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Repetitive Transcranial Magnetic Stimulation (rTMS) to Treat Refractory Panic Disorder Patient: A Case Report
Abstract
Panic disorder (PD) is an anxiety disorder that is highly disruptive to the patient’s life and in need of options of effective treatments. In this case report, we present an application of repetitive transcranial magnetic stimulation (rTMS) in a refractory patient resistant to cognitive behavior therapy (CBT) and pharmacotherapy who was treated with a combined protocol of rTMS with a sequential stimulation of right and left dorsolateral prefrontal cortex (DLPFC). The protocol was conducted 3 times per week during 4 weeks, with one month follow-up. Patient improved and the results suggest that rTMS can an effective option of treatment.
... The most used neurostimulator, as reported in the documents was Magstim 18,19,22,23,25,42 , followed by Dantec MagPRo 14,28-30 , and only one report 13 used Neuronetics XPLOR, and other one MagVenture MagPro 100 45 . Depersonalization Jay et al. 16 Parkinson, anxiety and depression Kormos 22 Automatic emotional reactions/ emotional processing Berger et al. 31 ; De Raedt et al. 38 Vennewald et al. 32 suffering any other disease of the central nervous system, psychiatric or neurological, or cardiovascular; only the concomitance of some other disease was allowed ...
Psychiatric disorders, particularly related to depression and anxiety, are emerging as the most disabling diseases of the new era. Finding different intervention methods to treat these conditions is a public health challenge. Thus, exploring the results obtained by transcranial magnetic stimulation (TMS) is critical since this neurostimulation technique could position itself as a blunt alternative to manage anxiety pathologies. In this review, a systematic search for TMS use in anxiety disorders was carried out based on the PRISMA criteria. It was found that the most effective protocol for TMS treatment for anxiety disorders is performed with low-frequency stimulation (1 Hz), with 110% of the motor threshold. Furthermore, repeated TMS has proven its effectiveness in different psychiatric disorders — not only as a therapeutic alternative but also in the search for neurological biomarkers—. TMS favors neuromodulation through the generation of action potentials, which facilitates the treatment of pathologies related to emotional components, such as anxiety. However, further research is needed to specify the neurobiological mechanisms present in the improvement of symptoms.
... Panic disorder is characterized by the presence of unexpected and repeated periods of intense fear followed by physical symptoms, in addiction to fear of having future episodes of panic. Preliminary studies show that rTMS application (1 Hz; 10 sessions) to the right dlPFC in panic disorder comorbid with major depression can result in clinical im-provement 45 , and benefits are also found when stimulation is applied both to the right and the left dlPFC 46 . Therefore, it is suggested that rTMS could help to normalize altered brain activity in patients affected by this disorder 47 . ...
Introduction:
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that could be used as a therapeutic intervention in order to treat psychiatric disorders.
Aim:
Reviewing the effectiveness of TMS in the modulation of cognitive functions and also detailing its potential applications in psychiatric treatments.
Development:
TMS has been traditionally used for the treatment of a great variety of neurological or psychiatric conditions by modulating the activity in brain areas and networks. Therapeutic benefit has been found in depressive disorders, anxiety, schizophrenia, addiction, and neurodevelopmental disorders as well as in brain damage and neurodegenerative disorders. Moreover, TMS is a technique which offers great tolerance and can be used as complement with other therapies. However, it is not easy to define an optimal treatment for every pathology: the parameters of stimulation are variable, and its effects at the cellular level of the nervous system are not well-known.
Conclusion:
While it is true that TMS provides many therapeutic benefits, it requires further investigation. It is necessary to detail the action mechanism of the stimulation and the long-term side effects, if any. This information would allow the design of specific treatment protocols for different psychiatric disorders.
... A final single case study was performed by Machado et al. ( 2014). The authors tested one patient (mean age = 34 years old) affected by refractory PD and resistant to Cognitive Behavioral Therapy and drugs, by applying a combined rTMS protocol (3 times per week during 4 weeks) with a sequential stimulation of the right (low frequency, 1 Hz) and left (high frequency, 10 Hz) DLPFC. ...
