Neurobiology of Repeated Transcranial Magnetic Stimulation in the Treatment of Anxiety: a Critical Review Stefano Pallantia,B,C and Silvia Bernardia,B

Review 163

Neurobiology of repeated transcranial magnetic stimulation in the treatment of anxiety: a critical review Stefano Pallantia,b,c and Silvia Bernardia,b

Transcranial magnetic stimulation (TMS) has been applied the posttraumatic stress disorder symptom core can be to a growing number of psychiatric disorders as hypothesized. TMS remains an investigational intervention a neurophysiological probe, a primary brain-mapping tool, that has not yet gained approval for the clinical treatment of and a candidate treatment. Although most investigations any anxiety disorder. Clinical sham-controlled trials are have focused on the treatment of major depression, scarce. Many of these trials have supported the idea that increasing attention has been paid to anxiety disorders. TMS has a significant effect, but in some studies, the effect The aim of this study is to summarize published findings is small and short lived. The neurobiological correlates about the application of TMS as a putative treatment for suggest possible efficacy for the treatment of social anxiety disorders. TMS neurophysiological and mapping anxiety that still has to be investigated. Int Clin findings, both clinical and preclinical, have been included Psychopharmacol 24:163–173 c 2009 Wolters Kluwer when relevant. We searched Medline, PsycInfo, and the Health | Lippincott Williams & Wilkins. Cochrane Library from 1980 to January 2009 for the terms

‘generalized anxiety disorder’, ‘social anxiety disorder’, International Clinical Psychopharmacology 2009, 24:163–173 ‘social phobia’, ‘panic’, ‘anxiety’, or ‘posttraumatic stress Keywords: anxiety, cortical excitability, panic, posttraumatic stress disorder, disorder’ in combination with ‘TMS’, ‘cortex excitability’, repeated transcranial magnetic stimulation, social anxiety, transcranial ‘rTMS’, ‘motor threshold’, ‘motor evoked potential’, ‘cortical magnetic stimulation silent period’, ‘intracortical inhibition’, ‘neuroimaging’, or ‘intracortical facilitation’. Most of the therapeutic aDepartment of Psychiatry, The Mount Sinai School of Medicine, New York, USA, b c experiences with repetitive TMS available in the literature Universita` degli Studi di Firenze and Istituto di Neuroscienze, Firenze, Italy are in the form of case reports, not controlled or blinded Correspondence to Stefano Pallanti, Department of Psychiatry, Box 1230, studies. Stimulation of the right dorsolateral prefrontal The Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, cortex, especially at high frequencies, has been reported to NY 10029, USA Tel: + 1 3933 8279 1581; fax: + 1 3905 5587 8789; reduce anxiety symptoms in posttraumatic stress disorder e-mail: [email protected] and panic disorder; nevertheless, results are mixed. A specific role for the right dorsolateral prefrontal cortex in Received 21 January 2009 Accepted 26 March 2009

Introduction with neuronal transmission, leading to word-finding Transcranial magnetic stimulation (TMS) is a noninvasive, difficulties and speech arrest (Pascual-Leone et al., 1991). relatively focal technique for directly stimulating cortical neurons. TMS causes a depolarization of neurons Emerging data suggest that different rTMS frequencies (Belmaker and Fleischmann, 1995) with cortical changes can lead to alterations of cerebral metabolism, with in monoamines (Ben-Shachar et al., 1997). However, the high-frequency stimulation (20 Hz) leading to increased effect of magnetic stimulation varies depending on the regional cerebral metabolism (George et al., 1996) and location, intensity, and frequency of the magnetic pulses lower-frequency stimulation (1–5 Hz) leading to decreased and it is still not completely understood. Examples of the regional cerebral metabolism in normal volunteers variety of effects and potentialities of TMS are: single (Speer et al., 2000). or paired-pulse magnetic stimulation over the motor cortex can lead to excitation of the motor cortex and Therapeutic potential for rTMS in the treatment of subsequent motor-evoked potential (MEP) and move- neuropsychiatric conditions has been hypothesized, and ment (Wassermann, 1992). Recordings of the MEP allow trials mostly using the focal figure-eight coil have been for noninvasive mapping of this cortical area in humans. applied to neuropsychiatric conditions. Most clinical trials Repeated pulses of magnetic stimulation (rTMS) to with rTMS have been focused on major depression. Broca’s area in the dominant hemisphere can interfere Today, therapeutic rTMS has been accepted as a standard treatment for resistant depression in Canada, Israel, and Part of the data presented in this article has been presented as poster format at recently in the US. A smaller number of rTMS studies the congress ‘XI CONGRESSO della Societa` Italiana di Psicopatologia’ 21–25 February 2006, Rome, Italy and at ‘Advanced Maudsley Forum 2008’, London, have also focused attention on rTMS’s therapeutic 8–12 September 2008. potential in anxiety disorders.

