Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation in Psychiatric Disorders: A Systematic Review

Brain Stimulation 7 (2014) 158e169

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Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation in Psychiatric Disorders: A Systematic Review Tilmann Bunse a, Thomas Wobrock b, c, Wolfgang Strube a, Frank Padberg a, Ullrich Palm a, Peter Falkai a, Alkomiet Hasan a, * a

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany Centre of Mental Health, County Hospital Darmstadt-Dieburg, Groß-Umstadt, Germany c Department of Psychiatry and Psychotherapy, Georg-August-University, Göttingen, Germany b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 April 2013 Received in revised form 16 August 2013 Accepted 26 August 2013

Background: Transcranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions. Objective: To provide a systematic review of TMS studies (1985e2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). Methods: Systematic literature-based review. Results: Across disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction. Conclusions: The results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Transcranial magnetic stimulation Psychiatric disorder Cortical inhibition Cortical excitability Systematic review

Introduction Since its introduction, transcranial magnetic stimulation (TMS) has been extensively used as a non-invasive brain stimulation technique to explore cortical physiology in humans. In particular, single- and paired-pulse TMS-protocols applied to the human motor cortex have allowed the physiological investigation of various intracortical inhibitory and facilitatory networks, and cortico-cortical connectivity. In order to determine the activity of associated neurotransmitters and to characterize them further, pharmacological manipulations using different neuroactive agents

Conflict of interest: The authors deny any potential conflict of interest as it relates to the subject of this report. * Corresponding author. Tel.: þ49 089 5160 5511; fax: þ49 89 5160 5530. E-mail address: [email protected] (A. Hasan). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2013.08.009

have been performed [1,2]. However, until today, no systematic review has summarized the evidence available to indicate altered physiological TMS parameters in psychiatric disorders. Therefore, we aimed to systematically review all available evidence for impaired motor cortical excitability, as revealed by TMS, in psychiatric disorders. This review is limited to dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome, substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). Apart from certain exceptions, only studies comparing cortical excitability in patients suffering from mental disorders to that in healthy controls have been included. Different TMS protocols can be implemented to investigative motor cortical excitability in humans. A detailed description of all

T. Bunse et al. / Brain Stimulation 7 (2014) 158e169

available paradigms and their underlying physiology would go far beyond this systematic review. However, multiple recent and excellent reviews on this topic offer a good introduction to readers interested in learning more about this [1,3,4]. Parameters measured by single-pulse TMS Motor evoked potential (MEP) The motor evoked potential (MEP) is defined as the overall reaction of a peripheral muscle, measured by electromyography (EMG), that is induced via TMS of the contralateral motor cortex [5]. Based on the observation that excitation propagation is subject to substantial variability [6], each MEP may reveal variance of its amplitude, latency and configuration [7]. Therefore, to answer neurophysiological questions, it is recommended that, rather than investigating single MEPs, a mean MEP value is determined [8]. Motor thresholds The resting motor threshold (RMT)/active motor threshold (AMT) is defined as the minimum TMS intensity needed to induce a motor evoked potential larger than 50 mV (200 mV) in at least 5 of 10 trials [5,9]. Motor thresholds reflect the activity of neuronal membranes and the excitability of corticocortical axons, synapses and their sodium channels, with NMDA-associated transmission and GABAergic mechanisms thought to be less involved [1,10]. Cortical silent period The cortical silent period can be subdivided into the contralateral (CSP) and the ipsilateral (ISP) cortical silent period. The CSP is defined as a suppression of or reduction in ongoing tonic muscle activity, lasting up to 300 ms following TMS applied to the contralateral motor cortex [3,11,12]. Its length can be defined as the duration from the beginning of an MEP to the re-emergence of baseline EMG-activity. It is supposed that approximately the first 50 ms represent spinal mechanisms of inhibition, while later inhibition is influenced by cortical networks [13]. It has been proposed that this inhibitory network is mainly influenced by GABAB-receptors, although other neurotransmitters may also be involved [1,14,15]. The ISP represents neuronal activity on the hemibody identical to the site of stimulation and, therefore, involves neuronal tracts of the corpus callosum connecting both hemispheres [16]. Parameters measured by paired-pulse TMS Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) The application of a first stimulus below motor threshold followed by a second stimulus above motor threshold, with a short interstimulus interval (ISI) of 1e5 ms, results in a physiological reduction of cortical excitability (short-interval intracortical inhibition (SICI)) [17]. This parameter reflects inhibitory effects mediated mainly by GABAA-receptors, as well as dopamine and acetylcholine [1]. The same pulse configuration applied at longer ISIs of 10e15 ms or longer results in increased excitability [17]. This intracortical facilitation (ICF) seems to be mediated principally by glutamatergic neurotransmission, although the underlying physiology is less clear in this case [1]. Short-interval intracortical facilitation (SICF) Paired-pulse TMS with an initial stimulus above threshold and a second one below threshold, applied at a short interstimulus interval of 0.5e5 m, results in a short-interval intracortical facilitation (SICF). It has been discussed that GABAA-receptors are involved in the generation of the SICF and that this phenomena is related to intracortical I-wave generation [18,19].

159

Short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) TMS can be paired with electric stimulation of a peripheral or facial muscle to investigate both short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI) [20,21]. A short interstimulus interval (best effects at 20 ms) leads to an SAI, representing a junction between sensory and motor components and leading to inhibitory effects in the primary motor cortex [20]. It is thought that SAI may be critically dependent upon the activity of cholinergic receptors and non-alpha2/3-GABAA-receptors [22,23]. A longer interval (best effects at 200 ms) conducts a long-latency afferent inhibition (LAI), reflecting inhibitory effects to the motor cortex mediated by the primary somatosensory cortex and secondary somatosensory areas [24,25]. Transcallosal inhibition (TCI) The connectivity between the motor cortical areas of each hemisphere can be investigated using a twin-coil paired-pulse paradigm (transcallosal inhibition). For this protocol, a conditioning stimulus is given to the motor cortex of one hemisphere and is followed by a second stimulus applied to the other hemisphere. The interaction between the two stimuli is usually inhibitory at ISIs of 6e50 ms, with GABAergic interneurons thought to be principally responsible for determining this interhemispheric inhibition [26,27]. At short ISIs of 4e6 ms, a weak facilitatory effect is observed [28]. Methods and materials The systematic literature research for this article was conducted via the internet databases PubMed and MEDLINE (1985e2013), using the following search items: “Transcranial magnetic stimulation” and “schizophrenia,” “Transcranial magnetic stimulation” and “bipolar disorder,” “cortical inhibition” and “depression,” “Transcranial magnetic stimulation” and “borderline personality disorder,” “Transcranial magnetic stimulation” and “alcohol,” “Transcranial magnetic stimulation” and “nicotine,” “Transcranial magnetic stimulation” and “tobacco,” “Transcranial magnetic stimulation” and “thc,” “Transcranial magnetic stimulation” and “cannabis,” “Transcranial magnetic stimulation” and “cocaine,” “Transcranial magnetic stimulation” and “attention deficit hyperactivity disorder,” “cortical inhibition” and “Tourette,” “Transcranial magnetic stimulation” and “Tourette,” “Transcranial magnetic stimulation” and “Posttraumatic stress disorder,” “Transcranial magnetic stimulation” and “OCD,” “Transcranial magnetic stimulation” and “Alzheimer disease” and “cortical inhibition” and “Alzheimer disease.” The literature research offered a total of 684 publications. Due to our scientific question of neurophysiological fundamentals, publications obviously concerning the treatment of psychiatric disorders where excluded (especially repetitive TMS studies). We then reviewed the titles and abstracts of the remaining studies carefully to identify those dealing with single- or paired-pulse TMS protocols revealing outcomes about parameters described above. 80 publications were considered to be promising. Next we read through the full text of the papers to evaluate relevant data for our review. Review papers, cited papers, and papers suggested by the reviewers and appearing to be relevant led to an extended search and highlighted 11 further publications for consideration. Only studies published in English and describing the study population, methods and study design were included. Results 89 studies dealing with TMS in psychiatric disorders and fulfilling the pre-defined criteria could be identified. According to