The interest in the use of non-invasive brain stimulation for enhancing neural functions and reduction of symptoms in anxiety disorders is growing. Based on the DSM-V classification for anxiety disorders, we examined all available research using rTMS and tDCS for the treatment of this psychiatric condition. A systematic literature search conducted in PubMed and Google Scholar databases provided 26 results: 12 sham-controlled studies and 15 not sham-controlled studies. With regard to the latter subgroup of studies, 9 were case reports, and 6 open label studies. Overall, our work provides preliminary evidence that both excitatory stimulation of the left prefrontal cortex and inhibitory stimulation of the right prefrontal cortex can reduce symptom severity in Anxiety Disorders. The current results are discussed in the light of a model for the treatment for anxiety disorders via non-invasive brain stimulation, which is based on up/down regulation mechanisms and might serve as guide for future systematic investigations in the field.
... The protocol was conducted 3 times per week during 4 weeks, with one month follow-up. The fact that the patient showed improvement suggests that rTMS can be an effective option of treatment [66]. ...
The rapid methodological development and growing availability of neuromodulation techniques have spurred myriad studies investigating their clinical effectiveness. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has in many instances been proven to exert antidepressant-like effects superior to placebo and equivalent to standard psychopharmacological treatment. Due to the similar neuroanatomy and neurophysiology of executive and affective control processes, rTMS to the DLPFC may be able to address multiple issues simultaneously. This review pools available literature on the therapeutic usage of rTMS on non-motor symptoms of Parkinson's disease associated with the DLPFC (i.e. mood disturbance and cognitive impairment). To the best of the author's knowledge, it is one of the few available of its' kind, up to this date. Most studies included in the review found beneficial effects of high frequency prefrontal rTMS on PD-related depression. In regard to the usability of rTMS to alleviate cognitive impairment associated with PD, definitive claims are yet to be established.
... The protocol was conducted 3 times per week during 4 weeks, with one month follow-up. The fact that the patient showed improvement suggests that rTMS can be an effective option of treatment [66]. ...
Despite advances in diagnostics and clinical recognition, depressive symptoms in Parkinson's disease (PD) exceeding normal limits remain effectively untreated. In this study, we report on the prevalence and severity of depressive symptoms as well as their association with brainstem raphe echogenicity in patients with PD and non-PD controls. The study included 266 Estonian PD patients and 168 age- and education-matched controls. Demographic and clinical data was documented. Brainstem raphe (BR) was visualized by transcranial sonography (TCS). The prevalence of depressive symptoms in the patient sample was found to be significantly higher than in controls. BR echogenicity in both patients and controls was directly related to their total BDI score, although we found a significantly greater reduction of BR echogenicity in patients with PD and depressive symptoms compared to depressed non-PD controls. The present results corroborate the hypothesis that morphological alteration of the BR is involved in the pathogenesis of depressive disorders. TCS of BR could be used as a non-invasive biomarker to improve detection of depressive symptoms in early PD stages where clinicians may not recognize affective disturbances in the context of PD phenomena.
... A significant reduction in the scores of HADS anxiety and a significant elevation in GAF were observed after the rTMS session. In a previous case report, levels of anxiety were decreased after rTMS stimulation in panic disorder comorbid with major depressive disorder (Machado et al., 2014). In this study, the levels of anxiety in the BN group were significantly elevated compared with those of healthy controls. ...
Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self-regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.
The present overview was aimed at presenting the state of the art of the clinical use of Transcranial Magnetic Stimulation (TMS) protocols in the treatment of anxiety disorders. Available evidence shows that TMS therapeutic protocols over the prefrontal cortex, with excitatory stimulation at the left side and/or inhibitory stimulation of the right side, are effective and well tolerated to reduce anxiety symptoms in Panic Disorder and Generalized Anxiety Disorder. To date, the level of evidence is, however, relatively low regarding the clinical use of TMS therapeutic protocols in anxiety disorders. Future investigation, with an improvement both in methodological issues and in study design, will reveal the real usefulness of TMS therapeutic protocols in the treatment of anxiety disorders.
