Evidence for Cortical Inhibitory and Excitatory Dysfunction in Obsessive Compulsive Disorder

Abstract

Several lines of evidence suggest that obsessive-compulsive disorder (OCD) is associated with an inability to inhibit unwanted intrusive thoughts. The neurophysiological mechanisms mediating such inhibitory deficits include abnormalities in cortical g-aminobutyric acid (GABA) inhibitory as well as N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms. Molecular evidence suggests that both these neurotransmitter systems are involved in OCD. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to ascertain neurophysiological indices of inhibitory GABA and facilitatory NMDA receptor-mediated mechanisms. In this study, both mechanisms were indexed in 34 patients with OCD (23 unmedicated and 11 medicated) and compared with 34 healthy subjects. Cortical inhibitory and facilitatory neurotransmission was measured using TMS paradigms known as short-interval cortical inhibition (SICI), cortical silent period (CSP), and intracortical facilitation (ICF). Patients with OCD demonstrated significantly shortened CSP (po0.001, Cohen's d ¼ 0.91) and increased ICF (po0.009, Cohen's d ¼ 0.71) compared with healthy subjects. By contrast, there were no significant deficits in SICI. After excluding patients with OCD and comorbid major depressive disorder (MDD) from the analysis, these differences remained significant. Our findings suggest that OCD is associated with dysregulation in cortical inhibitory and facilitatory neurotransmission. Specifically, these findings suggest impairments in GABA B receptor-mediated and NMDA receptor-mediated neurotransmission. These findings are consistent with previously published genetic studies implicating GABA B , and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form the basis for this disorder.

Investigation of Cortical Glutamate–Glutamine and γ-Aminobutyric Acid in Obsessive–Compulsive Disorder by Proton Magnetic Resonance Spectroscopy

“…MRS measures total GABA levels, which predominantly reflect intracellular stores (Petroff, 2002). Thus, decreased GABA levels could reflect fewer GABAergic interneurons and result in reduced MPFC inhibitory tone, consistent with reports of cortical inhibitory dysfunction in OCD (Greenberg et al, 2000;Richter et al, 2012). Reduced MPFC inhibitory tone is also consistent with current OCD models that posit abnormal frontostriatal activation (Maia et al, 2008;Pittenger et al, 2011;Ting and Feng, 2011;Wu et al, 2012), as reduced MPFC inhibitory tone could generate abnormal striatal activation either directly due to ACC projections to the striatum or indirectly due to ACC projections to the OFC (Price and Drevets, 2010;Schmahmann and Pandya, 2006).…”

“…This increased activity may reflect primary abnormalities in glutamatergic neurotransmission (Carlsson, 2001;Pittenger et al, 2011;Rosenberg and Keshavan, 1998;Wu et al, 2012). At the same time, the inhibitory neurotransmitter g-aminobutyric acid (GABA) modulates cortical glutamatergic neurons (GonzalezBurgos and Lewis, 2008), and abnormalities in cortical inhibitory processes have been reported in OCD (Greenberg et al, 2000;Richter et al, 2012). Alterations in GABA neurotransmission could also have a role in OCD (Rosenberg et al, 2001).…”

Abnormal interhemispheric connectivity in male psychopathic offenders

“…The CSP taps into GABA B receptor-mediated neurotransmission, whereas SICI is more commonly associated with GABA A receptor functioning. 29 The ICF relates to N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms 30 (see the Appendix, available at cma.ca/jpn, for a schematic representation of the different TMS paradigms). We applied TMS to the hand area of the left and right motor cortex with a 70 mm loop figure-8 magnetic coil and 2 Magstim 200 magnetic stimulators (Magstim).…”

“…In addition, decreases in cortical inhibition are often detected in psychiatric patients. 30,[48][49][50] In contrast, increases in cortical inhibition have also been reported, for instance, in abstinent cocaine-dependent patients. 51 Similar to cocaine, drugs that target the dopamine (DA) system (e.g., pergolide, L-DOPA, clozapine) prolong CSP.…”

Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions

“…82,83 Patients with OCD have decreased short interval cortical inhibition and cortical silent periods and enhanced intracortical facilitation independent of medication status. [73][74][75] Lastly, patients with bipolar disorder treated with antipsychotics or anticonvulsant mood stabilizers have shown impairments in short interval cortical inhibition, the cortical silent period and interhemispheric inhibition. 63 In Appendix 1, Table S2, we summarize these TMS findings for each neuropsychiatric disorder.…”