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different psychiatric disorders, the following division could be performed: 24 studies investigated the effects of TMS-measured motor cortical excitability in patients with attention deficit hyperactivity disorder (ADHD), Tourette Syndrome (TS) or obsessive compulsive disorder (OCD). 24 studies concerned cortical excitability in patients with schizophrenia. A further 20 studies could be identified for diseases related to dementia, and 12 studies covered addictive disorders. Finally, 8 studies dealt with affective disorders, and 3 studies were about other psychiatric disorders. TMS in patients with ADHD, OCD or Tourette Syndrome Due to the early onset of this disease during childhood, most ADHD studies (n ¼ 8) included rather young subjects (Table 1). A very consistent finding is a reduced SICI in children with ADHD compared to healthy subjects [29e32]. With regard to ADHD symptom severity, Gilbert et al. showed that higher severity correlates with a reduction in SICI [30]. Alterations in ICF, CSP or RMT could only be observed in a few studies, with no clear pattern emerging. In contrast to children, different results are observed in adults. For instance, Hoeppner et al. demonstrated an unchanged SICI and ICF in 21 ADHD adult patients compared to 21 healthy subjects, which might be explained by a normalization of motor cortical excitability in adults [33]. However, other authors have shown reduced SICI or enhanced ICF in adult, unmedicated ADHD patients, pointing to decreased motor cortical inhibition in this population [34e36]. The application of different stimulants in childhood ADHD resulted either in a decrease of SICI (atomoxetine) [31] or in an increase in SICI (methylphenidate) [32]. The latter could also be observed in adult ADHD patients [37]. Another indicator of a disturbed motor cortical inhibition in patients with ADHD is the reduction of the CSP as well as the ISP, which can also be restored by the application of methylphenidate [32]. Similar to ADHD patients, a reduced cortical inhibition can be found in OCD patients. Although there is currently only minimal data available, a reduced CSP and SICI, reduced motor thresholds, as well as an increase in ICF, have already been described as a very consistent finding [38,39]. Proton magnetic resonance spectroscopy (MRS) data indicate that unmedicated adults suffering from OCD have decreased GABA levels in the medial prefrontal cortex [40]. Furthermore, preliminary results in medication-resistant OCD patients reveal that application of inhibitory 1 Hz rTMS to the supplementary motor area improved symptoms, and increased both motor thresholds [41,42] and SICI [43], thought to be GABAergic in basis [44,45]. In TS, a decreased SICI was observed in all analyzed studies. In some studies, this decrease correlated with motor tic severity and hyperactivity [46,47]. In particular, Tourette patients with comorbid ADHD showed an increased ICF as another marker for motor cortical disinhibition. These findings are in line with neuropathological studies from the basal ganglia of Tourette patients, pointing toward alterations of the distribution of parvalbumin-positive GABAergic interneurons [48]. In summary, a reduced SICI is a very consistent finding in child and adult patients suffering from ADHD, OCD and TS. The alterations in other TMS parameters (e.g. CSP or ICF) are less consistent. The picture of reduced SICI across disorders and age groups may be due to a common symptom domain of motor disturbances, likely related to a deficit in GABAergic transmission [49].

transmission in schizophrenia (Table 2) [50e52]. Inconsistent findings related to alterations in CSP might be explained by different disease states (e.g. first-episode patients, chronically-ill patients) or different medications (e.g. clozapine was shown to have a prominent effect on CSP). In general, the effects of antipsychotics on cortical excitability in schizophrenia remain to be fully understood. Treatment with clozapine, olanzapine, quetiapine and risperidone revealed different effects on cortical excitability in schizophrenia patients. Compared to healthy subjects, the intake of clozapine was associated with an increase of CSP. In contrast, the intake of olanzapine, quetiapine and risperidone led to a shorter CSP. Compared to healthy subjects and patients taking other drugs, a reduced SICI value was observed when clozapine was administered, although other studies failed to show this effect [53,54]. However, an impact of antipsychotics on ICF in schizophrenia patients could not be observed. Other investigations have shown a reduced RMT and prolonged TCI after application of olanzapine [55]. In addition to these findings, TMS studies have provided evidence for an impaired intercortical connectivity in schizophrenia, reflected by a modulated hemispheric pattern of motor thresholds [56] and ICF [34], or by impairments in transcallosal inhibition and ISP. The analyses of RMT revealed inconsistent results and it is very likely that differences in RMT between patients and healthy controls are due to antipsychotic medication [56]. In summary, TMS studies have revealed motor cortical disinhibition in schizophrenia patients, whereas the most consistent parameter was again SICI. In general, the reduced SICI can be linked to alterations in GABAergic interneurons, a finding strongly supported by neuropathological studies. Postmortem studies conducted on schizophrenia brains have revealed significant alterations in the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and a GABAergic interneuron reduction in various cortical areas, including the motor cortex [50e52,57e59]. These studies did not only investigate frontal regions in schizophrenia patients, but also showed prominent reductions in the number and functionality of GABAergic interneurons within the motor cortex [51]. TMS in patients with dementia Depending on the type of dementia and its particular pathophysiological state, various alterations in motor cortical excitability in dementia patients could be observed compared to healthy controls (Table 3). A reduced SAI in forms of dementia characterized by impaired cholinergic neurotransmission (e.g. Alzheimer’s disease) has been reported in most of the studies investigating this parameter. Interestingly, in dementia forms associated with no detectable cholinergic deficits (e.g. FTD), SAI was not altered. Furthermore, a general cortical disinhibition was observed by a reduced SICI, higher MEP amplitudes and reduced RMT in a remarkable proportion of studies, whereas other studies failed to replicate these findings. Application of a cholinesterase inhibitor (e.g. rivastigmine) normalized the reduced SAI as well as the reduced SICI [60e62]. In summary, TMS studies are in line with the hypotheses of cholinergic dysfunction in Alzheimer’s disease and the normalization of impaired SAI and SICI following treatment may serve as a neurophysiological response and progression parameter. TMS in patients with drug addiction