The interest in the use of non-invasive brain stimulation for enhancing neural functions and reducing symptoms in anxiety disorders is growing. Based on the DSM-V classification for anxiety disorders, we examined all available research using repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) for the treatment of specific phobias, social anxiety disorder, panic disorder, agoraphobia, and generalized anxiety disorder. A systematic literature search conducted in PubMed and Google Scholar databases provided 26 results: 12 sham-controlled studies and 15 not sham-controlled studies. With regard to the latter sub-group of studies, 9 were case reports, and 6 open label studies. Overall, our work provides preliminary evidence that both, excitatory stimulation of the left prefrontal cortex and inhibitory stimulation of the right prefrontal cortex can reduce symptom severity in anxiety disorders. The current results are discussed in the light of a model for the treatment for anxiety disorders via non-invasive brain stimulation, which is based on up-/downregulation mechanisms and might serve as guide for future systematic investigations in the field.
https://www.sciencedirect.com/science/article/pii/S014976341830647X
Angststörungen zählen zu den häufigsten psychischen Störungen in der Allgemeinbevölkerung. Die Lebenszeitprävalenz liegt insgesamt bei 15–20 %. Diagnostisch werden folgende Untergruppen unterschieden: Panikstörung, die generalisierte Angststörung, die Agoraphobie, die soziale Phobie und die spezifischen Phobien. Ursache und Entstehung sind multifaktoriell bedingt. Angststörungen neigen häufig zu einem chronischen Krankheitsverlauf und gehen mit einer bedeutsamen psychosozialen Behinderung einher. Es existieren differenzierte störungsbezogene Ansätze von Pharmako- und Psychotherapie mit hohem Evidenz- und Empfehlungsgrad. Häufig ist auch eine Kombinationsbehandlung notwendig.
Panic attacks may present with conspicuous respiratory symptoms, which may also occur between attacks. Patients with panic attacks and respiratory symptoms have increased susceptibility to respiratory panicogenic challenges than patients without respiratory symptoms. Highly stressful situations, which may trigger a severe anxiety state such as panic attacks are characterized by a prothrombotic phenotype that increases the risk of thromboembolic events. Although episodes of pulmonary embolism might be accompanied by panic attacks, pulmonary embolism is seldom suspected when anxiety is the most likely alternative diagnosis. Given that recurrent thromboembolic disease may complicate with pulmonary artery hypertension and death, the diagnosis of pulmonary thromboembolism is fundamental. The diagnosis of pulmonary thromboembolism requires a high index of suspicion, because showers of microemboli are often asymptomatic or they may present with dyspnea, cough and wheezing, mimicking asthma. Notably, many patients with pulmonary thromboembolism have a relatively clear chest X-rays while severely hypoxemic. Confirmation of diagnosis usually depends on ventilation/perfusion lung scan or invasive imaging studies, such as computed tomographic pulmonary angiography. This paper discusses the characteristics of panic attacks that invite the suspicion of pulmonary embolism. It also suggests some diagnostic algorithms that help rule out thromboembolic disorders in the setting of panic attacks.
The available treatment methods for panic disorder (PD; pharmacotherapy and cognitive behavioral therapy) are well documented as safe and effective. However, few patients remain free of panic attacks or in complete remission. With the advancement in the understanding of the neurobiological mechanisms involved in PD, new treatments have been proposed. One such method is transcranial magnetic stimulation (TMS), a non-invasive method of focal brain stimulation. TMS is based on the Faraday's law of electromagnetic induction, where an electric current is influenced by the magnetic field into the brain, inducing an electric current that depolarizes or hyperpolarizes neurons. Unlike for depression, only few studies are available today investigating the therapeutic effects of rTMS for PD. Thus, this chapter aimed to provide information on the current research approaches and main findings regarding the therapeutic use of rTMS in the context of PD. So far, there is no conclusive evidence of the efficacy of rTMS as a treatment for PD. While positive results were found in most of studies, various treatment parameters, such as location, frequency, intensity and duration have been used unsystematically, making difficult the interpretation of results and providing little guidance about which treatment parameters (i.e., the stimulus location and frequency) may be more useful for the PD treatment. Therefore, further studies are needed to clearly determine the role of rTMS in PD treatment.
Background: Transcranial magnetic stimulation (rTMS) can modulate cortical activity. The goal of our study was to assess whether rTMS would facilitate effect of serotonin reuptake inhibitors in patients with panic disorder. Methods: Fifteen patients suffering from panic disorder resistant to serotonin reuptake inhibitor (SRI) therapy were randomly assigned to either active or to sham rTMS. The aim of the study was to compare the 2 and 4 weeks efficacy of the 10 sessions 1 Hz rTMS with sham rTMS add on SRI therapy. We use 1Hz, 30 minutes rTMS, 110% of motor threshold administered over the right dorso-lateral prefrontal cortex (DLPFC). The same time schedule was used for sham administration. Fifteen patients finished the study. Psychopathology was assessed using the rating scales CGI, HAMA, PDSS and BAI before the treatment, immediately after the experimental treatment and 2 weeks after the experimental treatment by an independent reviewer. Results: Both groups improved during the study period but the treatment effect did not differ-between groups in any of the instruments. Conclusion: Low frequency rTMS administered over the right dorso-lateral prefrontal cortex after 10 sessions did not differ from sham rTMS add on serotonin reuptake inhibitors in patients with panic disorder.
