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High and low frequency repetitive transcranial magnetic stimulation (rTMS) are both used to treat major depressive disorder(MDD). However, the physiological mechanisms underlying the therapeutic benefit and the effect of the stimulation frequency are unclear. Twelve healthy participants received 1Hz, 2Hz, and 5Hz active rTMS. Twenty 5 second trains were delivered at left dorsolateral prefrontal cortex at 110% of resting motor threshold with a 25 second inter-train interval. Blood oxygenation (HbO) was significantly reduced following the 1Hz trains compared to the HbO increases observed in both the 2Hz and 5Hz conditions. There was no significant inter-hemispheric difference in response. These results suggest that short trains of high and low frequency rTMS delivered to prefrontal cortex evoke a differential HbO response and provide additional evidence that high frequency trains result in increased neural activity. The findings may provide further explanation for the improved symptoms observed in MDD patients treated with high frequency rTMS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Prefrontal transcranial magnetic stimulation (TMS) is being investigated as a treatment for several neurological and psychiatric disorders. The direction of the cortical current induced by TMS can be modulated by the coil orientation and this influences the extent of neural depolarization. Although the optimal coil orientation has previously been established for motor cortex, identifying an optimal coil orientation for prefrontal areas is more challenging due to the absence of a motor response. The current study used near infra-red spectroscopy (NIRS) to investigate the impact of coil orientation on TMS induced changes in prefrontal blood oxygenation (HbO). It was hypothesized that a greater change in HbO would be observed when current was induced in a posterior to anterior direction., Methods: Single pulse and trains of 1 Hz repetitive TMS (rTMS) were administered to the left prefrontal cortex while simultaneously recording HbO response bilaterally. The effect of coil orientation was examined at 45°, 135°, and 225° counterclockwise from midline., Results: Greatest changes in HbO were observed at a 45° orientation when both single and rTMS were applied, and only minor changes were observed at 135° and 225°. Application of short trains of rTMS at 45° resulted in transient increases in HbO that were significantly greater in magnitude than when the coil orientation was reversed., Conclusions: The utility of NIRS for examining the TMS evoked physiological response at non-motor areas is highlighted in this study. Prefrontal HbO response evoked by TMS is sensitive to the direction of induced cortical current and it appears that the de facto 45° angle utilized in most clinical studies may prove to be optimal., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is increasingly being investigated in clinical settings for the treatment of neurological and psychiatric disorders such as dystonia, schizophrenia, and major depressive disorder (MDD). Using near infra-red spectroscopy (NIRS), very short trains of rTMS have previously been shown to modulate cortical blood oxygenation., Methods: In order to investigate the effect of longer, clinically relevant trains of 1 Hz rTMS on oxy-hemoglobin (HbO) at prefrontal cortex, the current study applied ten minute trains of rTMS at both subthreshold and suprathreshold intensities., Results: A similar profile of oxygenation change was observed during the beginning 30-40 s of the trains, however for the remainder, subthreshold rTMS returned to baseline while the suprathreshold TMS resulted in a long period of reduced oxygenation., Limitations: Small sample size., Conclusions: The differences observed may be a product of changes in HbO requirements by inhibitory/excitatory neural circuits, either by reduced HbO demand or by increased HbO consumption, while sustained HbO reduction may be a consequence of a modulation of vaso-motor reactivity. This study has implications for understanding the mechanisms involved in the physiological changes evoked by rTMS and efficacious clinical application of rTMS in disorders such as MDD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including major depressive disorder and schizophrenia. In this regard, the DLPFC has been targeted in repetitive transcranial magnetic stimulation (rTMS) studies as a form of treatment to those patients who are resistant to medications. The '5-cm method' and the '10-20 method' for positioning the transcranial magnetic stimulation (TMS) coil over DLPFC have been scrutinised due to poor targeting accuracies attributed to inter-subject variability. We evaluated the accuracy of such methods to localise the DLPFC on the scalp in 15 healthy subjects and compared them with our novel neuronavigational method, which first estimates the DLPFC position in the cortex based on a standard template and then determines the most appropriate position on the scalp in which to place the TMS coil. Our neuronavigational method yielded a scalp position for the left DLPFC between electrodes F3 and F5 in standard space and was closest to electrode F5 in individual space. Further, we found that there was significantly less inter-subject variability using our neuronavigational method for localising the DLPFC on the scalp compared with the '5-cm method' and the '10-20 method'. Our findings also suggest that the '10-20 method' is superior to the '5-cm method' in reducing inter-subject variability and that electrode F5 should be the stimulation location of choice when MRI co-registration is not available., (© 2010 Wiley-Liss, Inc.)

Background: Dorsolateral prefrontal cortex (DLPFC) is a common target for repetitive transcranial magnetic stimulation (rTMS) experiments and therapeutic protocols., Objective: The aim of this study was to investigate the optimal method for the localization of DLPFC for use in these studies., Methods: Twelve healthy subjects underwent a structural magnetic resonance imaging (MRI) scan, a TMS procedure to establish the location of the motor cortex and a neuronavigational procedure to assess the relative position of the DLPFC. Several electroencephalographic (EEG) points and a position 5 cm anterior to motor cortex were established., Results: The DLPFC site used was identified as being approximately halfway between the EEG points F3 and AF3. This point is considerably more anterior than the point identified by measuring 5 cm anterior to motor cortex., Conclusions: EEG points provide a useful way to optimally identify DLPFC.

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery-Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

Several studies have demonstrated that cortical inhibition (CI) can be recorded by paired transcranial magnetic stimulation (TMS) of the motor cortex and recorded by surface electromyography (EMG). However, recording CI from other cortical regions that are more closely associated with the pathophysiology of some neurological and psychiatric disorders (eg, dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously unattainable. This study, therefore, was designed to investigate whether CI could be measured directly from the motor cortex and DLPFC by combining TMS with electroencephalography (EEG). Long-interval CI (LICI) is a TMS paradigm that was used to index CI in the motor cortex and DLPFC in healthy subjects. In the motor cortex, LICI resulted in significant suppression (32.8+/-30.5%) of mean cortical evoked activity on EEG, which was strongly correlated with LICI recorded by EMG. In the DLPFC, LICI resulted in significant suppression (30.1+/-26.9%) of mean cortical evoked activity and also correlated with LICI in the motor cortex. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurological and psychiatric disorders.

A number of studies using paired pulse transcranial magnetic stimulation (TMS) have demonstrated that cortical inhibition (CI) of the motor cortex can be recorded and also gauged through surface electromyography. However, recording CI from other brain regions that are more directly related with the pathophysiology of some neurologic and psychiatric disorders (e.g., dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously fraught with technical difficulties. This study was therefore designed to examine, through a combination of TMS with EEG, whether CI could be measured directly from the motor cortex, DLPFC, and another non-motor region. To index CI, long interval cortical inhibition (LICI; a TMS paradigm) was used in the motor cortex and DLPFC in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. In the motor cortex, LICI resulted in a significant suppression in mean cortical evoked activity on EEG (37.31 +/- 47.51%). In the DLPFC, LICI resulted in a significant suppression (32.45 +/- 47.86%) in mean cortical evoked activity and did not correlate with LICI in the motor cortex although they did not significantly differ. In the parietal lobe, LICI resulted in significant suppression (47.76 +/- 44.70%) in mean cortical evoked activity. In conclusion, CI in the dorsolateral prefrontal cortex, motor cortex and parietal cortex were similar at 120% of motor threshold. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurologic and psychiatric disorders.