TMS in patients with schizophrenia Cortical disinhibition, reflected by a reduced SICI, was detected in most of the studies examining this parameter in schizophrenia patients, supporting the theory of a disturbed GABAergic-

TMS has frequently been used to investigate motor cortical excitability in patients suffering from drug addiction (Table 4). Due to the unique receptor profile of each drug, the observed effects were, unsurprisingly, quite heterogenous. However, as most drugs’

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161

Table 1 Cortical excitability in ADHD, OCD and Tourette syndrome. Reference

MEP RMT AMT CSP ISP

SICI ICF SAI Subjects

Notes

Adults ADHD Hasan et al. (2013) [34]

C

C

w

:

w

C

:

w

28 ADHD 41 HC 25 FE-SZ

Schneider et al. (2011) [37]

w

C

C

w

w

:

C C

13 ADHD

Hoeppner et al. (2008) [33]

C

C

w

w

w

C

C w

Hoeppner et al. (2008) [102]

C

C

w

C

;/C w

Richter et al. (2007) [103]

C

C

w

w

w

;

C w

Schneider et al. (2007) [36]

C

C

C

w

w

;

C w

21 21 21 21 10 10 26 26

ADHD HC ADHD HC ADHD HC ADHD HC

For differences to schizophrenia patients please see original paper. Schizophrenia patients and ADHD patients showed impaired cortical excitability compared to healthy controls. Both patient groups differed significantly in ICF and CSP distribution across hemispheres. 13 drug-free patients with diagnosed ADHD showed increased SICI but unchanged ICF under treatment with long-acting methylphenidate. All patients were adults and no differences between groups could be detected. Shortened ISP-duration in ADHD, latency unchanged; intake of methylphenidate restored changes to ISP-duration. Only adults were included in the study and the impaired cortical inhibition detected in children studies could be replicated in adults. Reduced SICI could be detected on the left, but not the right, hemisphere.

C

C

w

; w

C

:

w

;

;

C

w

;

C w

Greenberg et al. (1998) [104] w

w

w

w

w

;

w

34 34 16 11 12 12

OCD HC OCD HC OCD HC

OCD Richter et al. (2012) [39] Greenberg et al. (2000) [38]

w

w

w

w

TS Heise et al. (2010) [105]

w

C

w

w

w

;

C w

Orth et al. (2009) [106]

w

:

:

C

w

;

:

11 TS 11 HC

; 29 TS-U 24 HC

Gilbert et al. (2005) [47]

w

w

w

w

w

;

w

Orth et al. (2005) [76]

w

C

C

C

C

;

C ; 10 TS 10 HC

Gilbert et al. (2004) [46]

w

w

w

C

w

;

w

w

36 TS

Ziemann et al. (1997) [107]

w

C

w

; w

;

w

w

20 TS 21 HC

C

C

w

w

w

;

w

w

43 ADHD 29 HC

Wu et al. (2012) [108]

C

C

C

C

:

;

:

w

50 ADHD 64 HC

Gilbert et al. (2011) [30]

w

C

C

C

w

;

C w

Gilbert et al. (2007) [31]

w

C

C

w

w

;

C w

49 ADHD 49 HC 11 ADHD

Buchmann et al. (2007) [109] C

C

w

w

w

:

; w 18

Buchmann et al. (2006) [110] C

C

w

w

:/; w

w

C

C

C

w

;

w

w

Buchmann et al. (2003) [112] C

C

w

C

;/: w

w

w

C

C

w

; w

w

w

Children ADHD Hoegl et al. (2012) [29]

Garvey et al. (2005) [111]

Moll et al. (2001) [113]

C

w

w

28 TS

23 12 12 13 13 16 16 16 16

Adult OCD patients showed significant alterations in cortical excitability compared to healthy controls. The decreased intracortical inhibition was greatest in patients suffering from OCD and comorbid tics. First study investigating cortical inhibition in OCD.

SICI was reduced at rest but there were no differences in other parameters. During the pre-movement phase, groups differed in single pulse motor evoked potential amplitudes and SICI. Furthermore, SICI was reduced in the early phase of movement preparation (similar to rest) followed by a transition toward more inhibition. In patients, the modulation of shortinterval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. TS with comorbid ADHD was associated with more pronounced changes in the motor cortex excitability compared to uncomplicated TS, or TS with comorbid OCD. Severity of ADHD correlated significantly with reduction of SICI in 28 adult and under-aged TS patients across two visits. SAI and SICI were both reduced in patients compared to healthy controls, and a single application of nicotine reduced these differences between groups. SICI was significantly and inversely associated with greater ADHD and motor tic severity in adult and under-aged TS patients. Additionally, the strength of the association with ADHD symptom severity was greater. Impaired cortical inhibition was mainly observed when tics were present in the EMG target muscle or in patients without antipsychotic treatment.

Patients subdivided into groups of high and low hyperactivity/impulsivity. The high hyperactivity group showed a significant decrease of SICI in the resting condition. Further data during the performance of a go/no go task are reported in the paper. 50 children with ADHD were compared with 64 normally developing children (all children aged below 12 years). ISP latency was prolonged in patients, whereas ISP duration did not differ between groups. Impaired SICI correlated with ADHD diagnosis and symptom severity.

One month of treatment with atomoxetine reduced ADHD severity, but resulted in a further decrease of SICI. ADHD In ADHD children, the application of methylphenidate resulted in an enhanced inhibition and reduced facilitation. ADHD Treatment with methylphenidate in children suffering from ADHD resulted in an increased duration and reduced latency of ISP. ADHD ADHD patients showed a delayed maturation of finger speed and an HC absence of the age-related decrease in ISP latency compared to controls. ADHD In the patient group, ISP duration was shorter, while ISP latency was longer HC compared to controls. TD patients (TD only or ADHD/TD) had a shorter CSP than children without ADHD TD. Children with ADHD (ADHD only or ADHD/TD) had reduced HC intracortical inhibition compared to children without ADHD (HC or TD TD only). ADHD/TD

MEP ¼ motor evoked potential, RMT ¼ resting motor threshold, AMT ¼ activated motor threshold, CSP ¼ cortical silent period, ISP ¼ ipsilateral silent period, SICI ¼ short-interval intracortical inhibition, ICF ¼ intracortical facilitation, SAI ¼ short-latency afferent inhibition, HC ¼ healthy control subjects, ADHD ¼ patients with attention-deficit/hyperactivity disorder, FE-SZ ¼ patients with first-episode schizophrenia, OCD ¼ patients with obsessive compulsive disorder, TS ¼ patients with Tourette Syndrome, TS-U ¼ untreated patients with Tourette Syndrome, TD ¼ tic disorder.