We aimed to investigate the efficacy of 20 Hz repetitive transcranial magnetic stimulation (rTMS) of either right or left dorsolateral prefrontal cortex (DLPFC) as compared to sham rTMS for the relief of posttraumatic stress disorder (PTSD)-associated symptoms.
In this double-blind, placebo-controlled phase II trial conducted between October 2005 and July 2008, 30 patients with DSM-IV-diagnosed PTSD were randomly assigned to receive 1 of the following treatments: active 20 Hz rTMS of the right DLPFC, active 20 Hz rTMS of the left DLPFC, or sham rTMS. Treatments were administered in 10 daily sessions over 2 weeks. A blinded rater assessed severity of core PTSD symptoms, depression, and anxiety before, during, and after completion of the treatment protocol. In addition, a battery of neuropsychological tests was measured before and after treatment.
Results show that both active conditions-20 Hz rTMS of left and right DLPFC-induced a significant decrease in PTSD symptoms as indexed by the PTSD Checklist and Treatment Outcome PTSD Scale; however, right rTMS induced a larger effect as compared to left rTMS. In addition, there was a significant improvement of mood after left rTMS and a significant reduction of anxiety following right rTMS. Improvements in PTSD symptoms were long lasting; effects were still significant at the 3-month follow-up. Finally, neuropsychological evaluation showed that active 20 Hz rTMS is not associated with cognitive worsening and is safe for use in patients with PTSD.
These results support the notion that modulation of prefrontal cortex can alleviate the core symptoms of PTSD and suggest that high-frequency rTMS of right DLPFC might be the optimal treatment strategy.
Panic disorder still remains a pervasive, life quality impairing disorder requiring adequate treatment options. In this case report we present the data of a patient with panic disorder and comorbid depression who was treated with high-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the left prefrontal cortex over a course of 3 weeks. Measurements of the cerebral oxygenation with near-infrared spectroscopy (NIRS) during an emotional Stroop task before and after the rTMS treatment suggests that rTMS may modulate panic-related prefrontal brain dysfunctions in panic patients and that it may serve as a possible treatment option for anxiety disorders.
In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance.
The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals.
There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder.
Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.
Many clinical syndromes in neuropsychiatry suggest focal brain activation. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a method for selectively altering neural activity.
Studies assessing effects of "slow" rTMS, administered up to once per second, in normal people and in those with pathological conditions are reviewed. The findings are compared with those of animal studies examining long-term depression and long-term depotentiation through direct electrical stimulation of cortical tissue.
Data suggest that slow rTMS reduces cortical excitability, both locally and in functionally linked cortical regions. Preliminary studies of patients with focal dystonia, epileptic seizures, and auditory hallucinations indicate symptom reductions following slow rTMS. Long-term depotentiation exhibits many features congruent with those of slow rTMS, including frequency dependence, spread to functionally linked cortical regions, additive efficacy, and extended duration of effects.
Slow rTMS offers a new method for probing and possibly treating brain hyperexcitability syndromes. Further studies linking slow rTMS to animal models of neuroplasticity are indicated.
The International 10-20 system for EEG electrode placement is increasingly applied for the positioning of transcranial magnetic stimulation (TMS) in cognitive neuroscience and in psychiatric treatment studies. The crucial issue in TMS studies remains the reliable positioning of the coil above the skull for targeting a desired cortex region. In order to asses the precision of the 10-20 system for this purpose, we tested its projections onto the underlying cortex by using neuronavigation.
In 21 subjects, the 10-20 positions F3, F4, T3, TP3, and P3, as determined by a 10-20 positioning cap, were targeted stereotactically. The corresponding individual anatomical sites were identified in the Talairach atlas.