0268-1315 c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0b013e32832c2639

Anxiety, fear, and stress responses are conditions the amygdala/limbic system. In contrast, disorders such as characterized by cognitive arousal accompanied by bodily generalized anxiety disorder (GAD) and OCD that sensation because of activation of the peripheral nervous involve worry and rumination seem to be characterized system, with subsequent autonomic and sympathetic by increased activity of the PFC. Thus, differences in the responses (hyperventilation, dizziness, tachycardia, activity of the PFC and, subsequently, the cortical/limbic increased blood pressure, gastrointestinal disease). The network, might underlie the puzzling results obtained for peripheral activation seems to reflect a central increase in the application of rTMS as a treatment for anxiety. Given cortical excitability in different regions of the brain. In the current mixed results of the actual research on the fact, an association between relative electroencephalogram topic, and given the recent hypothesis of Berkowitz et al. (EEG) right-frontal hyperactivity and the state or trait (2007), there is a need to critically revisit the area. This measures of anxiety has been shown (Sutton and study also cites neurophysiological investigations relevant Davidson, 1997; Davidson et al., 2000; Crost et al., to the future anxiolytic potential of rTMS. Neuronal 2008). This increase in cortical excitability in association correlates and current opinions in neurobiology, with a with increased cognitive arousal and autonomic system special focus on cortical excitability, are reviewed for each responses may provide a rationale for the potential disorder to provide critical knowledge of the hypotheses therapeutic effect of rTMS in anxiety. regarding the treatment potential of rTMS.

Transcranial magnetic stimulation and anxiety TMS also serves as an investigational tool for cortical excitability in anxiety, revealing a correlation between the The aim of this review paper is to critically revisit the amplitude ratio of the MEP threshold and neuroticism evidence regarding the effect of rTMS on anxiety (N), a stable measure of trait-level anxiety (Wassermann disorders. We excluded obsessive compulsive disorder et al., 2001). Oathes et al. (2008) assessed corticospinal (OCD), which we consider separately because of its motor responses during worry induction, motor imagery, peculiar clinical features, which seem to involve distinct and mental arithmetic. TMS applied over the primary brain circuitries and systems (Berkowitz et al., 2007). motor cortex elicited larger corticospinal motor responses rTMS has been hypothesized to have anxiolytic potential during worry than during mental arithmetic and smaller in humans. The first studies in humans were conducted responses than during motor imagery of the maximum on healthy volunteers. Schutter et al. (2001) reported voluntary contraction of targeted muscles. a reduction in self-rated anxiety levels after slow rTMS in the right dorsolateral prefrontal cortex (DLPFC), associated with a contralateral increase in y-activity. Low-frequency Search strategy rTMS of the right DLPFC was followed by selective We searched Medline, PsycInfo, and the Cochrane attention to angry faces, which was interpreted as an Library from 1980 to April 2008 for the terms ‘generalized anxiolytic effect through right-hemispheric inhibition anxiety disorder’, ‘social anxiety disorder’, ‘social phobia’, (D’Alfonso et al., 2000). There is also a preclinical study ‘panic’, ‘anxiety’, or ‘posttraumatic stress disorder’ in supporting the anxiolytic potential of rTMS. Kanno et al. combination with ‘TMS’, ‘cortex excitability’, ‘rTMS’, (2003) investigated the effects of TMS in Wistar rats ‘motor threshold’, ‘motor evoked potential’, ‘cortical using the elevated plus-maze test. After a 3-day series silent period’, ‘intracortical inhibition’, ‘neuroimaging’, of rTMS, a significant improvement in anxiety-related or ‘intracortical facilitation’. Owing to the small number behavior was observed. of studies identified, all reports including controlled randomized clinical trials, open-label trials and case However, opposing findings have also been published. reports were included in this review. The review was Other reports suggested that rTMS may instead induce limited to published reports only. Discussion has been anxiety in normal volunteers (George et al., 2000). focused mainly on studies reported in the past 10 years Preclinical studies taken together suggest that rTMS but also included commonly referenced studies relevant may be anxiogenic instead of anxiolytic. Two studies to neurobiology of the diseases and possible rationales for investigated the effects of rTMS treatment for 10 days rTMS application. Review articles and book chapters are [150% motor threshold (MT), 15 Hz] on anxiety-related cited to provide readers with more details and references behavior and found that rTMS under these circumstances than can be accommodated within this paper. led to a pronounced increase in anxiety-related behavior (Isogawa et al., 2003, 2005). Posttraumatic stress disorder: phenomenology and neural correlates Recently, Berkowitz et al. (2007) suggested that disorders Cardinal symptoms of PTSD include intrusive memories, involving intense fear and panic, such as panic disorder flashbacks, hypervigilance, sleep disturbance, avoidance (PD), posttraumatic stress disorder (PTSD), and pho- of traumatic stimuli, physiological hyperresponsivity, bias, seem to be characterized by reduced activity of the numbing of emotions, and social dysfunction. Recent prefrontal cortex (PFC) and subsequent disinhibition of theories of PTSD pathogenesis suggest that the fear

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. rTMS in anxiety treatment Pallanti and Bernardi 165 response mechanism, behavioral sensitization, and failure role of the hippocampus and parahippocampus in PTSD of the extinction of fear play key roles. are less consistent.

