significantly (p = .008) greater than the 6.1% (2/33) rate in the sham group. The remission rate for the TMS group was 20% (7/35), significantly (p = .033) greater than the 3% (1/33) rate in the sham group. The HDRS scores showed a significantly (p < .002) greater decrease over time in the TMS group compared with the sham group. CONCLUSIONS: Transcranial magnetic stimulation can produce statistically and clinically significant antidepressant effects in patients with medication-resistant major depression.     

Influence of repetitive transcranial magnetic stimulation on psychomotor symptoms in major depression

Psychomotor symptoms related to an impairment of the nigrostriatal dopaminergic system are frequent in major depression (MD). Repetitive transcranial magnetic stimulation (rTMS) has been discussed as a new treatment option for MD. In neurobiological terms, an influence of high-frequency rTMS on dopaminergic neurotransmission has previously been shown by several studies in animals and humans. Therefore, an improvement of psychomotor symptoms by rTMS could be assumed. The aim of this pilot study was to investigate the effect of high-frequency rTMS on psychomotor retardation and agitation in depressive patients. We investigated the effect of left prefrontal 10 Hz rTMS on psychomotor retardation and agitation in 30 patients with MD. Patients were randomly assigned to real or sham rTMS in addition to a newly initiated standardized antidepressant medication. We found a trend in the reduction of agitation (t ₂₈ = 1.76, p = 0.09, two-tailed), but not in the reduction of retardation. Furthermore, no general additional antidepressant effect of rTMS was observed. Although there was no statistical significant influence of high-frequency rTMS on psychomotor symptoms in depressive patients, the results showed a trend in the reduction of psychomotor agitation in MD. This effect should be systematically investigated as the primary end point in further studies with larger sample sizes.     

Occurrence of delusions during repetitive transcranial magnetic stimulation (rTMS) in major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been suggested as a potentially useful treatment for major depression. Nonpsychotic depressed patients appear to have a better outcome than those with psychotic symptoms. METHODS: We report findings in a patient suffering from recurrent, nonpsychotic major depression (DSM-IV) who had 13 daily sessions of rTMS monotherapy within a 3 week period. RESULTS: During rTMS treatment, the patient developed recurrent severe delusions, which he had never experienced before. Psychotic symptoms remitted quickly with neuroleptic medication. CONCLUSIONS: In light of preclinical findings showing increased dopaminergic activity after rTMS treatment, occurrence of psychotic symptoms should be considered a potential side effect of rTMS treatment.     

Connectome-guided transcranial magnetic stimulation treatment in depression

European Child & Adolescent Psychiatry -     

Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression

Twelve patients with comorbid posttraumatic stress disorder (PTSD) and major depression underwent repetitive transcranial magnetic stimulation (rTMS) to left frontal cortex as an open-label adjunct to current antidepressant medications. rTMS parameters were as follows: 90% of motor threshold, 1 Hz or 5 Hz, 6,000 stimuli over 10 days. Seventy-five percent of the patients had a clinically significant antidepressant response after rTMS, and 50% had sustained response at 2-month follow-up. Comparable improvements were seen in anxiety, hostility, and insomnia, but only minimal improvement in PTSD symptoms. Left frontal cortical rTMS may have promise for treating depression in PTSD, but there may be a dissociation between treating mood and treating core PTSD symptoms.     

Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression

There is evidence that repetitive transcranial magnetic stimulation (rTMS) applied to the prefrontal cortex has antidepressive properties. In the present study we evaluated the clinical status and the hemodynamic responses during mental work in the prefrontal cortex before therapeutic rTMS. Twelve patients diagnosed with major depression (DSM-IV) were randomized in a sham-controlled cross-over treatment protocol of 4 weeks' duration consisting of two periods of 5 days with rTMS separated by 9 days of no stimulation. rTMS (10 Hz) was applied to the left dorsolateral prefrontal cortex. Hemodynamic changes in the prefrontal cortex during mental work were evaluated by multi-site near-infrared spectroscopy (NIRS). Scores on the Hamilton Depression Rating Scale (HAMD) decreased significantly by -5.4 points after 5 days of active stimulation, whereas it did not change (+1.6 points) after sham stimulation. Absence of a task-related increase of total hemoglobin concentrations at the stimulation site (P<0.005), but not at other locations, before the first active rTMS significantly predicted the clinical response to active rTMS. Clinical benefits of rTMS are predicted by low local hemodynamic responses and support the idea of activation-dependent targeting of rTMS location.     

Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression.

OBJECTIVE: The efficacy and safety of left prefrontal repetitive transcranial magnetic stimulation (rTMS) for treating resistant major depression were examined in a double-blind, controlled study. METHOD: Eighteen medication-resistant depressed subjects were randomly assigned to 2 weeks of real or sham rTMS, then permitted up to 4 weeks of real rTMS. Effects on mood, neuropsychological function, EEG, and hearing were assessed. RESULTS: The groups receiving real and sham rTMS improved in mood significantly over the 2-week double-blind period, but there was no significant difference between groups. CONCLUSIONS: Repetitive transcranial magnetic stimulation did not provide significantly greater improvement than did sham treatment. A 4-week course of rTMS, as administered in this study, was safe.     