The main targeted regions were: for F3 Brodmann areas (BA) 8/9 within the dorsolateral prefrontal cortex, for T3 BA 22/42 on the superior temporal gyrus, for TP3 BA 40/39 in thearea of the supramarginal and angular gyrus, and for P3 BA 7/40 on the inferior parietal lobe. However, in about 10% of the measurements adjacent and possibly functionally distinct BAs were reached. The ranges were mainly below 20 mm.
Using the 10-20 system for TMS positioning is applicable at low cost and may reach desired cortex regions reliably on a larger scale level. For finer grained positioning, possible interindividual differences, and therefore the application of neuroimaging based methods, are to be considered.
In this study, we examined the impact of goal-directed processing on the response to emotional pictures and the impact of emotional pictures on goal-directed processing. Subjects (N=22) viewed neutral or emotional pictures in the presence or absence of a demanding cognitive task. Goal-directed processing disrupted the BOLD response to emotional pictures. In particular, the BOLD response within bilateral amygdala and inferior frontal gyrus decreased during concurrent task performance. Moreover, the presence of both positive and negative distractors disrupted task performance, with reaction times increasing for emotional relative to neutral distractors. Moreover, in line with the suggestion of the importance of lateral frontal regions in emotional regulation [Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D., et al. (2004). For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion. NeuroImage, 23(2), 483-499], connectivity analysis revealed positive connectivity between lateral superior frontal cortex and regions of middle frontal cortex previously implicated in emotional suppression [Beauregard, M., Levesque, J., and Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. J. Neurosci., 21 (18), RC165.; Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003). Neural circuitry underlying voluntary suppression of sadness. Biol. Psychiatry, 53 (6), 502-510.; Ohira, H., Nomura, M., Ichikawa, N., Isowa, T., Iidaka, T., Sato, A., et al. (2006). Association of neural and physiological responses during voluntary emotion suppression. NeuroImage, 29 (3), 721-733] and negative connectivity with bilateral amygdala. These data suggest that processes involved in emotional regulation are recruited during task performance in the context of emotional distractors.
Previous studies on neuronal activation correlates of panic attacks were mostly based on challenge tests, sensory-related stimulation or fear conditioning in healthy subjects. In the present study, we report on a female patient with panic disorder experiencing a spontaneous panic attack under an auditory habituation paradigm in the last stimulation block with sine tones captured with fMRI at 3T. The panic attack was associated with a significantly increased activity in the right amygdala. This is the first report on neuronal activation correlates of a spontaneous panic attack in a patient with panic disorder as measured by fMRI, which lends further support to a pivotal role of the amygdala in the pathogenesis of the disease.
Threat-related stimuli are strong competitors for attention, particularly in anxious individuals. We used functional magnetic resonance imaging (fMRI) with healthy human volunteers to study how the processing of threat-related distractors is controlled and whether this alters as anxiety levels increase. Our work builds upon prior analyses of the cognitive control functions of lateral prefrontal cortex (lateral PFC) and anterior cingulate cortex (ACC). We found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli. Participants with higher anxiety levels showed both less rostral ACC activity overall and reduced recruitment of lateral PFC as expectancy of threat-related distractors was established. This supports the proposal that anxiety is associated with reduced top-down control over threat-related distractors. Our results suggest distinct roles for rostral ACC and lateral PFC in governing the processing of task-irrelevant, threat-related stimuli, and indicate reduced recruitment of this circuitry in anxiety.
Objective:
In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance.
Method:
The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals.
Results:
There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder.
Conclusions:
Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.