The identification of several neural correlates of PTSD Repeated transcranial magnetic stimulation allowed the hypothesis of a neurological model of the as an anatomical and cortical excitability probe alteration underlying this disorder (reviewed in Francati in posttraumatic stress disorder et al., 2007). Two of the most frequent positron emission The neuroimaging data reported above suggest that the tomography (PET) and functional magnetic resonance DLPFC may be a promising target for rTMS treatment of imaging (fMRI) findings suggest decreased activity in the PTSD. Evidence of altered cortical excitability in PTSD medial prefrontal cortex (mPFC), including Brodmann’s suggests a possible modulator role for rTMS treatment. area 11, the anterior cingulate cortex (Brodmann’s area 32), and the mPFC proper (Brodmann’s areas 9 and 25); increased amygdala activation is also seen (Francati et al., In a recent neurophysiological study, Centonze et al. 2007). The mPFC, particularly the affective division of (2005) hypothesized that stress-induced long-term the anterior cingulate gyrus, is thought to promote fear potentiation of glutamate-mediated transmission might extinction through its descending influence on the represent a synaptic correlate of the maintenance of amygdala. The amygdala is considered to be involved in traumatic memories that cause PTSD. Given that an threat assessment, in reallocation of resources in response imbalance between glutamate (the main excitatory to a threat, and in fear conditioning itself. The mPFC is neurotransmitter) and the inhibitory transmitter GABA thought to provide a system of negative feedback to within the cortex is generally considered one of the the amygdala, regulating amygdala activation during mechanisms for changes in cortical excitability (Ziemann emotional and fearful conditions. Thus, an increase in et al., 1996a, 1996b; Ricker and Zafonte, 2000; Chistyakov mPFC activity will inhibit activation of the amygdala, et al., 2001), the authors applied paired-pulse stimulation whereas in the case of decreased mPFC activity, the TMS to investigate whether changes in cortical excit- amygdala will not receive sufficient inhibitory feedback, ability are associated with the development of PTSD and resulting in higher autonomic arousal and exaggerated to gain insights into the functioning of intracortical responses. This is observed in patients with PTSD inhibitory transmission in this pathologic condition (failure of fear extinction) (Nutt and Malizia, 2004). (Centonze et al., 2005). Paired-pulse TMS (different The amygdala–mPFC connection is thought to be short interstimuli intervals from 1 to 6 ms, randomized) mediated by g-aminobutyric acid (GABA) interneurons was applied to a sample that included 14 patients who (Charney, 2004), which might malfunction in PTSD. had developed PTSD after minor head trauma, 12 Other systems involved in the extinction process may healthy volunteers without a clinical history of head include NMDA receptors and voltage-gated calcium trauma, and 11 healthy participants who had reported channels (Charney, 2004) and the neurotransmitters accidental minor head trauma 1–4 months before the norepinephrine (Southwick et al., 1999) and dopamine study. All patients with PTSD exhibited significantly (Pezze and Feldon, 2004). lower MEP inhibition than the controls, showing that PTSD after minor head trauma is coupled with the loss of Several structural and functional neuroimaging studies physiologic inhibition of cortical excitability. have shown abnormalities in the PFC in PTSD patients. Lower metabolism than in normal controls was found at Centonze et al. (2005) speculated that the observed baseline in the temporal and prefrontal cortical areas impairment of GABA-mediated MEP inhibition might (Bremner et al., 1997) and in the parietal cortex of also reflect a selective vulnerability of cortical GABAergic substance-dependent PTSD patients (Semple et al., interneurons to glutamate-mediated excitotoxic events. 1996, 2000) with PET techniques. In a recent symptom Through long-term potentiation of excitatory synapses, provocation study consisting of the presentation of reorganization of GABAergic interneurons takes place in emotional faces, activity in the mPFC was significantly patients who develop PTSD. reduced in patients with PTSD when compared with normal controls (Shin et al., 2005). The hypothesis of the interhemispheric imbalance, based on the observations of several studies implicating Although there is significant agreement on this model of preferential right hemispheric involvement in the experi- interaction between mPFC and the amygdala, some ence of unpleasant emotions (Schwartz et al., 1975; studies have shown inconsistencies (Bremner et al., 1999; Lavidas et al., 1984; Ahern et al., 1985), seems to suggest a Rauch et al., 2000; Lanius et al., 2001, 2002, 2003; Gilboa lateralization of the putative rTMS anxiolytic effect. et al., 2004; Britton et al., 2005). Furthermore, Freeman et al. (1998) showed, through an Patients with PTSD show significant deficits in memory elegant investigation with proton magnetic resonance (Bremner et al., 1993, 1995), but findings regarding the spectroscopy, that the ratio of N-acetyl-L-aspartic acid to