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Table 2 Cortical excitability in schizophrenia. Reference

RMT

AMT CSP

ICF/SICF Subjects

Notes

Hasan et al. (2012) [134]

C

w

:/C w

;

C

18 FE-SZ 18 At-Risk 18 HC

Hasan et al. (2011) [152]

:

w

C

w

;

C

Individuals at-risk of developing schizophrenia already showed reduced cortical inhibition (SICI), but no differences in CSP compared to healthy controls. First-episode schizophrenia patients (FE-SZ) show differences in both inhibitory networks. Cortical excitability was measured at baseline before anodal tDCS. As a group, schizophrenia patients showed elevated RMT and reduced SICI.

Soubasi et al. (2010) [135] Wobrock et al. (2010) [69]

:

w

:

w

w

w

C

w

C

w

;

:

C

w

:

w

;

C

C

w

:/; w

C

C

Wobrock et al. C (2008) [137] Hoy et al. (2008) [138] w

w

w

w

;

C

w

w

;

w

w

Daskalakis et al. (2008) [54]

C

w

:

w

C

C

Fitzgerald et al. (2004) [151]

C

w

;

C

;

C

Saka et al. (2005) [139] C

C

C

C

w

w

Bajbouj et al. (2004) [140] Eichhammer et al. (2004) [141] Fitzgerald et al. (2003) [142]

C

C

:

:

w

w

;

(;) w

w

C

C

C

w

w

w

w

:

Fitzgerald et al. (2002) [55]

:/; C

;

:/C

C

C

Pascual-Leone et al. (2002) [56]

:/C C

C

C

;/C

Fitzgerald et al. (2002) [143] Daskalakis et al. (2002) [144]

C

w

:/C

w

w

;/C w

;/: ;

;

C

Fitzgerald et al. (2002) [145] Hoeppner et al. (2001) [146] Boroojerdi et al. (1999) [147] Davey et al. (1997) [148]

C

w

;

w

;

C

w

w

w

:/C

w

w

C

w

w

:

w

w

C

w

w

C

w

w

;

w

w

w

w

w

Puri et al. (1996) [150] C

w

C

w

w

w

9 RO-SZ 13 ME-SZ 22 HC 51 SZ Schizophrenia patients (SZ) receiving ziprasidone had the highest RMT, quetiapine 51 HC revealed intermediate values and olanzapine showed the lowest RMT. 17 SZ-NSUD Schizophrenia patients with comorbid cannabis abuse showed reduced SICI and 12 SZ-SUD increased ICF-values, indicating cortical inhibition was enhanced by substance abuse. 29 FE-SZ First-episode schizophrenia patients (FE-SZ) showed longer CSP and reduced SICI 44 HC compared to healthy controls (HC), while RMT was similar in both groups. Patients medicated with clozapine (SZ-C) showed longer CSP compared to healthy 32 SZ-O subjects. Patients taking risperidone (SZ-R) or olanzapine (SZ-O) and unmedicated 20 SZ-R patients (SZ-U) had shorter CSP compared to healthy subjects. SICI was also reduced 19 SZ-C in patients taking olanzapine compared to other groups. 9 SZ-U 38 HC 29 FE-SZ Reduced SICI in first-episode schizophrenia supports the hypothesized GABAergic 28 HC deficits present at an early stage of the disease. 15 SZ TCI was decreased in patients, while no differences in transcallosal facilitation were 15 HC detected between patients and healthy controls. Intake of clozapine (SZ-C) led to a prolonged CSP compared to that in unmedicated 10 SZ-C patients (SZ-U) and HC. 6 SZ-U 10 HC Baseline measures were obtained before a 1 Hz rTMS train. All patients had shorter CSP 10 SZ-U compared to healthy controls, but SICI was only reduced in medicated patients. 16 SZ-M 18 HC 12 SZ-Rel Although there were no significant differences between relatives of schizophrenia 14 HC patients (SZ-Rel) and HC, 3 out of 12 relatives demonstrated reduced transcallosal inhibition. 16 SZ Prolonged CSP and ISP in schizophrenia indicated a disturbed interhemispheric 16 HC connection. 21 FE-SZ 21 drug-naïve, first-episode schizophrenic patients demonstrated lower RMT (and 21 HC AMT, trend level) but no differences in SICI and ICF. SICF was increased in medicated (SZ-M) as well as unmedicated (SZ-U) patients with 9 SZ-M schizophrenia compared to healthy controls. No differences for LICI could be 9 SZ-U detected. 8 HC Schizophrenia patients taking olanzapine (SZ-O) had lower RMT, while patients taking 20 SZ-O risperidone (SZ-R) had higher RMT compared to HC. Both patient groups showed 20 SZ-R shortened CSP compared to HC. In addition SZ-O had prolonged TCI, compared to SZ22 HC R and healthy controls. A decreased SICI and increased RMT were observed in medicated patients (SZ-M), but 7 SZ-M no difference was observed between unmedicated patients (SZ-U) and healthy 7 SZ-U controls. While healthy controls had higher thresholds on the left hemisphere 7 HC compared to the right one, patients showed the opposite effect. 25 SZ Patients showed a prolongation of TCI correlated with the medication dose, but no 20 HC differences in the latency compared to HC. RMT was lower in medicated patients (SZ-M) compared to unmedicated patients (SZ15 SZ-M U) and healthy controls. SICI decreased in both patient groups, whereas the 15 SZ-U reduction was largest in unmedicated patients; CSP was shortened in unmedicated 15 HC patients and prolonged in medicated patients; less TCI was detected in unmedicated patients (23.25%) and medicated patients (9.92%) compared to healthy controls. 22 SZ In schizophrenia patients, CSP duration and SICI were reduced, while RMT and ICF 21 HC showed no differences to HC. 12 SZ In patients, the duration of ISP was prolonged, while the latency of ISP was similar to 12 HC healthy controls. 10 SZ Transcallosal conduction time and duration of inhibition were shown to be prolonged 10 HC in schizophrenia patients. 9 SZ-U Examination of the silent period after the cMEP response showed that medicated 9 SZ-M patients (SZ-M) exhibited an early component of weaker EMG suppression before a later stronger period of suppression developed. RMT was lower in schizophrenia patients compared to patients with MD and HC. No 10 SZ differences for the central conduction time across groups could be detected. 10 MD 10 HC 9 SZ-U Unmedicated schizophrenia patients (SZ-U) had a shorter latency for the activated MEP 9 HC prior to the suppression of voluntary muscle activation.

