Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

Biological Psychiatry Branch, National Institutes of Health, Bethesda, Maryland, Psychiatry Department, University of Arkansas, Little Rock, USA.
Biological Psychiatry (Impact Factor: 10.26). 12/1999; 46(12):1603-13. DOI: 10.1016/S0006-3223(99)00195-X
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Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect.
We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS.
We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism.
These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

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    • "The PFC-thalamo-limbic (e.g., amygdala) pathway is one of the key circuits implicated in depression [11] and its disruption may be specific to refractory MDD. High-frequency prefrontal rTMS has been reported to enhance cortical excitability/activity [5], [12], [13] and to improve PFC inhibitory functions through enhanced GABA-mediated inhibitory neurotransmission [14], and therefore normalizes the PFC-limbic dys-regulation of the depressive circuit [7], [15]. The amygdala is a major structure in the emotional limbic system of human subjects with depression [16]. "
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    ABSTRACT: Prefrontal left-right functional imbalance and disrupted prefronto-thalamic circuitry are plausible mechanisms for treatment-resistant depression (TRD). Add-on repetitive transcranial magnetic stimulation (rTMS), effective in treating antidepressant-refractory TRD, was administered to verify the core mechanisms underlying the refractoriness to antidepressants. Thirty TRD patients received a 2-week course of 10-Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). Depression scores were evaluated at baseline (W0), and the ends of weeks 1, 2, and 14 (W14). Responders were defined as those who showed an objective improvement in depression scores ≥50% after rTMS. Left-right frontal alpha asymmetry (FAA) was measured by magnetoencephalography at each time point as a proxy for left-right functional imbalance. Prefronto-thalamic connections at W0 and W14 were assessed by studying couplings between prefrontal alpha waves and thalamic glucose metabolism (PWTMC, reflecting intact thalamo-prefrontal connectivity). A group of healthy control subjects received magnetoencephalography at W0 (N = 50) to study whether FAA could have a diagnostic value for TRD, or received both magnetoencephalography and positron-emission-tomography at W0 (N = 10) to confirm the existence of PWTMC in the depression-free state. We found that FAA changes cannot differentiate between TRD and healthy subjects or between responders and non-responders. No PWTMC were found in the TRD group at W0, whereas restitution of the PWTMC was demonstrated only in the sustained responders at W14 and euthymic healthy controls. In conclusion, we affirmed impaired prefronto-thalamic functional connections, but not frontal functional imbalance, as a core deficit in TRD.
    PLoS ONE 08/2013; 8(8):e70089. DOI:10.1371/journal.pone.0070089 · 3.23 Impact Factor
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    • "Repetitive TMS (rTMS) has been found to exert excitatory or inhibitory modulation on brain activity, depending on the stimulation frequency. High-frequency rTMS (Ͼ10 Hz) has been posited to increase regional brain activity and facilitate synaptic potentiation , whereas low-frequency rTMS (Ͻ1 Hz) downregulates and inhibits brain activity (Kimbrell et al., 1999; George and Belmaker, 2000; Maeda et al., 2000; Speer et al., 2000; Fitzgerald et al., 2006). rTMS has been investigated as a potential treatment for PTSD in several clinical trials (Grisaru et al., 1998; McCann et al., 1998; Rosenberg et al., 2002; Cohen et al., 2004). "
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    ABSTRACT: Facilitating fear extinction is clinically important to improve the efficacy of current exposure therapies for the treatment of anxiety disorders, such as post-traumatic stress disorder (PTSD). The aim of this study was to determine if repeated transcranial magnetic stimulation (rTMS) facilitates fear extinction in rats, especially when paired with exposure to a conditioned stimulus (CS). Thirty-five rats were conditioned to a tone CS by pairing the tone with an electric foot shock as an aversive unconditioned stimulus (US). We assessed the effects of 10 Hz rTMS before fear extinction (experiment 1) and rTMS paired with CS during extinction (experiment 2) on the following day. Fear responses of the rats were estimated using the level of freezing upon tone stimulus and were compared between the rTMS and corresponding sham groups. The rats treated with rTMS before fear extinction showed no difference in freezing time when compared with the sham group. However, the rats treated with rTMS paired with CS during extinction showed significantly less freezing behavior than the sham group, and this enhancement of fear extinction remained after 24 h without further stimulation. This finding suggests that high-frequency rTMS paired with trauma-reminding stimuli enhances fear extinction and that rTMS in conjunction with exposure therapy is potentially useful for facilitating extinction memory in the treatment of PTSD.
    Neuroscience 01/2012; 200:159-65. DOI:10.1016/j.neuroscience.2011.09.050 · 3.36 Impact Factor
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    • "Par exemple, la dépression entraîne des modifications dans l'activation fonctionnelle du cortex préfrontal dorsolatéral, mesurée par le biais de son métabolisme ou de son débit sanguin, et qui sont différentes selon l'hémisphère considéré. Kimbrell et al. [210] ont montré que le niveau métabolique basal du cortex préfrontal dorsolatéral gauche pouvait prédire la probabilité de réponse thérapeutique à la rTMS appliquée dans cette région. Ces relations peuvent avoir un impact sur les effets thérapeutiques attendus, mais aussi sur la survenue d'effets secondaires. "
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    ABSTRACT: During the past decade, a large amount of work on transcranial magnetic stimulation (TMS) has been performed, including the development of new paradigms of stimulation, the integration of imaging data, and the coupling of TMS techniques with electroencephalography or neuroimaging. These accumulating data being difficult to synthesize, several French scientific societies commissioned a group of experts to conduct a comprehensive review of the literature on TMS. This text contains all the consensual findings of the expert group on the mechanisms of action, safety rules and indications of TMS, including repetitive TMS (rTMS). TMS sessions have been conducted in thousands of healthy subjects or patients with various neurological or psychiatric diseases, allowing a better assessment of risks associated with this technique. The number of reported side effects is extremely low, the most serious complication being the occurrence of seizures. In most reported seizures, the stimulation parameters did not follow the previously published recommendations (Wassermann, 1998) [430] and rTMS was associated to medication that could lower the seizure threshold. Recommendations on the safe use of TMS / rTMS were recently updated (Rossi et al., 2009) [348], establishing new limits for stimulation parameters and fixing the contraindications. The recommendations we propose regarding safety are largely based on this previous report with some modifications. By contrast, the issue of therapeutic indications of rTMS has never been addressed before, the present work being the first attempt of a synthesis and expert consensus on this topic. The use of TMS/rTMS is discussed in the context of chronic pain, movement disorders, stroke, epilepsy, tinnitus and psychiatric disorders. There is already a sufficient level of evidence of published data to retain a therapeutic indication of rTMS in clinical practice (grade A) in chronic neuropathic pain, major depressive episodes, and auditory hallucinations. The number of therapeutic indications of rTMS is expected to increase in coming years, in parallel with the optimisation of stimulation parameters.
    Neurophysiologie Clinique/Clinical Neurophysiology 12/2011; 41(5-6):221-95. DOI:10.1016/j.neucli.2011.10.062 · 1.24 Impact Factor
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