creatinine in the right hemisphere of PTSD patients was The first double-blind, placebo-controlled investigation significantly lower than in the left hemisphere and was was recently conducted by Cohen et al. (2004) on also significantly lower than in the controls. 24 patients with PTSD randomly assigned to receive rTMS at low frequency (1 Hz) or high frequency (10 Hz) On the basis of the possibility of lateralization, McCann or sham rTMS at 80% of the MT over the right et al. (1998) studied the effects of low-frequency rTMS dorsolateral PFC for 10 daily sessions over 2 weeks. on the right frontal cortex of two patients with PTSD core symptoms (re-experiencing, avoidance) noncombat PTSD; the stressors were rape and a shooting markedly improved with this treatment. Moreover, incident. The patients’ PTSD symptoms were highly high-frequency rTMS over the right dorsolateral PFC refractory to medications, and one patient had not alleviated anxiety symptoms in PTSD patients. rTMS at responded to a previous trial of left frontal rTMS. Both high frequency showed greater therapeutic effects than patients had baseline prefrontal hypermetabolism as low frequency or sham stimulation. It was speculated that detected by [18F]fluorodeoxyglucose PET. The investigators the improvement shown in PTSD symptoms was administered rTMS over the right frontal cortex for 20–30 the result of activation of the right dorsolateral PFC by daily sessions at 1 Hz, at 80% of the MT, administering high-frequency rTMS and that this activation might be a a total of 1200 stimuli daily. rTMS was delivered openly source of activation of the hypothalamic–pituitary– over the right DLPFC using a focal coil. After 1 month adrenal axis, enhanced activity of the depressor area of of rTMS treatment, the first patient, who received autonomic responsiveness, or increased suppression of seventeen daily sessions, reported selective improvement the amygdala. An alternative explanation to the efficacy in PTSD symptoms without a change in global anxiety. of high-frequency rTMS over the dorsolateral PFC in The second patient, who received rTMS in 30 sessions over PTSD was proposed by Rossi et al. (2006). On the basis of the same region, also reported significant symptom improve- the evidence that high-frequency TMS over the frontal ment. After rTMS treatment, [18F]fluorodeoxyglucose cortex ‘interferes’ with episodic visual (Rossi et al., 2001) PET images showed normalization of both global and and auditory (Sandrini et al., 2003) memory, the authors right PFC hypermetabolism. formulate a memory-oriented hypothesis to explain bene- ficial effects of rTMS in PTSD regarding the classical manifestation of an episodic memory dysfunction (i.e. This case report not only constituted the beginning of amnesia). TMS induced as the mechanism responsible for rTMS treatment application to PTSD, but it also showed symptom alleviation for these patients. TMS-related reduction of PFC hyperactivity, providing a potential mechanism for TMS treatment in this anxiety disorder. Recently, Osuch et al. (2009) showed superior efficacy during imaginal exposure therapy in a preliminary double- blind, sham-controlled cross-over study of rTMS (1 Hz over Repeated transcranial magnetic stimulation right DLPFC). Active rTMS showed greater improvement as a treatment for posttraumatic stress disorder for hyperarousal symptoms when compared with sham in A provocative open-pilot study of therapeutic effects of nine PTSD patients. Other studies on the efficacy of rTMS in PTSD was conducted by Grisaru et al. (1998). rTMS as a treatment for PTSD are listed in Table 1. The authors administered rTMS to 10 patients with PTSD with a stimulation rate of 0.3 Hz at the maximum output of a Magstim single-pulse stimulator, administering Panic disorder: phenomenology and neural 30 pulses bilaterally over the motor cortex with a nonfocal correlates coil. Transient improvement was found in both self and PD (prevalence: 4.7%) is a syndrome characterized by observer ratings of PTSD symptoms. rTMS was found to recurrent and unexpected attacks of sudden onset and be effective in lowering the core PTSD symptom of short duration (10–15 min) that consist of the following avoidance as well as anxiety and somatization, and in symptoms: feelings of shortness of breath, subsequent improving ratings on the Clinical Global Impression scale. hyperventilation, palpitations, chest pain, sweating, These preliminary results were taken to show that TMS chills, nausea, trembling, fear of dying or losing control, is a safe and tolerable intervention with possible numbness, and a feeling of detachment or unreality. therapeutic efficacy for PTSD patients. This finding was intriguing, even if limited by the open study design The work of LeDoux et al. (1988) and Davis (1992) has and the small number of participants. proposed an amygdala-centered neurocircuit to explain the ‘intrinsic fear response’ (Fig. 1). The sensory input More recently, Rosenberg et al. (2002) observed substantial for the stimulus runs through the anterior thalamus to the improvement in mood, anxiety, and sleep symptoms, but lateral nucleus of the amygdala and is then transferred to not in PTSD core symptoms, after adjunctive left the central nucleus of the amygdala (LeDoux et al., 1990). frontal cortical rTMS in patients with comorbid PTSD The central nucleus of the amygdala stands as the central and major depression. point for the dissemination of information that then