Wobrock et al. (2009) [136] Liu et al. (2009) [53]

Abarbanel et al. (1996) [149]

C

ISP/TCI SICI

RMT ¼ resting motor threshold, AMT ¼ activated motor threshold, At-Risk ¼ subjects at-risk of developing schizophrenia, MD ¼ major depression CSP ¼ cortical silent period, ISP ¼ ipsilateral silent period, SICI ¼ short-interval intracortical inhibition, ICF ¼ intracortical facilitation, FE-SZ ¼ patients with first-episode schizophrenia, HC ¼ healthy control subjects, SZ ¼ schizophrenia patients, SZ-SUD ¼ schizophrenia patients with substance use disorder, SZ-NSUD ¼ schizophrenia patients without substance use disorder, SZ-C ¼ schizophrenia patients medicated with clozapine, SZ-O ¼ schizophrenia patients medicated with olanzapine, SZ-R ¼ schizophrenia patients medicated with risperidone, SZ-M ¼ schizophrenia patients medicated, SZ-U ¼ schizophrenia patients unmedicated, SZ-Rel ¼ relatives of schizophrenia patients, MD ¼ patients with mild depression, ME-SZ ¼ multi-episode-SZ, RO-SZ ¼ recent-onset SZ.

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163

Table 3 Cortical excitability in dementia. Reference

MEP RMT

AMT

CSP ISP

SICI

ICF SICF SAI

Nardone et al. (2012) [114]

w

C

C

w

w

C

C w

;

w

Hoeppner et al. (2012) [115]

C

;

w

w

:/C ;

C w

w

w

Khedr et al. (2011) [116] Pennisi et al. (2011) [117]

C

;

;

:

:

w

w w

w

w

:

;

w

C

w

w

w w

w

w

Olazarán et al. (2010) [118] Martorana et al. (2009) [119] Martorana et al. (2008) [120] Nardone et al. (2008) [121] DiLazzaro et al. (2007) [122]

w

w

w

w

w

C

C w

w

w

w

w

w

w

w

w

w w

;

w

w

;

C

w

w

;

C w

w

w

w

C

C

w

w

C

C w

;

w

w

C/; C/; w

w

C

w w

;

w

Sakuma et al. (2007) [123]

w

C

w

w

w

w

w w

;/C w

Nardone et al. (2006) [124]

w

C

C

w

w

;

C w

;

w

Nardone et al. (2006) [125]

w

C

C

C

w

C

C w

;

w

Di Lazzaro et al. w (2005) [126] Pierantozzi et al. C (2004) [127]

w

w

w

w

w

w w

;

w

C

C

w

w

;/C C w

w

w

w

;

w

w

w

C

w w

;

w

:

w

w

w

w

w

w w

w

w

w

;

C

C

w

C

w C

;

w

:

;

w

; w

w

w w

w

w

Liepert et al. w (2001) [130] de Carvalho et al. w (1997) [131]

w

w

w

w

;

C w

w

w

;

w

w

w

w

w w

w

w

Di Lazzaro et al. (2004) [61] Ferreri et al. (2003) [128] Di Lazzaro et al. (2002) [60] Alagona et al. (2001) [129]

LAI Subjects

Notes

SAI was significantly reduced in amnestic mild cognitive impairment (aMCI) patients in comparison to healthy controls, with no differences between amnestic and nonamnestic MCI (nMCI) patients. A single dose of donepezil increased SAI in a subgroup of 4 aMCI patients. 19 AD Patients with mild to moderate stages of Alzheimer’s disease (AD) showed 19 HC reduced motor-cortical inhibition. ISP latency was prolonged, while ISP duration was unchanged. 45 AD Patients showed a reduced MEP onset latency. MMSE and CDR correlated 37 HC positively with MTs and negatively with CSP and TI durations. In subcortical ischemic vascular dementia (SIVD), RMT was reduced and MEP 20 SIVD amplitudes increased compared to subcortical ischemic disease without 20 SIDWD dementia (SIDWD) and healthy controls (HC), supporting the hypothesis of 20 HC cortical hyperexcitability in different subtypes of dementia. 11 AD Only patients with mild Alzheimer’s disease were included. SICI and ICF tended 12 HC to increase but only at an ISI of 2 ms were the results significant. 10 AD In AD patients, SAI was reduced, although it did increase following a single dose 10 HC of L-Dopa. In HC, L-Dopa administration had no effect on SAI. 11 AD RMT and SICI were reduced in AD patients; application of levodopa increased 12 HC SICI. 17 AD In patients with early stage AD, SAI was reduced compared to HC, providing 22 HC evidence of a central cholinergic dysfunction. RMT and AMT were unchanged in patients with dementia of Lewy bodies (DLB), 10 DLB but decreased in patients with AD; SAI was reduced in both patient groups, 10 AD SICI did not significantly change in either group. 10 HC SAI was reduced in AD patients but not in patients with MCI, leading to the 12 AD conclusion that compensatory mechanisms might keep the cholinergic 16 MCI system at a normal level in MCI. 15 HC SICI and SAI were reduced in AD patients, but not in patients with Lewy body 13 AD dementia (DLB), reflecting different cholinergic and GABAergic effects 10 DLB between AD and DLB. 15 HC 12 DS Similar to AD patients in the normal population, in patients with Down 15 HC Syndrome (DS) developing AD, SAI was also reduced and could be restored by a single dose of donezepil. 16 AD SAI was reduced in AD patients, but increased after a single dose of rivastigmine. 20 aMCI 20 nMCI 10 HC

12AD 8 FTD 12 HC 28 AD 12 HC 16 AD 13 HC 15 AD 12 HC 21 AD 18 HC 11 10 14 11

AD HC AD HC

SICI was reduced in patients with early-onset AD, but not in frontotemporal dementia (FTD) patients; application of galantamine increased SICI in AD patients. SICI tended to be reduced in AD, but not significantly; application of rivastigmine restored a reduced SAI to its prior level. Motor-cortical excitability was increased in patients with mild AD and revealed no interhemispheric asymmetry. RMT and SAI were reduced in AD patients; SAI increased after application of rivastigmine. MEP was increased in AD patients, while the motor threshold and CSP were reduced. Motor threshold correlated with the severity of cognitive impairment. SICI was reduced in AD patients, but increased following application of donepezil. RMT was reduced in AD patients; no differences were found between hemispheres.

