Regional cerebral blood flow changes after low-frequency transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in treatment-resistant depression

Several studies have proved that low-frequency transcranial magnetic stimulation (TMS) of the right dorsolateral prefrontal cortex (DLPFC) showed an antidepressant effect, although its mechanism is still not completely elucidated. The aim of the present study was to clarify the alteration in neuroanatomical function elicited by low-frequency TMS of the right DLPFC in treatment-resistant depression and to detect the difference between responders and nonresponders to TMS. Single-photon emission computed tomography with (99m)Tc-ethyl cysteinate dimer was performed in 14 right-handed male patients with treatment-resistant unipolar depression before and after low-frequency TMS of the right DLPFC. Five 60-second 1-Hz trains were applied and 12 treatment sessions were administered within a 3-week period (total pulses, 3,600). The Hamilton Rating Scale for Depression was administered and the regional cerebral blood flow (rCBF) was analyzed using statistical parametric mapping (SPM2). After TMS treatment in 14 patients, the score on the Hamilton Rating Scale for Depression decreased significantly, and considerable decreases in rCBF were seen in the bilateral prefrontal, orbitofrontal, anterior insula, right subgenual cingulate, and left parietal cortex, but no significant increase in rCBF occurred. Additionally, as compared with 8 nonresponders, 6 responders showed significant increases in rCBF at baseline in the left hemisphere including the prefrontal and limbic-paralimbic regions. These results suggest that the antidepressant effect of low-frequency TMS of the right DLPFC is associated with a decrease in rCBF in the limbic-paralimbic regions via the ipsilateral subgenual cingulate, and increased rCBF at baseline in the left hemisphere may be involved in the response to low-frequency TMS treatment.     

Chronic vagus nerve stimulation for treatment-resistant depression increases regional cerebral blood flow in the dorsolateral prefrontal cortex

The purpose of the present study was to assess the effects of vagus nerve stimulation (VNS) therapy on regional cerebral blood flow (rCBF) in depressed patients. Regional cerebral blood flow (rCBF) was assessed by [^99mTc]-HMPAO-single photon emission computed tomography (SPECT) before and after 10 weeks of VNS in patients participating in an open, uncontrolled European multi-center study investigating efficacy and safety of VNS. Patients suffered from major depression, with a baseline score of ≥ 20 on the 24-item Hamilton Depression Rating Scale (HDRS) and had been unsuccessfully treated with at least two adequately prescribed antidepressant drugs. Data of 15 patients could be analyzed using SPM 2. After 10 weeks of VNS (20 Hz, 500 μs pulse width, stimulation during 30 s every 5 min at the maximal comfortable level) rCBF was increased in the left dorsolateral/ventrolateral prefrontal cortex (Brodmann areas 46 and 47) and decreased in the right posterior cingulate area, the lingual gyrus and the left insula. Our findings are in line with earlier results which showed that VNS increases rCBF in the left dorsolateral prefrontal cortex. The modulation of the activity in this region could be associated with the antidepressant efficacy of VNS.     

Decrease of middle cerebral artery blood flow velocity after low-frequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in a variety of neuropsychiatric disorders. Both, inhibition and activation of cortical areas may be achieved using different stimulation parameters. Using low-frequency rTMS (0.9 Hz), inhibition of cortical areas can be observed. METHODS: In the present study, 38 right-handed, healthy, normotensive subjects (aged 21-50 years, mean 30.2 years, SD=4.9; 17 women) were enrolled. Twenty-five participants received active rTMS (5 min of 0.9 Hz rTMS, stimulus intensity 90% of motor threshold) of the right dorsolateral prefrontal cortex. Sham stimulation (n=13 subjects) occurred in the same manner as active rTMS, except that the angle of the coil was at 45 degrees off the skull. Simultaneously, ipsilateral and contralateral maximal middle cerebral artery (MCA) flow velocity (and pulsatility index, PI) was monitored using transcranial Doppler sonography. RESULTS: In the group with active rTMS, maximal MCA flow velocity decreased from a baseline (before rTMS) of 101.6 cm/s (SD=26.0) to a mean of 92.6 cm/s (SD=23.7) immediately after rTMS, T=5.06, P<0.001. This equals a mean decrease of 9.0 cm/s (SD=8.3) or approximately 8.9% of baseline flow. Five and 10 min after rTMS, there was a return to baseline. PI significantly decreased 10 min after rTMS (mean difference -0.05, SD=0.05, T=2.29, P<0.05). In the contralateral MCA, maximal flow velocity tended to increase 10 min after rTMS (mean difference +7.4 cm/s, SD=17.5; T=-2.03, P=0.054). With sham rTMS, no significant changes occurred. CONCLUSIONS: The results from our study support the hypothesis that low-frequency rTMS may influence cerebral blood flow (CBF) over short periods of time, inducing a temporary decrease of maximal CBF in the ipsilateral MCA followed by an increase in the contralateral MCA.     