Table 1 Summary of open and controlled studies of rTMS as a treatment of anxiety in PTSD

Target site of Authors Sample stimulation Frequency (Hz) Duration (s) Intensity Results

Grisaru et al. 10 PTSD ± SRI Motor cortex bilaterally 0.3 15 stimuli were given 100% of machine Improved markedly in (1998) treatment on each side, over capacity avoidance, anxiety, and a period of 15 min, somatization single treatment McCann 2 PTSD Right frontal cortex 1 Openly 80% MT PTSD symptoms improved et al. during the final week in one (1998) participant and during weeks 2, 3, and 5 in the other participant. Scores returned to baseline after the conclusion of treatment. Prefrontal hypermetabolism on PET reversed with rTMS treatment Rosenberg 12 PTSD and comorbid Left frontal cortex Either 1 or 5 Hz 6000 stimuli over 90% MT Substantial improvement in et al. depression ± SRI (randomized) 10 days mood, anxiety, and sleep (2002) treatment symptoms; minimal improvement in PTSD symptoms Cohen et al. 24 PTSD Right dorsolateral Either 1, 10 Hz or sham 10 daily sessions over 80% MT Markedly improved PTSD (2004) prefrontal cortex (randomized) two weeks core symptoms (re-experiencing, avoidance) with high frequency Osuch et al. 9 PTSD-crossover Right dorsolateral Either 1 Hz or sham At least 3 sessions per 100% MT Active rTMS showed a (2009) prefrontal cortex week and no more than larger effect size of 5 per week. Each improvement for session lasted 30 min hyperarousal symptoms (1800 stimulations per compared with sham session; for a total of 36 000 stimuli in each condition)

MT, motor threshold; PTSD, posttraumatic stress disorder; rTMS, repetitive transcranial magnetic stimulation; SRI, serotonin reuptake inhibitor.

Fig. 1 when stimulated by subsequent experiences, actual or anticipated, that match with the original emotional Lateral hypothalamus Parabrachial nucleus Activates sympathetic Influences respiratory center, memory. The explicit memory may lead the patient to nervous system dyspnea avoid contextual factors that are reminiscent of the panic attack and that could potentially stimulate the conditioned anxiety response. The functional anatomy of this Paraventricularis Locus ceruleus nucleus Central memory process is thought to involve the hippocampus, Nucleusof Enhances learning, whereas phobic avoidance involves the medial/orbital Activates corticotropin- the Amygdala Blood pressure releasing factor stress axis and heart frequency PFC and its reciprocal interaction with the amygdala. Excessive activation of the amygdala decreases prefrontal activity, reflected in a reduction of the PFC Periacqueductal gray Nucleus reticularis inhibitory control over the amygdala (Grace and Rosenk- pontis caudalis Induces freezing ranz, 2002). Enhances somatic reflexes

Anxiety response, amygdala-centric model. The advent of fMRI technology allowed the study of patients with PD during real-time panic attacks. Inhal- ation of small amounts of CO2 during brain imaging coordinates autonomic and behavioral responses (LeDoux studies is a method of provoking anxiety or panic without et al., 1988; Davis, 1992). causing hyperventilation-induced hypocapnia. Concen- trations as low as 5% in room air have been shown to Nevertheless, there are also important reciprocal connections increase anxiety levels in most patients, with patients between the amygdala and the sensory thalamus, PFC, with PD showing significantly more anxiety and higher insula, and primary somatosensory cortex. rates of frank panic (Gorman et al., 1994). Corfield et al. (1995) showed regional differences in the brain in The experience of a panic attack also elicits an emotional response to CO2 inhalation, with the amygdala showing memory, which will elicit a ‘conditioned’ anxiety response particularly strong effects.