MEP ¼ motor evoked potential, RMT ¼ resting motor threshold, AMT ¼ activated motor threshold, CSP ¼ cortical silent period, ISP ¼ ipsilateral silent period, SICI ¼ shortinterval intracortical inhibition, ICF ¼ intracortical facilitation, SICF ¼ short-interval intracortical facilitation, HC ¼ healthy control subjects, aMCI ¼ amnestic mild cognitive impairment patients, nMCI ¼ non-amnestic mild cognitive impairment patients, AD ¼ Alzheimer disease patients, SIVD ¼ subcortical ischemic vascular dementia patients, SIDWD ¼ subcortical ischemic disease without dementia, DLB ¼ dementia with Lewy bodies, DS ¼ patients with Down Syndrome, FTD ¼ frontotemporal dementia.

modes of action have been determined from preclinical and clinical pharmacological manipulations, the TMS studies in patients have offered an improved insight into the underlying pathophysiology. The most investigated drug was alcohol. Interestingly, in an early study conducted on healthy subjects, Ziemann et al. showed that a single administration of ethanol leads to a prolonged CSP, increased SICI and decreased ICF in healthy volunteers. It was considered that enhanced intracortical inhibition, in addition to a prolonged CSP, might reflect GABAergic mechanisms of ethanol [63]. A later comparison between healthy female and male volunteers showed that only females have a reduced TCI after administration of alcohol [64], whereas TCI was unaffected in males. These observations should be taken into consideration when analyzing patient studies. In one study comparing individuals with alcohol withdrawal

syndrome (AWS), patients with chronic alcohol abuse and healthy subjects, ICF was increased in AWS patients, but could be restored after application of the glutamate receptor antagonist riluzole. Other parameters such as RMT, SICI and CSP were not affected. These results speak to the theory of glutamatergic dysfunction during withdrawal from alcohol [65]. Application of facilitatory 5 Hz-rTMS in healthy subjects after administration of ethanol resulted in MEP facilitation as well as an increase in CSP. In contrast, alcohol addicted patients showed no changes in the MEP amplitude after the same procedure, while the CSP was already increased prior to ethanol administration and did not subsequently change [66]. Examination of individuals with low-risk for alcohol addiction and those at high-risk revealed a reduced CSP and ISP in high-risk persons, leading to the conclusion that cortical hyperexcitability

164

T. Bunse et al. / Brain Stimulation 7 (2014) 158e169

Table 4 Cortical excitability in substance abuse disorders. References

MEP RMT AMT CSP

ISP SICI/LICI ICF/LICF SICF SAI LAI Subjects

Alcohol Nardone et al. (2010) [65]

w

C

C

C

w

Muralidharan et al. w (2008) [67]

C

w

;

;

w

w

C

C

Hasan et al. (2010) [70] Cocaine/stimulants Flavel et al. (2012) [74]

w

:/w

w

w

w

; w

w

w

w

w

C

w

w

w

w

w

w

C

C

w

;/C

C

w

w

w

C

w

:

w

:

w

w

w

w

:

C

w

C/: w

C

w

w

w

w

Gjini et al. (2012) [132]

w

:

:

:

w

C/C

C/:

w

w

w

Sundaresan et al. (2007) [71] Boutros et al. (2005) [72]

w

:

w

w

w

C

:

w

w

w

w

:

:

C

w

w

w

w

w

w

Boutros et al. (2001) [73] Nicotine Lang et al. (2007) [75]

w

:

w

w

w

w

w

w

w

w

;

C

C

:

w

C

;

w

:

C

22 S 22 NS

Orth et al. (2005) [76]

:

C

C

C

w

:

C

w

:

w

8 TS 10 HC

Conte et al. (2008) [66]

Cannabis Fitzgerald et al. (2009) [68]

C

Notes

13 AP-WS ICF increased in alcohol addicted patients with withdrawal syndrome (AP-WS) in a mild pre-delirious state, but not in alcohol-addicted 12 AP-CA patients with chronic abuse (AP-CA) and healthy controls (HC). A 15 HC single-dose of orally administered riluzole in a subgroup of eight patients significantly reduced ICF. 15 HR-AD CSP and ISP were decreased in HR-AD. High risk (HR) for alcohol 15 LR-AD dependence in this study was “defined to denote an alcohol-naïve offspring of early-onset (having developed dependence before 25 years of age) alcohol-dependent fathers with two or more alcoholdependent first-degree relatives.” Low risk for alcohol dependence was “defined as alcohol-naïve individuals with an absence of family history of alcohol dependency in any of the first-degree relatives.” 13 AP Facilitatory 5 Hz-rTMS increased MEP size and CSP duration before and 10 HC after ethanol intake in healthy subjects. In patients showing chronic ethanol abuse (AP), 5 Hz-rTMS failed to induce MEPs facilitation, but left the CSP increase unchanged. 17 CP-LU SICI was reduced in both cannabis groups compared to healthy controls, without a difference among cannabis users. In this publication heavy 25 CP-HU users (HU) were defined as using cannabis seven or more times per 19 HC week. Furthermore, they had consumed cannabis within 48 h before testing. In contrast, light users (LU) were “those who used cannabis between 1 and 4 times per week. Light users were required to have consumed cannabis within the last 7 days but not the 24 h before testing.” 1 TS Case report describing a 15-year-old boy with treatment refractory TS plus ADHD. Administration of D9-THC increased SICI and CSP. 26 abstinent stimulant users (ASU), 9 cannabis users (CU), and 17 nondrug users (NDU) were investigated. ASU “exhibit significantly larger MEPs during relaxation and contraction, increased muscle activity during a given task and a prolonged MEP latency” and tended to have a prolonged CSP compared to the other groups. 52 CoP(a) Motor thresholds and CSP were increased in abstinent cocaine42 HC dependent patients. There were no significant differences in SICI and LICI between subjects and healthy controls. While no differences in ICF occurred, LICF was increased in abstinent cocaine-dependent patients. 10 CoP Cocaine-dependent patients had higher RMTs, increased LICF and 10 HC normal LICI. 19 CoP AMT was elevated in cocaine-dependent patients in both hemispheres, 12 HC whereas RMT was only elevated in the right hemisphere. No CSP differences between groups were detected, but subjects with cocaine-induced paranoia had a longer CSP in the right hemisphere compared to those without psychotic experience. 10 CoP Enhanced RMT was revealed in cocaine-dependent patients compared 10 HC to healthy controls. 26 ASU 9 CU 17 NDU

Chronic smokers (continuous and uninterrupted consumers of at least 10 cigarettes per day within the past 4 years) showed a cortical hypoexcitability and an increased SAI compared to non-smokers. Application of single-dose nicotine increased SICI, SAI and MEP in TS and it abolished the baseline difference between TS and controls in SICI and SAI.