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.     

Using imaging to target the prefrontal cortex for transcranial magnetic stimulation studies in treatment-resistant depression

Structural imaging studies of the brains of patients with treatment-resistant depression (TRD) have found several abnormalities, including smaller hippocampus, orbitofrontal cortex, or pre­frontal cortex. Transcranial magnetic stimulation (TMS) is a noninvasive means of modulating brain activity, and has shown antidepressant treatment efficacy.¹ The initial methods used for targeting the prefrontal cortex are most likely insufficient. Herwig et al found that a common rule-based approach (the 5-cm rule) resulted in approximately one third of subjects receiving stimulation over the premotor, and not the prefrontal, cortex.² The work of Kozel et al,³ replicated by Mosimann et al,⁴ showed that increasing prefrontal cortical atrophy was correlated with TMS nonresponse. These studies have raised the question of whether there might be prefrontal location methods that result in higher TMS antidepressant efficacy. Measurement of distance from skull to cortex (ds-c) provides information about both normal and pathological cortical atrophy. It has been proposed that ds-c can be used to adjust the dosage of TMS. The ds-c can be measured manually after a scan or with automated software. We are currently involved in a four-site NIMH-sponsored trial (Optimization of TMS in Depression - OPT-TMS), testing whether daily prefrontal repetitive IMS (rTMS) has antide­pressant efficacy All subjects receive a baseline MRI scan with fiducials marking the motor and putative prefrontal cortex. We report the results concerning atrophy (intensity) and location in the first 20 subjects in this trial (estimated final sample: 240).     

High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients

Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in major depression. In order to investigate the therapeutic efficacy of rTMS in psychotic patients, 12 participants (four women, eight men) with schizophrenia according to DSM-IV criteria, aged 25 to 63 years (mean (+/-s.d) 40.4+/-11.0), were enrolled in the study. Following a double-blind crossover design, patients were treated at random with 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. Prefrontal rTMS might be effective in the non-pharmacological treatment of psychotic patients.     

Release of premotor activity after repetitive transcranial magnetic stimulation of prefrontal cortex

In the present study we aimed to explore by means of repetitive transcranial magnetic stimulation (rTMS) the reciprocal influences between prefrontal cortex (PFC) and premotor cortex (PMC). Subjects were asked to observe on a computer monitor different pictures representing manipulations of different kind of tools. They had to produce a movement (go condition) or to keep the resting position (no-go condition) at the appearance of different cue signals represented by different colors shown alternatively on the hands manipulating the tools or on the picture background. Motor evoked potentials (MEPs) were collected at the offset of the visual stimuli before and after a 10 minute, 1 Hz rTMS train applied to the dorsolateral PFC (Experiment 1), to the PMC (Experiment 2) or to the primary motor cortex (Experiment 3). Following rTMS to the PFC, MEPs increased in the go condition when the cue for the go command was presented on the hand. In contrast, following rTMS to the PMC, in the same condition, MEPs were decreased. rTMS to the primary motor cortex did not produce any modulation. Results are discussed according to the presence of a visual-motor matching system in the PMC and to the role of the PFC in the attention-related processes. We hypothesize that the perceptual analysis for action selection within the PFC was modulated by rTMS and its temporary functional inactivation in turn influenced the premotor areas for motor programming.     

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.     

Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression

Aims: Low‐frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, and its antidepressant effects have proven to correlate with decreases in cerebral blood flow (CBF) in the orbitofrontal cortex and subgenual cingulate cortex. However, a predictor of treatment response to low‐frequency right prefrontal rTMS in depression has not been identified yet. The aim of this study was to estimate regional CBF in the frontal regions and investigate the correlation with treatment response to low‐frequency right prefrontal rTMS in depression. Methods: We examined 26 depressed patients for the correlation between treatment response to rTMS and regional CBF in the frontal regions, by analyzing their brain scans with ^99mTc‐ethyl cysteinate dimer before rTMS treatment. CBF in 16 brain regions was estimated using fully automated region of interest analysis software. Two principal components were extracted from CBF in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization. Results: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions) and ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was not correlated with CBF in the dorsolateral prefrontal cortex, but it was correlated with CBF in the ventromedial prefrontal cortex. Conclusion: These findings suggest that CBF in the ventromedial prefrontal cortex may be a potential predictor of low‐frequency right prefrontal rTMS, and depressed patients with increased CBF in the ventromedial prefrontal cortex may show a better response.     