Cortical excitability probe in panic disorder drugs were tested on motor cortical excitability by means To our knowledge, there are no studies directly investigating of TMS; the findings suggested that changes in MT cortical excitability in PD patient populations using depend on the conductivity of voltage-gated ion channels TMS. However, TMS has been used for investigations and may reflect membrane excitability, whereas changes in of cortical excitability in the general population intracortical excitability are generated by GABA-controlled during hyperventilation, one of the most characteristic interneuronal circuits in the primary motor area (M1). symptoms of PD (Cowley and Roy Byrne, 1987). Epileptic activity in the EEG of patients with PD without Panic is considered to be distinct from general emergency any other signs of epilepsy (Beauclair and Fontaine, 1986; fear response alarm syndrome because of the prominence Jabourian et al., 1992) has led some authors to hypothesize of intense dyspnea and subsequent hyperventilation the existence of a subgroup of PD with epileptic activity during panic attacks. Acute air hunger rarely occurs in in the limbic system (Gallinat et al., 2003). This acute, external danger-initiated fear (Klein, 1993; Preter hypothesis was further supported by other findings, such and Klein, 1998). Smoking and pulmonary complaints are as EEG alterations in panic patients (described in the independent, multiplicative risk factors for PD but not Introduction of this paper), and limbic electrical stimulation for other anxiety disorders (Pohl et al., 1992; Amering frequently evoking sudden anxiety of astonishing reality, et al., 1999). including epigastric sensations, that correspond to the Diagnostic and Statistical Manual of Mental Disorders These observations, added to the ability to induce panic definition of panic attacks. attacks through chemical challenge, led to the recognition that increasing brain CO2 and lactate are both harbingers Repeated transcranial magnetic stimulation of potential asphyxiation that prompt the suffocation as a treatment for panic disorder false alarm theory of PD (Klein, 1993). For PD, only case reports were available as of last year, and the results are mixed (rTMS treatments for PD are Hypocapnia, synonymous with hyperventilation (Stocchetti listed in Table 2). Garcia-Toro et al. (2002) were the first et al., 2005), is known to increase the excitability of to report on three patients suffering from PD who sensory and motor axons in the peripheral nervous system showed mild improvement after rTMS of the right (Somjen et al., 1987; Macefield and Burke, 1991; DLPFC. The patients had a PD history of at least Mogyoros et al., 2000). Hyperventilation is also considered 1 year, and they had received unsuccessful psychotherapy to promote greater excitability at the level of cortical and pharmacological treatment. The patients received 10 structures; this state has also been shown to be promoted sessions over a period of 2 weeks; each session consisted by TMS. Seyal et al. (1998) showed a direct relationship of 30 trains of 60 s at a frequency of 1 Hz on the right dorsolateral PFC at 110% of the MT. Symptom between pressure of end-tidal CO2 (PETCO2 ) levels and MEP amplitude. A negligible change was found for MEP improvements were modest and partial. A second phase of the study included an application of 30 trains of 20 Hz amplitudes up to 30 or 20 Torr, whereas a PETCO2 of 15 Torr significantly enhanced MEP amplitude and for 2 s on the left PFC, but this phase failed to produce shortened MEP onset latency. Changes in MEP amplitudes additional improvements. after magnetic stimulation and hyperventilation were observed by Kukumberg et al. (1996); the same authors Zwanzger et al. (2002) showed a marked improvement in argued that this observation applied to PD after obtaining both anxiety and occurrence of panic attacks lasting similar results through electromyographic examination of 1 month in a 52 year-old woman after low-frequency PD patients (1993). rTMS of the right DLPFC, as well as a reduction of panic symptoms experimentally induced by cholecystokinin Sparing et al. (2007) recently expanded the data regarding tetrapeptide (CCK-4) and CCK-4-induced adrenocorti- the effects of hyperventilation on the human cortex, cotropic hormone and cortisol release. reporting significant increases in MEP amplitudes, particularly at lower TMS intensities. Paired-pulse Experimental panic induction with CCK-4 is considered a stimulation revealed that hyperventilation decreases suitable model for the evaluation of antipanic effects in intracortical inhibition (ICI) without changing intracortical novel treatment strategies. CCK-4 induces panic attacks

facilitation. The authors argued that low PETCO2 levels in both patients with PD and healthy volunteers; attacks particularly modulate the intrinsic neuronal circuits of are blocked or attenuated after treatment with state- ICI, which are largely mediated by neurons containing of-the-art compounds for panic and anxiety, such as g-aminobutyric acid, whereas modulation of MT probably antidepressants (Bradwejn and Koszycki, 1994; Shlik resulted from alterations of Na + channel conductances et al., 1997), alprazolam (Zwanzger et al., 2003), and even in agreement with Ziemann et al. (2002) (Ziemann et al., aerobic exercise (Strohle et al., 2005). Starting from this 1996a, 1996b). The effects of central nervous system-active point, the same group (2007) recently reported a negative

Table 2 rTMS and panic disorder: clinical trials

Target site of stimula- Authors Sample tion Frequency (Hz) Duration (s) Intensity Results

Garcia-Toro 3 PD First phase: right First phase: 1 First phase: 60 110% MT Modest and partial symptom et al. (2002) DLPFC Second phase: 20 Second phase: 2 improvement Second phase: left PFC Zwanzger 1 PD Right DLPFC 1 10 Â 2 weeks (1200 110% machine Marked improvement of anxiety et al. (2002) stimuli/day) capacity and panic attacks; marked reduction in CCK-4-associated panic symptoms Guaiana et al. 1PD Right frontal area First phase: 1 First phase: a total of 100% MT First phase: No changes (2005) Second phase: 20 5400 pulses Second phase: significantly Second phase: 1620 improved stimuli Â 20 sessions Sakkas et al. 1 PD comorbid Right DLPFC 20 1600 stimuli Â 3 110% MT Significantly improved (2006) depression post weeks stroke patient Zwanzger 11 healthy Right DLPFC 1 1800 stimuli, 30 min 120% MT No difference between treatment et al. (2007) participants and sham in reducing symptoms of CCK-4 challenge induced panic Prasko et al. 15 PD SRI resistant Right DLPFC 1 110% MT No difference between treatment (2007) and sham Mantovani 6 PD and comorbid Right DLPFC 1 1200 stimuli/day Â 100% MT Significant and sustained (up to et al. (2007) depression 10 days six months) improvement