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.

BACKGROUND: Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS: Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS: The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS: A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.     

The effects of repetitive transcranial magnetic stimulation (rTMS) on procedural memory and dysphoric mood in patients with major depressive disorder.

OBJECTIVE: To study the effects of depression and treatment with repetitive transcranial magnetic stimulation (rTMS) on sequence learning. BACKGROUND: Prefrontal dysfunction in depression may affect sequence learning and be amenable to normalization by rTMS. METHOD: The serial reaction time test (SRTT) was administered to 19 patients with major depressive disorder (MDD) and 20 nondepressed control participants. MDD patients were examined before and following treatment with rTMS to the left dorsolateral prefrontal cortex in daily sessions of 1600 stimuli at 10 Hz and at an intensity of 110% of the motor threshold. Treatment occurred over a 2-week interval of time. RESULTS: MDD and nondepressed groups differed significantly with respect to baseline response speed. Following treatment with rTMS, MDD participants demonstrated significantly improved mood, improved response speed, and improved procedural learning. CONCLUSIONS: Findings suggest that rTMS over a 2-week period improves performance on tasks of response speed and procedural memory in patients with MDD. These cognitive effects are greater in those patients who showed a significant antidepressant effect to rTMS intervention.     

Improvement of depression following transcranial magnetic stimulation

Psychiatry as a field was transformed by the discovery and introduction of electroconvulsive therapy (ECT) as a treatment in the early part of this century. ECT demonstrated that depression was a disease of the brain and that it could be treated with a direct brain intervention. Psychiatry’s evolution continued in 1958 with the discovery of the antidepressant activity of the monoamine oxidase inhibitors. Interestingly, although the area of neuropsychopharmacology has continued to advance, the realm of physical somatic interventions in psychiatry has lagged behind. With perhaps the exception of light therapy, there were no advances in somatic interventions in psychiatry. However, in 1985, Barker et al. 1 developed a brief high intensity electromagnet capable of depolarizing cortical neurons, called transcranial magnetic stimulation (TMS). There has been much interest in the past 10 years in whether TMS might have antidepressant actions, similar to ECT but without causing a seizure and with no apparent cognitive side effects. This review examines the basic principles underlying TMS, and describes how TMS differs from electrical stimulation and the other uses of magnets.     

Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation

BACKGROUND: Imaging and electroencephalographic studies have reported inter-hemispheric asymmetries in frontal cortical regions associated with depression. This study aimed at comparing motor corticospinal excitability assessed by methods of transcranial magnetic stimulation (TMS) between the right and left hemispheres in patients with major depression and healthy controls. METHOD: Patients with major depression (n=35) and healthy controls (n=35) underwent a bilateral study of various motor corticospinal excitability parameters, including rest motor threshold (RMT), corticospinal silent period (CSP) duration and intra-cortical inhibition (ICI) and facilitation (ICF). Indexes of asymmetry were calculated, and the relationships between excitability parameters and clinical scores of depression were statistically analyzed. RESULTS: Depressed patients showed a reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere, compared to the right hemisphere and to healthy controls. CONCLUSION: The present results confirmed the existence of inter-hemispheric asymmetries in frontal cortex activities of depressed patients in favor of a left-sided reduced excitability. This neurophysiological approach may help to guide repetitive TMS procedures in the treatment of depressive disorders.     

重复经颅磁刺激联合舍曲林对精神分裂症后抑郁影响的随机对照研究

目的探讨重复经颅磁刺激(r TMS)联合舍曲林对精神分裂症后抑郁的疗效及认知功能的影响。方法采用随机数字表法将符合《国际疾病分类(第10版)》(ICD-10)精神分裂症后抑郁诊断标准的78例患者分为观察组和对照组各39例,对照组采用舍曲林治疗,观察组在对照组治疗方案的基础上辅用r TMS治疗,两组均于治疗前及治疗6周后采用汉密尔顿抑郁量表(HRSD)、Herth希望指数量表(HHI)、威斯康辛卡片分类测验(WCST)进行测评。结果治疗后,两组HRSD评分均低于治疗前(t=34.212,26.631,P0.01),且观察组低于对照组(t=6.705,P0.01);治疗后两组HHI总分及各项因子评分高于治疗前(t=6.737,6.245,11.008,6.403,P0.01),两组HHI总分及各项因子评分比较差异均有统计学意义(t=3.184,2.799,4.265,2.855,P0.01);治疗后观察组WCST评分较治疗前差异有统计学意义(t=20.399,18.558,5.101,5.894,15.385,P0.01),观察组WCST评分较对照组差异有统计学意义(t=11.900,10.614,3.739,3.573,6.229,P0.01)。结论重复经颅磁刺激合并舍曲林可能提高精神分裂症后抑郁的疗效及心理希望水平,改善患者的认知功能。     