BACKGROUND: In an open-label trial low-frequency repetitive transcranial magnetic stimulation (rTMS) to the right dorsolateral prefrontal cortex (DLPFC) significantly improved symptoms of panic disorder and major depression. Here we present data of a randomized double-blind study. METHODS: Twenty-five patients were assigned 4 weeks of active or sham rTMS to the right DLPFC. rTMS parameters consisted of 1800 stimuli/day, 1-Hz, at 110% of resting motor threshold. Response was defined as a ≥40% decrease on the panic disorder severity scale and a ≥50% decrease on the Hamilton depression rating scale. At the end of the randomized phase, patients were offered the option of receiving open-label rTMS for an additional 4 weeks. RESULTS: Repeated-measures ANOVA revealed significantly better improvement in panic symptoms with active compared with sham rTMS, but no significant difference in depression. At 4 weeks, response rate for panic disorder was 50% with active rTMS and 8% with sham. After 8 weeks of active rTMS, response rate was 67% for panic and 50% for depressive symptoms. Repeated-measure ANOVA showed significant improvements in panic disorder, major depression, clinical global impression, and social adjustment. Clinical improvement was sustained at 6-month follow-up. LIMITATIONS: Limitation of this study is the relatively small sample size. CONCLUSIONS: Although 4 weeks of rTMS was sufficient to produce a significant effect in panic symptoms, a longer course of treatment resulted in better outcomes for both panic disorder and major depression. These data suggest that inhibitory rTMS to the right DLPFC affects symptoms expression in comorbid anxiety and depression. ClinicalTrials.gov Identifier: NCT00521352.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure whereby a pulsed magnetic field stimulates electrical activity in the brain. Anxiety disorders are the most common of all mental health problems for which effective, mechanism-based treatments remain elusive. Consequently, more advanced non-invasive therapeutic methods are required. A possible method to modulate brain activity and potentially viable for use in clinical practice is rTMS. Here, we focus on the main findings of rTMS from animal models of anxiety and the experimental advances of rTMS that may become a viable clinical application to treat anxiety disorders, one of the most common causes of disability in the workplace in the world. Key advances in combining rTMS with neuroimaging technology may aid such future developments. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Unlike for depression, only few studies are available today investigating the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders. This review aims to provide information on the current research approaches and main findings regarding the therapeutic use of rTMS in the context of various anxiety disorders. Although positive results have frequently been reported in both open and randomized controlled studies, our review of all identified studies indicates that at present no conclusive evidence of the efficacy of rTMS for the treatment for anxiety disorders is provided. Several treatment parameters have been used, making the interpretation of the results difficult. Moreover, sham-controlled research has often been unable to distinguish between response to rTMS and sham treatment. However, there is a limitation in the rTMS methods that likely impacts only the superficial cortical layers. It is not possible to directly stimulate more distant cortical areas, and also subcortical areas, relevant to the pathogenesis of anxiety disorders, though such effects in subcortical areas are thought to be indirect, via trans-synaptic connections. We thus recommend further studies to clearly determine the role of rTMS in the treatment of anxiety disorders. Key advances in combining TMS with neuroimaging technology may aid in such future developments.
Brain imaging studies performed over the past 20 years have generated new knowledge about the specific brain regions involved in the brain diseases that have been classically labeled as psychiatric. These include the mood and anxiety disorders, and the schizophrenias. As a natural next step, clinical researchers have investigated whether the minimally invasive brain stimulation technologies (transcranial magnetic stimulation [TMS] or transcranial direct current stimulation [tDCS]) might potentially treat these disorders. In this review, we critically review the research studies that have examined TMS or tDCS as putative treatments for depression, mania, obsessive-complusive disorder, posttraumatic stress disorder, panic disorder, or schizophrenia. (Separate controversy articles deal with using TMS or tDCS to treat pain or tinnitus. We will not review here the large number of studies using TMS or tDCS as research probes to understand disease mechanisms of psychiatric disorders.) Although there is an extensive body of randomized controlled trials showing antidepressant effects of daily prefrontal repetitive TMS, the magnitude or durability of this effect remains controversial. US Food and Drug Administration approval of TMS for depression was recently granted. There is much less data in all other diseases, and therapeutic effects in other psychiatric conditions, if any, are still controversial. Several issues and problems extend across all psychiatric TMS studies, including the optimal method for a sham control, appropriate coil location, best device parameters (intensity, frequency, dosage, and dosing schedule) and refining what subjects should be doing during treatment (activating pathologic circuits or not). In general, TMS or tDCS as a treatment for most psychiatric disorders remains exciting but controversial, other than prefrontal TMS for depression.
The central endocannabinoid system is a neuroactive lipid signalling system in the brain which acts to control neurotransmitter release. The expression patterns of this system throughout limbic regions of the brain ideally situate it to exert regulatory control over emotional behaviour, mood and stress responsivity. A growing body of evidence unequivocally demonstrates that deficits in endocannabinoid signalling may result in depressive and anxiogenic behavioral responses, while pharmacological augmentation of endocannabinoid signalling can produce both antidepressive and anxiolytic behavioral responses. The aim of this review is to summarize current knowledge of the role of the endocannabinoid system in the etiology and treatment of mood and anxiety disorders, such as depression, anxiety and post-traumatic stress disorder. Collectively, both clinical and preclinical data argue that cannabinoid receptor signalling may be a realistic target in the development of a novel class of agent for the pharmacotherapy of mood and anxiety disorders.