MEP ¼ motor evoked potential, RMT ¼ resting motor threshold, AMT ¼ activated motor threshold, CSP ¼ cortical silent period, ISP ¼ ipsilateral silent period, SICI ¼ shortinterval intracortical inhibition, ICF ¼ intracortical facilitation, SICF ¼ short-interval intracortical facilitation HC ¼ healthy control subjects, AP-WD ¼ alcohol addicted patients with withdrawal syndrome, AP-CA ¼ alcohol-addicted patients with chronic abuse, HR-AD ¼ subjects with high risk for alcohol dependence, LR-AD ¼ subjects with low risk for alcohol dependence, CP-LU ¼ cannabis-addicted patients with light use, CA-HU ¼ cannabis-addicted patients with heavy use, TS ¼ Tourette syndrome patients, ASU ¼ abstinent stimulant users, CU ¼ cannabis users, NDU ¼ non-drug users, CoP(a) ¼ cocaine addicted patients (abstinent), S ¼ smokers, NS ¼ non-smokers.

might be linked to an enhanced risk and predisposition for developing alcohol addiction [67]. Compared to healthy controls, patients who had abused cannabis displayed a reduced SICI, whereas other motor cortical excitability parameters were not affected. Interestingly, no differences between high and low users of cannabis could be detected [68]. Another study of patients with schizophrenia and a comorbidity of cannabis abuse revealed a reduced SICI and an enhanced ICF compared to schizophrenia patients without a comorbidity of cannabis abuse [69]. Both studies indicate that the chronic application of cannabis

might lead to long-lasting alterations in GABAergic neurotransmission and to cortical hyperexcitability. In contrast to these studies, the acute application of THC in a 15 year old boy suffering from severe TS and comorbid ADHD resulted in enhanced cortical inhibition reflected by an increase of SICI and CSP. However, no parameters of cortical facilitation were investigated [70]. Some studies have aimed to investigate the cortical excitability in patients with cocaine abuse showing increased motor thresholds as well as an increased CSP [71e73]. Boutros et al. were able to assert that AMT was elevated in both hemispheres in cocaine-users,

T. Bunse et al. / Brain Stimulation 7 (2014) 158e169

165

Table 5 Cortical excitability in affective disorders. Reference

RMT

Levinson et al. (2010) [79]

:/C w

AMT CSP ISP SICI

ICF TCI Subjects Notes

; w ;/C C w 25 D-TR All depressive patients demonstrated a reduced CSP duration compared to healthy controls

Lefaucheur et al. (2008) [81] ;

; w ;

; w

; w ;

w

w

Bajbouj et al. (2006) [78]

;/C w

Steele et al. (2000) [77]

(C)

w

:

w

w

w

w

Maeda et al. (2000) [80]

w

w

w

w

w

w

w

Levinson et al. (2007) [84]

w

w

; w ;

16 19 25 35 35

D-U E-M HC D HC

20 D-U 20 HC 16 D 19 HC 8D 8 HC

C ; 15 BD 15 HC

(HC), but only treatment-resistant patients (D-TR) showed impaired SICI and increased RMT.

Reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere compared to the right hemisphere and to healthy controls was revealed in depressed patients. CSP and SICI were reduced in unmedicated depressive patients, RMT of the right hemisphere was reduced, and there were no differences in the left hemisphere. The silent period was increased in depressive patients but showed no correlation to the depressive score. Patients suffering from major depressive disorder presented significant interhemispheric differences for RMT and paired-pulse curves, namely lower excitability on the left hemisphere. This difference could not be detected in healthy controls. Bipolar patients displayed inhibitory deficits in three different paradigms.

RMT ¼ resting motor threshold, AMT ¼ activated motor threshold, CSP ¼ cortical silent period, ISP ¼ ipsilateral silent period, SICI ¼ short-interval intracortical inhibition, ICF ¼ intracortical facilitation, HC ¼ healthy control subjects, D ¼ patients with depression, D-TR ¼ patients with treatment-resistant depression, D-U ¼ patients with unmedicated depression, E-M ¼ euthymic patients with medication, BD ¼ patients with bipolar disorder.

whereas RMT was only elevated in the right hemisphere. Furthermore, CSP was prolonged in the right hemisphere in patients with cocaine-induced paranoia in comparison to those ones without paranoia [72]. Finally, larger MEPs, and trend-level increases in CSP, were detected in abstinent stimulant users [74]. In chronic smokers, a cortical hypoexcitability, reflected by reduced active MEPs and ICF, as well as a prolonged CSP and increased SAI, could be detected. The increased SAI in chronic smokers was linked to a pronounced cholinergic activation [75]. Application of single-dose nicotine in patients with TS significantly modulated cortical excitability by increasing SAI and SICI, but CSP and ICF remained unchanged in this study [76]. TMS in affective disorders A study of medicated patients with either unipolar or bipolar depression revealed a prolonged CSP (Table 5) [77]. A later study in unmedicated patients revealed a reduced CSP and SICI as signs of cortical disinhibition [78]. The comparison between healthy subjects, medicated euthymic patients with a previous major depressive disorder, unmedicated patients with a major depressive disorder and treatment-resistant patients with a major depressive disorder showed that all subgroups had a significantly shortened CSP compared to healthy subjects. In contrast, only in treatmentresistant patients were a significantly reduced SICI and an increased RMT detected. Treatment-resistant patients showed additionally an increased RMT compared to all other depression groups indicating reduced excitability of the frontal cortex [79]. In another study, subjects with major depressive disorder were

shown to have inter-hemispheric differences in motor thresholds (Left > Right) and in paired-pulse measures showing a reduced excitability of the left hemisphere when compared to controls [80]. An interhemispheric asymmetry was shown by Lefaucheur et al., who demonstrated a reduction of the inhibitory and excitatory excitability in the left hemisphere in depressive patients compared to the right hemisphere and to healthy subjects [81]. In addition to these studies, changes in cortical inhibition following non-invasive brain stimulation have been reported. The application of electroconvulsive therapy (ECT) combined with 3 Hz rTMS or 10 Hz rTMS (facilitatory rTMS) to the left prefrontal cortex in subjects with major depressive disorder led to clinical improvement, enhanced cortical excitability in the left motor cortex, as indicated by an increased MEP/M-wave ratio, decreased motor threshold, a shortened CSP, and reduced SICI [82,83]. In patients with a bipolar affective disorder, cortical hyperexcitability, reflected by reduced CSP, SICI, and interhemispheric inhibition, was shown in one study [84]. These studies show variable results in depressive and bipolar disorder, making definitive conclusions difficult. This might be explained by the heterogenous phenotype of affective disorders and their great diagnostic overlap. TMS in other psychiatric disorders In addition to the discussed studies above, TMS was used to investigate other psychiatric conditions like borderline personality disorder or PTSD (Table 6). In 19 unmedicated female patients with a borderline personality disorder a reduced CSP was found at the right, non-dominant, hemisphere [85] showing only minimal

Table 6 Cortical excitability in other disorders. Reference

RMT CSP

Barnow et al. (2009) [85]

C

Wassermann et al. (2001) [133] w Rossi et al. (2009) [86]

ICF

SAI

TCI/TCT Subjects Notes

C/; C

SICI

C

w

C

w

w

w

w

w

C/C C/C ;/C C/: C/(;) w

19 BPD In unmedicated female patients with borderline personality disorder, a reduced CSP 19 HC was detected in the right (non-dominant) hemisphere. No other parameters differed between groups. 46 HC The paired-pulse conditioned/unconditioned MEP amplitude ratios at all interstimulus intervals (3, 4, 10, 15 ms) correlated with neuroticism. 20 PTSD In PTSD, SICI was reduced in the left, but not in the right hemisphere. ICF was 16 HC increased in the right, but not in the left hemisphere. SAI showed a trend toward a reduction in the right, but not in the left hemisphere.