Repetitive transcranial magnetic stimulation influences mood in healthy male volunteers

The influence of repetitive transcranial magnetic stimulation (rTMS) on mood in healthy people is uncertain, as former studies show divergent results. Previous studies in healthy volunteers focused exclusively on the immediate effect of a single session of rTMS. In contrast the aim of this randomised sham-controlled study was to analyse the influence on mood of a series of 9 High Frequency (HF) rTMS stimulations of the left dorsolateral prefrontal cortex (DLPFC).44 young healthy male volunteers were randomly assigned to receive 9 sessions of active HF-rTMS (n = 22) or sham rTMS (n = 22) over the left DLPFC. Each session in the active group consisted of 15 trains of 25 Hz starting with 100% of motor threshold. Sham stimulation was performed following the same protocol, but using a sham coil. The variables of interest were the Beck Depression Inventory (BDI) and six Visual Analogue Scales (VAS) which quantified “mood”, “enjoyment” and “energy”. We found a significant reduction of the BDI sum score in the active group (GLM, p < 0.001) whereas no significant changes of the BDI sum score were caused by sham stimulation (GLM, p = 0.109). The BDI single item analyses revealed within and between group differences supporting the modifying effect of rTMS on BDI. According to the employed VAS we did not find significant differences caused by active or sham stimulation in five of six VAS. In the VAS labelled lively/gloomy the active group was found to be more “gloomy” (p = 0.0111) immediately after stimulation. Our data show that a 9-day long series of HF-rTMS of the left DLPFC improves mood, analysed by BDI in healthy young men, whereas no significant long-term changes were found in VAS.     

Augmenting antidepressants with deep transcranial magnetic stimulation (DTMS) in treatment-resistant major depression

Objectives. Deep transcranial magnetic stimulation (DTMS) has been shown to be efficacious and relatively safe for major depressive disorder (MDD). However, its clinical utility as an augmenting strategy for treatment-resistant depression (TRD) remains unexplored. Methods. In an open label trial, 17 outpatients with severe TRD received 4 weeks of daily high frequency DTMS over the left dorsolateral prefrontal cortex. Depressive and anxious symptoms, suicidality and quality of life (QOL) were measured at baseline (i.e., in the week prior to the start of the DTMS treatment) and at week 5 (i.e., in the week following the end of the DTMS treatment). Primary outcome measures were rates of response and remission at week 5 using an intention-to-treat approach. Results. Response and remission rates at week 5 were 70.6 and 41.2%, respectively. Also, depression, anxiety, and suicidality ratings were significantly improved by week 5 (with Hedges’ g estimates ranging from 0.6 to 1.72), as well as four of the five QOL domain scores (i.e., global, psychological, environmental and social). Finally, two patients dropped out of the study at week 1 because of significant scalp discomfort during stimulation. Conclusions. Our study suggests that DTMS, when used as an augmenting strategy for antidepressants in severe TRD, is efficacious, safe and relatively well tolerated. However, controlled studies with larger samples are needed to confirm and expand our preliminary findings.     

Daily and spaced treatment with transcranial magnetic stimulation in major depression: a pilot study

OBJECTIVE: Transcranial magnetic stimulation is an emerging treatment of treatment-resistant depression. Current protocols rely on daily treatments. This study was designed to determine whether the time period over which treatment is delivered is an important factor in efficacy. METHOD: Sixteen adult patients with treatment-resistant major depression were randomly assigned to one of the two treatment groups, both of which received 2 weeks of treatment. One group received daily treatment (10 treatments, on business days). The other group received three treatments in week one, and two treatments in week two (five treatments, on spaced business days). Mood was rated using the Hamilton Depression Rating Scale (HDRS) and a self-rated visual analogue scale. Response was defined as a 50% reduction in HDRS rating, and remission was defined as achieving an HDRS score of 8 or less. The groups were compared throughout the 2-week study period. RESULTS: At entry, there were no demographic differences between the groups. Multivariate tests showed a significant main effect for time (Pillai trace=0.76, F(4,56)=8.56, p<0.001, power=0.99) reflecting the improvement in both measures of depression during treatment. There was no significant difference between the groups overall (Pillai trace=0.25, F(2,13)=2.12, p=0.16, power=0.36). Additionally, there was no significant interaction between time and treatment group (Pillai trace=0.18, F(4,56)=1.35, p=0.26, power=0.39) indicating that the significant improvement in depression over time was similar for both treatment groups. There were no significant differences in response and remission rates between the groups. CONCLUSION: The time period of treatment appeared to be an important outcome factor. This suggests that less than daily transcranial magnetic stimulation treatment may be a useful clinical alternative.