Repetitive transcranial magnetic stimulation of the prefrontal cortex in depression

Transcranial magnetic stimulation is an interesting technique for non-invasively stimulating the brain in awake alert humans. It is a powerful research tool for examining brain behavior relationships. Additionally many researchers are investigating whether repeatedly applying TMS to specific regions over several days to weeks might have therapeutic effects. By far the largest amount of work has been done investigating whether daily applications of prefrontal TMS can improve the symptoms of major depression. We review the literature combining TMS with brain imaging, and then overview the clinical work done to date with TMS in depression. The literature to date suggests that daily prefrontal TMS for several weeks clearly has antidepressant effects, but much work remains to establish the effect sizes and improve the methods of delivery in order to improve its potential clinical utility.     

Effect of chronic repetitive transcranial magnetic stimulation on regional cerebral blood flow and regional cerebral glucose uptake in drug treatment-resistant depressives. A brief report.

Brain imaging studies have shown that repetitive transcranial magnetic stimulation (rTMS) is biologically active. The aim of the present study was to investigate the patterns of the regional cerebral glucose uptake rate (rCMRGlu) and regional (99m)Tc HMPAO uptake rate (regional cerebral blood flow; rCBF) during a series of therapeutic rTMS sessions at low frequency. Four drug-resistant depressed patients underwent 10 rTMS sessions as an add-on measure over 14 days. One day before and 1 day after the TMS series, 511-keV SPECT with simultaneous (18)F-fluorodeoxyglucose and (99m)Tc HMPAO measurements were carried out. All patients showed a good clinical outcome. Statistically significant common changes in rCBF and rCMRGlu patterns were found in the upper frontal regions bilaterally in terms of increased uptake rates and in the left orbitofrontal cortex in terms of decreased uptake rates of both isotopes compared to controls. However, the lateralization patterns of rCBF and rCMRGlu after rTMS treatment revealed marked differences. Thus, although no relevant changes in lateralization of the glucose uptake were observed, a clear right-sided preponderance of rCBF also in areas remote from the stimulation site was described. Therapeutic rTMS seems to influence distinct cortical regions, affecting rCBF and rCMRGlu in a homogeneous manner as well as in different ways, which are probably region dependent and illness related. The role of the stimulation coil placement site should be taken into account.     

Subthreshold prefrontal repetitive transcranial magnetic stimulation reduces motor cortex excitability

The prefrontal cortex plays an important role in central motor control. We have examined whether prefrontal repetitive transcranial magnetic stimulation (rTMS) induces changes of motor cortex excitability determined by motor evoked potentials (MEPs) following single-pulse TMS. We studied 18 healthy volunteers stimulated at 5 Hz with 10% subthreshold prefrontal vs. occipital rTMS for 12 s. MEPs from the flexor carpi radialis muscle after single-pulse vertex stimulation were recorded during rTMS at 0, 4, 8, and 12 s. MEP areas decreased significantly after 8 s of prefrontal rTMS (P < 0. 05) but not after occipital rTMS. We conclude that rTMS of the prefrontal cortex may inhibit the primary motor areas.     

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.     

The left dorsolateral prefrontal cortex and random generation of responses: studies with transcranial magnetic stimulation

Evidence from PET studies suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in generation of random responses. We used TMS to examine the specific role of this area in random generation of responses, a task which requires holding information 'on line', suppression of habitual or stereotyped response patterns, intrinsic response generation, monitoring of responses and modification of production strategies. From the results of a previous study of the effects of TMS on random number generation, we proposed a network modulation model, whereby suppression of habitual responses is considered a key process of random response generation and is achieved through the modulatory influence of the left DLPFC over an associative network distributed in the superior temporal cortex. The aim of the present study was to further investigate the generality of this model by examining the effects of short trains of TMS over the left or right DLPFC or medial frontal cortex on random letter generation in healthy participants. TMS over the left DLPFC significantly increased non-randomness relative to control no stimulation trials, which was not obtained with TMS over the right DLPFC or medial frontal cortex. The results suggest the generality of network modulation model of random response generation.     

Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex affects strategic decision-making

Although decision-making is typically seen as a rational process, emotions play a role in tasks that include unfairness. Recently, activation in the right dorsolateral prefrontal cortex during offers experienced as unfair in the Ultimatum Game was suggested to subserve goal maintenance in this task. This is restricted to correlational evidence, however, and it remains unclear whether the dorsolateral prefrontal cortex is crucial for strategic decision-making. The present study used repetitive transcranial magnetic stimulation in order to investigate the causal role of the dorsolateral prefrontal cortex in strategic decision-making in the Ultimatum Game. The results showed that repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex resulted in an altered decision-making strategy compared with sham stimulation. We conclude that the dorsolateral prefrontal cortex is causally implicated in strategic decision-making in healthy human study participants.