RMT ¼ resting motor threshold, CSP ¼ cortical silent period, SICI ¼ short-interval intracortical inhibition, ICF ¼ intracortical facilitation, SAI ¼ short latency afferent inhibition, TCI/TCT ¼ transcallosal inhibition/transcallosal transfer time, HC ¼ healthy control subjects, BP ¼ patients with borderline personality disorder, PTSD ¼ patients with posttraumatic stress disorder.

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T. Bunse et al. / Brain Stimulation 7 (2014) 158e169

evidence for cortical disinhibition in this patient group. An investigation of 20 drug-naive PTSD patients revealed a bilateral reduction of SICI and SAI, increased right ICF, and normal CSP and RMT. After multiple comparisons, SICI was reduced on the left, but not on the right hemisphere. ICF was increased on the right, but not on the left hemisphere. SAI showed a trend toward a reduction on the right, but not on the left hemisphere [86]. Conclusions The results of this systematic review show that no clear deficit pattern in cortical excitability measured by TMS can be detected for an individual psychiatric condition. Rather than disease-specific alterations, cortical disinhibition seems to be a consistent finding across different disorders. The clinical and diagnostic application of various experimental TMS measures has recently been the subject of controversial discussions by the International Federation of Clinical Neurophysiology (IFCN) [4,87]. Currently, the special importance of both single- and paired-pulse TMS is the possibility they offer to evaluate the physiology and pathophysiology of inhibitory and excitatory intracortical and subcortical brain networks at the system level of the human motor cortex. This represents a unique opportunity to improve the understanding of various psychiatric disorders and to translate preclinical findings so that they are applicable at the patient level. However, the findings are limited to the motor cortex and only a few of the described conditions (e.g. schizophrenia or TS) show a clear link to motor dysfunction and a clear neuropathological background. Nevertheless, findings from experimental studies of the motor cortex cannot be simply translated to other brain regions. For instance, differences in the cortical architecture, interneuron composition, neuron- and receptor-density, and receptor distribution might result in different responses compared to those observed in the motor system. Taking this and our main finding of a general impaired cortical excitability into consideration, the overall generalizability of our findings is limited. However, recent developments combining EEG and TMS make it possible to extend TMS-excitability measures to brain regions other than M1. For example, such a setup has allowed long-interval cortical inhibition (LICI) to be measured in the dorsolateral prefrontal cortex (DLPFC) [88], and has been used to assess the responses of various cortical areas (occipital, parietal, frontal) to a TMS pulse applied to a specific cortical region [89]. Furthermore, EEG-TMS studies have revealed a decrease in fronto-central gamma-band EEG-evoked responses 100 ms following the application of TMS [90], or deficits of cortical inhibition (LICI) of DLFPC gamma-band oscillations in schizophrenia patients [91]. Finally, a study with a small sample size showed that the TMS-EEG P30 amplitude was correlated with cognitive decline in Mild-Cognitive Impairment (MCI) and Alzheimer patients [92]. These examples highlight the possibility to extend TMS excitability measures, potentially to all cortical areas. Regarding M1, a recently published meta-analysis examined parameters of cortical inhibition and facilitation in schizophrenia patients, major depression and OCD and quantified a cortical inhibition deficit (decreased SICI, enhanced ICF, decreased CSP) in these disorders, with the largest effect sizes being on decreased SICI in OCD [93]. As there is an overlap between the studies analyzed in this meta-analysis and our systematic review, related results are evident for these three disorders. However, based on our results, a general inhibitory deficit in mental illness measured by TMS can be concluded. Only substance abuse disorders (alcohol, cocaine, nicotine and others) fail to consistently show such inhibitory deficits, which can be explained by the different receptor profiles of the investigated drugs.

The most consistent findings of our systematic review were reduced SAI in patients suffering from Alzheimer’s disease, and reduced SICI in schizophrenia patients, ADHD, OCD and TS. The SAI reduction can be linked to the impaired cholinergic function in Alzheimer’s patients. According to the IFCN’s 2008 report for the clinical diagnostic utility of motor cortex TMS, SAI was evaluated with a view to potential utility for diagnostics and course-observation in dementia [4]. In three quarters of patients with a clinical diagnosis of Alzheimer’s disease, SAI was reported to be reduced, while patients with non-cholinergic forms of dementia do not show this impairment [4]. However, most studies were cross-sectional, meaning that longitudinal studies starting with MCI patients are needed to improve the diagnostic reliability of SAI as a consistent marker for dementia. In the other psychiatric conditions, reduced motor cortical excitability is a very robust finding across studies and nosological entities. This is particularly well represented by a reduced SICI, which has been suggested as a potential marker of GABAA-related inhibition [1]. As described above, strong neuropathological evidence for impairments in the GABAergic system exists only for schizophrenia and TS, while preliminary evidence for impaired GABAergic functions has been reported for OCD [40]. With regard to the latter study, one should note that correlations between physiological measures of intracortical inhibition and GABA levels assessed by MRS have recently been reported using a TMS-MRS setup [94]. However, the physiology of SICI is very complex and it is far beyond the scope of a simple marker to interpret GABAergic interneuronal function [95]. All studies analyzed in this systematic review used only a very simple pulse configuration of SICI with no variation in interstimulus intervals or pulse intensities. Future investigations in psychiatric patients need to test SICI at multiple intervals with different ISIs and varying stimulus intensities to allow for more detailed investigations [95]. The reader should also note that the investigated TMS parameters have a complex physiology and can be influenced by many external and internal factors. In psychiatric patients, neuroactive medication can be considered as the main confounding factor since nearly all prescribed drugs impact cortical excitability [1]. However, some studies were conducted in medication-naive or medicationfree patients and have also shown reduced cortical inhibition (see Tables 1e6). Furthermore, the menstrual cycle [96,97], circadian effects [98] and voluntary movements [99] also have strong impacts on the discussed TMS parameters. Finally, it is well established that categorical diagnoses used in psychiatry overlap to a certain degree. This is especially true for affective disorders and non-affective psychoses and anxiety disorders, frequently making it difficult to define a strong dividing line between diagnoses [100]. Whether the observed overlap in inhibitory deficits can be explained by the diagnostic overlap needs to be addressed in future longitudinal studies quantifying the effects beyond diagnostic boundaries. In summary, changes in TMS-evaluated motor cortical excitability are evident in different psychiatric disorders, and an unspecific pattern of reduced cortical inhibition is rather more evident than disease-specific alterations. Future cross-sectional and longitudinal investigations, as well as the application of different validation processes (e.g. Ref. [101] may help to develop diagnostic tests and course parameters). The studies presented allow an improved understanding of the diseases at the level of the human cerebral cortex in awake subjects. In the absence of good animal models for most of the described conditions, these non-invasive tools offer a promising way to improve pathophysiological understanding, although many open questions remain. In future, longitudinal approaches in unmedicated patients and harmonized stimulation parameters are needed to improve the accuracy of these measures for diagnostic and course-prediction proposes.

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