CCK-4, cholecystokinin tetrapeptide; DLPFC, dorsolateral prefrontal cortex; MT, motor threshold; PD, panic disorder; rTMS, repetitive transcranial magnetic stimulation; SRI, serotonin reuptake inhibitor. result with TMS. Anxiolytic and antipanic properties patients with PD and comorbid depression treated with were not found for a single session of low-frequency TMS daily active 1-Hz rTMS to the right DLPFC for 2 weeks. in 11 healthy individuals for whom panic attacks were A significant increase was noticed in the right hemisphere experimentally induced. The authors applied 1 Hz rTMS resting MT from baseline to the second week of or sham rTMS over the right DLPFC in a randomized treatment administration. crossover protocol and found no differences between the treatment and sham conditions. It was thus concluded Conversely, Prasko et al. (2007) conducted the first that rTMS does not reach the efficacy of standard double-blind sham-controlled investigation on 15 PD pharmacological treatment for PD and anxiety. However, patients resistant to serotonin reuptake inhibitor therapy, because in this study only a single rTMS session was adding low-frequency rTMS or sham rTMS to serotonin applied, the treatment duration might have been too short. reuptake inhibitor therapy for 10 sessions. They administered 1-Hz rTMS at 110% of the MT over the right In 2006, Sakkas et al. (2006) reported the case of a DLPFC. Both sham and TMS groups improved during 55-year-old, married, Caucasian male patient with the study period, but the treatment effect did not differ comorbid depression and PD as well as a history of between groups in any of the instruments. myocardial infarction who had to stop taking pharma- cotherapies because of cardiac side effects. The patient Notably, the DLPFC is not the only target site to have was treated with two daily sessions of high-frequency been investigated for PD treatment. In 2005, Guaiana rTMS over the DLPFC (the frequency of the stimulation (Guaiana et al., 2005) published a case report of a was 20 Hz and the duration of each train 2 s, using 110% significant improvement in panic symptoms after of the magnetic power of the MT; approximately 40 trains high-frequency rTMS (20 Hz at 100% of MT for 2 s train were administered for a total of 1600 stimuli). After the intervals with an intertrain interval of 30 s, resulting in completion of the first 3-week period of twice-daily 1620 pulses per session for 20 sessions and a total of rTMS sessions, the patient’s condition was significantly 32 400 pulses) over the motor cortex with a figure-eight improved (more than 50% reduction in HDRS score, 15). coil. This result emphasizes the role of action preparation It was concluded that in cases of refractory post-stroke in anxiety. depression-anxiety or in patients with heart disease for whom antidepressant medication cannot be successfully Generalized anxiety disorder: used because of side effects, rTMS might be helpful. phenomenology and neural correlates The essential feature of GAD is persistent (not more days Finally, in 2007, Mantovani et al. (2007) reported in a pilot than for at least 6 months) and excessive worry about open study a clinically significant and sustained (up to several aspects of one’s life (e.g. work or school 6 months) improvement of panic symptoms in five of six performance) or the welfare of loved ones. Associated