Threat-related stimuli are strong competitors for attention, particularly in anxious individuals. We used functional magnetic resonance imaging (fMRI) with healthy human volunteers to study how the processing of threat-related distractors is controlled and whether this alters as anxiety levels increase. Our work builds upon prior analyses of the cognitive control functions of lateral prefrontal cortex (lateral PFC) and anterior cingulate cortex (ACC). We found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli. Participants with higher anxiety levels showed both less rostral ACC activity overall and reduced recruitment of lateral PFC as expectancy of threat-related distractors was established. This supports the proposal that anxiety is associated with reduced top-down control over threat-related distractors. Our results suggest distinct roles for rostral ACC and lateral PFC in governing the processing of task-irrelevant, threat-related stimuli, and indicate reduced recruitment of this circuitry in anxiety.
Lesion and neuroimaging studies suggest that left prefrontal lobe dysfunction is pathophysiologically linked to depression. Rapid-rate transcranial magnetic stimulation (rTMS) to prefrontal structures has a lateralised effect on mood in normal volunteers, and several preliminary studies suggest a beneficial effect of rTMS on depression. However, adequately controlled studies have not been conducted.
We have studied the effects of focal rTMS on the depressive symptoms in 17 patients with medication-resistant depression of psychotic subtype. The study was designed as a multiple cross-over, randomised placebo-controlled trial. Sham rTMS and stimulation of different cortical areas were used as controls.
Left dorsolateral prefrontal cortex rTMS resulted in a significant decrease in scores on the Hamilton depression rating scale HDRS (from 25.2 to 13.8) and the self-rated Beck questionnaire BQ (from 47.9 to 25.7). 11 of the 17 patients showed pronounced improvement that lasted for about 2 weeks after 5 days of daily rTMS sessions. No patient experienced any significant undesirable side-effects.
Our findings emphasise the role of the left dorsolateral prefrontal cortex in depression, and suggest that rTMS of the left dorsolateral prefrontal cortex might become a safe, non-convulsive alternative to electroconvulsive treatment in depression.
Abnormal left/right (L/R) hemispheric ratios of regional cerebral glucose metabolic rates (rCMRglc) (hippocampus and inferior prefrontal cortex) have been noted in unmedicated panic disorder patients.
An independent group of panic disorder patients placed on imipramine was studied with positron-emission tomography, testing for evidence of normalization versus persistence of the abnormal rCMRglc ratios. Differences in orbital frontal rCMRglc values between the imipramine-treated and the previously reported unmedicated panic disorder patients were tested examining for evidence that the differences would resemble those noted in obsessive-compulsive disorder (OCD) patients treated with clomipramine.
We found the same abnormally low L/R hippocampal and posterior inferior prefrontal rCMRglc ratios in the imipramine-treated panic disorder patients. In addition, we found posterior orbital frontal rCMRglc decreases in the imipramine-treated panic disorder patients compared with the unmedicated panic disorder patients.
These abnormal asymmetries found in unmedicated panic disorder patients and now in imipramine-treated panic disorder patients may reflect a trait abnormality. The orbital frontal rCMRglc differences between the imipramine-treated and unmedicated patients are similar to changes noted in OCD patients treated with clomipramine and may reflect direct or indirect effects of imipramine treatment in panic disorder patients.
Theories of human behavior from Plato to Freud have repeatedly emphasized links between emotion and reason, a relationship now commonly attributed to pathways connecting phylogenetically "old" and "new" brain regions. Expanding on this theory, this study examined functional interactions between specific limbic and neocortical regions accompanying normal and disease-associated shifts in negative mood state.
Regions of concordant functional change accompanying provocation of transient sadness in healthy volunteers and resolution of chronic dysphoric symptoms in depressed patients were examined with two positron emission tomography techniques: [15O]water and [18F]fluorodeoxyglucose, respectively.
With sadness, increases in limbic-paralimbic blood flow (subgenual cingulate, anterior insula) and decreases in neocortical regions (right dorsolateral prefrontal, inferior parietal) were identified. With recovery from depression, the reverse pattern, involving the same regions, was seen--limbic metabolic decreases and neocortical increases. A significant inverse correlation between subgenual cingulate and right dorsolateral prefrontal activity was also demonstrated in both conditions.
