A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders

Abstract

Objective

To evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive–compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ).

Methods

Paradigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012.

Results

A significant Hedge’s g was found for decreased SICI (g = 0.572, 95% confidence interval [0.179, 0.966], p = 0.004), enhanced intracortical facilitation (g = 0.446, 95% confidence interval [0.042, 0.849], p = 0.030) and decreased CSP (g = −0.466, 95% confidence interval [−0.881, −0.052], p = 0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g = 0.641, 95% confidence interval [0.384, 0.898], p = 0.000) and shortened CSP (g = −1.232, 95% confidence interval [−1.530, −0.933], p = 0.000). In SCZ, a significant Hedge’s g was shown for decreased SICI (g = 0.476, 95% confidence interval [0.331, 0.620], p = 0.000).

Conclusion

Inhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD.

Significance

Provides a clear platform from which diagnostic procedures can be developed.

Introduction

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, critical for the modulation of cortical excitability and neuroplasticity (DeFelipe et al., 1986, Schieber and Hibbard, 1993). GABAergic neurons constitute 25–30% of the neuronal population in the motor cortex and their horizontal connections can extend up to 6 mm or more (Gilbert and Wiesel, 1992, Jones, 1993). Pyramidal cell activity is synchronized through a balance of inhibitory postsynaptic potentials and excitatory postsynaptic potentials (Krnjevic, 1997). Inhibitory postsynaptic potentials are generated by GABAergic interneurons terminating on the pyramidal cell (Krnjevic, 1997). Cortical inhibition is a neurophysiological mechanism whereby GABA inhibitory interneurons attenuate the activity of other neurons (e.g. pyramidal neurons) in the cortex (Daskalakis et al., 2007).

Transcranial magnetic stimulation (TMS) is a non-invasive method used to assess inhibitory and excitatory mechanisms. TMS was first introduced in 1985 by Barker et al. for investigating the state of motor pathways in patients with neurological disorders and in healthy participants (Barker et al., 1985). They showed that a single TMS pulse applied to the motor cortex could activate cortical tissues associated with the hand or leg muscles and elicit motor evoked potentials (Fig. 1A).

TMS has been used to assess inhibitory processes, these paradigms are referred to as the cortical silent period (CSP) (Cantello et al., 1992), long-interval cortical inhibition (LICI) (Valls-Sole et al., 1992), and short-interval cortical inhibition (SICI) (Kujirai et al., 1993). The CSP duration is measured from the motor evoked potential onset to the return of electromyography activity (Fig. 1B) (Cantello et al., 1992). LICI involves the pairing of a suprathreshold conditioning stimulus followed by a suprathreshold test stimulus at long interstimulus intervals, resulting in inhibition of the motor evoked potential (Valls-Sole et al., 1992) (Fig. 1C). CSP and LICI appear to be assessing GABA_B receptor-mediated inhibitory neurotransmission as evidenced by pharmacological studies (McDonnell et al., 2006, Siebner et al., 1998), the time course of the GABA_B inhibitory postsynaptic potential (McCormick, 1989, Siebner et al., 1998, Werhahn et al., 1999) and the high intensity suprathreshold conditioning stimulus (Sanger et al., 2001). By contrast, SICI is measured by applying a subthreshold conditioning stimulus before the suprathreshold test stimulus at short interstimulus intervals, resulting in inhibition of the motor evoked potential response by 50–90% (Fig. 1D) (Kujirai et al., 1993). SICI has been associated with the GABA_A receptor-mediated inhibitory neurotransmission as demonstrated by the pharmacological effects on this measure (Ziemann et al., 1996a), the time course of the GABA_A inhibitory postsynaptic potential (Wang and Buzsaki, 1996) and the low intensity subthreshold conditioning stimulus (Sanger et al., 2001).

TMS has also been used to examine cortical excitability, these paradigms include: the motor evoked potential amplitude, resting motor threshold, and intracortical facilitation. The motor evoked potential amplitude is measured as the average response to a series of pulses applied at a consistent TMS intensity (Zaaroor et al., 2003). The resting motor threshold is defined as the minimal intensity that produces a motor evoked potential >50 μV in 5 of 10 trials in a relaxed muscle (Rossini et al., 1994). Finally, intracortical facilitation is a paired-pulse paradigm whereby a conditioning stimulus is applied to the motor cortex before the test stimulus, resulting in an enhanced motor evoked potential (Kujirai et al., 1993, Nakamura et al., 1997) (Fig. 1E). Intracortical facilitation originates from excitatory postsynaptic potentials transmitted by N-methyl-d-aspartate glutamate receptors (Nakamura et al., 1997). For a review of the pharmacological effects on inhibitory and excitatory TMS paradigms, please see (Paulus et al., 2008).

Numerous studies have implicated GABA in the pathophysiology of neuropsychiatric disorders, notably obsessive–compulsive disorder (OCD), major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder. Several lines of evidence suggest that cortical inhibition is impaired in these disorders. For example, previous TMS studies have demonstrated deficits in cortical inhibition assessed from the motor cortex in patients with OCD (Greenberg et al., 1998, Greenberg et al., 2000, Richter et al., 2012), MDD (Bajbouj et al., 2006, Fitzgerald et al., 2004a, Lefaucheur et al., 2008, Levinson et al., 2010), SCZ (Daskalakis et al., 2002, Daskalakis et al., 2008a, Fitzgerald et al., 2002a, Fitzgerald et al., 2002b, Fitzgerald et al., 2003, Liu et al., 2009, Wobrock et al., 2008, Wobrock et al., 2009, Wobrock et al., 2010) and bipolar disorder (Levinson et al., 2007). An overall deficit of GABAergic inhibition has been associated with these psychiatric disorders; however, each may have a distinct illness profile and response to treatment. This meta-analysis aims to quantitatively assess TMS evoked measures of inhibitory and excitatory paradigms in OCD, MDD and SCZ.