symptoms include irritability, restlessness, and concentra- Social and performance-demanding situations are either tion impairment. Somatic symptoms may include muscle avoided or endured with intense discomfort, leading to tension, sweating, dry mouth, nausea, and diarrhea. a severe impact on the individual’s normal routine or life functioning. Neurobiological studies using different investigative techniques in both clinical and preclinical studies have SAD is the third most common psychiatric disorder pointed out abnormalities of some brain regions respon- (Kessler et al., 1994), with prevalence rates ranging from sible for emotional processing and social behaviors, such 1.9 to 18.7% (Kessler et al., 1998; Wittchen et al., 1998), a as the amygdala, PFC, and temporal areas (Jetty et al., mean age of onset between 11 and 15 years, and a chronic 2001). As observed (Ferrari et al., 2008), a few studies and disabling course often leading to a significant impact using structural volumetric MRI are available for this in all areas of life (Burke et al., 1990). disorder, a fact that prevents definitive conclusions based on volumetric data. However, functional neuroimaging Despite being a disabling condition with high prevalence observations (Quirk et al., 1997; De Bellis et al., 2002) rates and a high rate of comorbidities, the scientific allow postulating the presence of anatomical abnormal- literature has only recently started to explore the biological ities localized in the amygdala and the temporal lobe, mechanisms underlying the etiology and pathophysiology of more specifically the superior temporal gyrus, in associa- SAD. Studies on the neural underpinnings of SAD tion with the diagnosis of GAD. An interesting fMRI implicate abnormalities of corticolimbic and possibly study in patients with GAD and/or social phobia shows corticostriatal circuitry. Amygdala activation in response to that patients with high intolerance of uncertainty emotional human faces has been shown to correlate with activated frontal or limbic regions, whereas individuals the severity of social anxiety symptoms (Phan et al., 2006), with less anxiety during the task deactivated the same as does the extent of activation in bilateral insular cortex regions in response to uncertainty (Krain et al., 2008). (Paulus and Stein, 2006) in anxious nonpatients. Another recent fMRI study found that the right amygdala and the right ventrolateral PFC showed strong negative Increased amygdala blood flow during public speaking in coupling specifically in response to masked angry faces, patients when compared with healthy controls has been which were presented only for a short duration (17 ms) shown by a PET study of regional cerebral blood flow (Monk et al., 2008). (Furmark et al., 2002) and can be decreased after cognitive behavioral therapy or pharmacological treatment of PETstudies have found metabolic differences in occipital social phobia. Functional MRI blood oxygenation lobe (Buchsbaum et al., 1987), as well as cortex, limbic level-dependent studies showed increased activation of regions, and basal ganglia (Wu et al., 1991) after the anterior cingulate cortex during the processing of benzodiazepine treatment in GAD patients versus normal disgust faces in individuals with social phobia (Amir et al., controls. Another imaging study has found significant 2005) and reduced striatal (left caudate) activation changes in cerebral benzodiazepine receptor distribution during implicit sequence learning (Sareen et al., 2007). in GAD patients compared with healthy controls (Tiihonen et al., 1997a, 1997b). The recent finding reported by Sareen et al. (2007) (specifically, significantly reduced activation in the left It is thought that the heterogeneity of anxiety disorders caudate head during an implicit learning task in social limits the specificity of the findings (Ferrari et al., 2008). anxiety patients) implicated the striatum and added Similarly, there is a lack of studies regarding cortex evidence to dopamine receptor PET studies. In fact, the excitability in GAD patients. However, an fMRI-guided results showed that changes in striatal dopaminergic low-frequency rTMS at 90% of the resting MT over the function in patients with SAD were specifically correlated frontal cortex in 10 GAD patients seemed to produce a with motor symptoms (Tiihonen et al., 1997a, 1997b; significant decrease in anxiety measures (Bystritsky Schneier et al., 2000). Further evidence is provided by the et al., 2008). This study constitutes the first preliminary high rates of SAD in patients with Parkinson’s disease, an open-label application of rTMS on GAD treatment. illness characterized by deficits in striatal dopamine function (Stein et al., 1990). Taken together, these Social anxiety disorder: phenomenology findings support the hypothesis of a link between and neural correlates movement diseases caused by striatal dopamine dysfunction Social anxiety disorder (SAD) is characterized by and social phobia. disabling anxiety, shaking, trembling, tremor, blushing, and sweating in both social and performance-related This hypothesis is intriguing given the evidence of motoric situations. Patients fear that these symptoms will symptoms (stutter, vegetative symptoms, palsy, etc.) lead others to watch them while doing something in patients with social phobia under stress. However, little embarrassing and that this will be negatively evaluated. is known about the electrophysiological correlates in SAD.

Sachs et al. (2004) conducted an EEG mapping study in The reliability of clinical trials is also limited by the patients with SAD, revealing significant differences from number of dosages that can be administered and by the normal controls and suggesting hyperarousal as a key depth that TMS coils can reach within the brain. factor of anxiety. Although a TMS study of cortical Magnetic coil design is important to the TMS technique excitability would be of particular interest given and to the distribution of the electric field on the surface TMS-derived changes already reported for movement of the scalp, and an optimal coil design is still needed. disorders including Parkinson’s disease (see Cantello Technology already exists to direct the TMS coil to the et al., 2002), currently there are no published studies. scalp position overlying the target cortical structure, but this technology has not yet been widely adopted in the Our group has collected preliminary data (Pallanti et al., clinical setting. unpublished work) comparing the cortical silent period duration (CSP), MT, MEP, and the amount of Studies with TMS also promise to improve the under- long-interstimulus interval ICI during single-pulse TMS standing of neuroanatomical networks possibly mediating and paired-pulse TMS investigation of a sample of symptoms and to help clarify the relationships between patients and normal controls. No differences were found cognitive and affective processing in each illness. in neurophysiological variables between groups, but a positive correlation was found between CSP and the TMS studies have revealed abnormal physiological ‘novelty-seeking’ dimension of Cloninger’s Tridimensional processes in anxiety disorders such as aberrant modula- Personality Questionnaire (Cloninger, 1987) in the SAD tion of cortical excitability. From this perspective, anxiety group. CSP is a cortical measure of inhibition. seems to be related to a phase of motor preparation or anticipation. The hypothesis that an altered pattern of SAD patients showed a significantly lower level of novelty cortical excitability may reflect an ‘endophenotypic’ trait seeking scoring than did normal controls. Even if these predisposing individuals to anxiety disorders and motor findings are limited by the small sample size and by symptoms should be further elucidated. 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