Reciprocal changes involving subgenual cingulate and right prefrontal cortex occur with both transient and chronic changes in negative mood. The presence and maintenance of functional reciprocity between these regions with shifts in mood in either direction suggests that these regional interactions are obligatory and probably mediate the well-recognized relationships between mood and attention seen in both normal and pathological conditions. The bidirectional nature of this limbic-cortical reciprocity provides additional evidence of potential mechanisms mediating cognitive ("top-down"), pharmacological (mixed), and surgical ("bottom-up") treatments of mood disorders such as depression.
Background:
High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits.
Methods:
Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test.
Results:
Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L > R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other.
Conclusions:
These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.
Transcranial magnetic stimulation (TMS) has been tried in some Anxiety Disorders (Obsessive-compulsive disorder and Posttraumatic Stress Disorder) with different results. We present a pilot study including three Panic Disorder patients. The subjects who were enrolled had a history of the disease for at least 1 year and they had unsuccessfully followed psychotherapy and pharmacological treatment. The patients received 10 sessions during two weeks; each session lasted 30 trains of 60 seconds at a frequency of 1 Hz, on the right dorsolateral prefrontal cortex, at 110% of the motor threshold. All three patients experienced a modest and partial symptom improvement that did not seemed to be clinically relevant. Two patients accepted to participate in a TMS second phase, where the previous stimulation parameters were alternated with an application of 30 trains of 20 Hz during 2 seconds on the left prefrontal cortex. This alternate application of high and low frequency TMS in each session was also well tolerated, but failed to produce additional improvement. In addition to presenting these three cases, we emphasize some features concerning the neurobiological basis of the anxiety disorders and we connect them to the previously described TMS neurophysiological actions in order to justify further investigation.
The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation.
In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses.
Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance.
The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal.
Application of repetitive transcranial magnetic stimulation was effective and safe in treating a 55-year-old man with comorbid depression and panic disorder, which occurred 6 months after a myocardial infarction.
Studies suggest that the dorsolateral prefrontal cortex (DLPFC) participates in neural circuitry that is dysregulated in Panic Disorder (PD) and Major Depressive Disorder (MDD). We tested whether low-frequency repetitive Transcranial Magnetic Stimulation (rTMS) could normalize the overactivity of right frontal regions and thereby improve symptoms.
Six patients with PD and comorbid MDD were treated with daily active 1-Hz rTMS to the right DLPFC for 2 weeks in this open-label trial.
Clinical improvements were apparent as early as the first week of treatment. After the second week, 5/6 of patients showed improvements in panic and anxiety, and 4/6 showed a decrease in depression, with sustained improvement at 6 months of follow-up. Right hemisphere resting motor threshold increased significantly after rTMS.
Limitations of this study are the open design and the small sample size.
Slow rTMS to the right DLPFC resulted in significant clinical improvement and reduction of ipsilateral motor cortex excitability. Replications in larger sample will help to clarify the relevance of this preliminary data and to define the potential role of right DLPFC rTMS in panic with major depression.
Regulatory interactions with the amygdala are thought to be critical for emotional processing in the extended limbic system. Structural equation modeling (path analysis) is a widely used method to quantify interactions among brain regions based on connectivity models, but is often limited by lack of precise anatomical and functional constraints. To address this issue, we developed an automated elaborative path analysis procedure guided by known anatomical connectivity in the macaque. We applied this technique to a large human fMRI data set acquired during perceptual processing of angry or fearful facial stimuli. The derived models were inferentially validated using a bootstrapping split-half approach in pairs of 500 independent groups. Significant paths across the groups were used to form a rigorously validated and consistent path model. We confirm and extend previous observations of amygdala regulation by an extended prefrontal network encompassing cingulate, orbitofrontal, insular, and dorsolateral prefrontal cortex, as well as strong interactions between amygdala and parahippocampal gyrus. This validated model can be used to study neurocognitive correlates as well as genotype or disease-related alterations of functional interactions in the limbic system.
Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The technique can be used to map brain function and explore the excitability of different regions. Brief interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has some clinical utility, and, because it can influence brain function if delivered repetitively, it is being developed for various therapeutic purposes.
The value of repetitive transcranial magnetic stimulation for the treatment of anxiety disorders
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