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

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Biological Psychiatry (Impact Factor: 10.26). 12/1999; 46(12):1603-13. DOI: 10.1016/S0006-3223(99)00195-X
Source: PubMed


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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    • "Although we have not compared to such samples, our results add that higher cerebellar CMRglc may be indicative for beneficial response to HF-rTMS treatment , even when controlled for the number of sessionsSpeer et al. 2009) found that the degree of antidepressant response to 1-Hz rTMS correlated with the initial degree of hyperperfusion (H 2 15 O PET) in particular in the cerebellum. This association however was not found with a high frequency approach and 99m Tc-ECD SPECT (Richieri et al. 2011Richieri et al. , 2015), and even a reversed pattern was found (Kimbrell et al. 1999). Methodological differences in stimulation protocol, patient inclusion, and brain imaging method may to some extent be responsible for the discrepant results. "
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    ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is an evidence based neurostimulation modality used to treat patients with Major Depressive Disorder (MDD). In spite that the duration of current a depressive episode has been put forward as a negative predictor for clinical outcome, little is known about the underlying neurobiological mechanisms of this phenomenon. To address this important issue, in a sample of 43 melancholic stage III treatment resistant antidepressant-free refractory MDD patients, we reanalysed regional cerebral glucose metabolism (CMRglc) before high frequency (HF)-rTMS treatment, applied to the left dorsolateral prefrontal cortex (DLPFC). Besides that a lower baseline cerebellar metabolic activity indicated negative clinical response, a longer duration of the depressive episode was a negative indicator for recovery and negatively influenced cerebellar CMRglc. This exploratory 18FDG PET study is the first to demonstrate that the clinical response of HF-rTMS treatment in TRD patients may depend on the metabolic state of the cerebellum. Our observations could imply that for left DLPFC HF-rTMS non-responders other brain localisations for stimulation, more specifically the cerebellum, may be warranted.
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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.
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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.
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