The Neural Substrates of Response Inhibition in Attention Deficit Hyperactive Disorder (ADHD)

Introduction: Response inhibition, often referred, as the ability to cancel an ongoing motor response, is a critical aspect of executive control. Deficient response inhibition has been found in various neurodevelopmental disorders (ND) most notably in attention deficit hyperactive disorder (ADHD), obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD). While many functional neuroimaging studies have identified the neural correlates of deficient response inhibition, they have often focused on a single aspect, which is the ability to cancel a response. In this thesis, I argue that the ability to inhibit a motor action in response to a stop signal (also known as reactive inhibition) is influenced by preparation or prospective inhibition and by the ability to detect inhibition errors and modify ongoing responses in response to errors. I argue that failure to separate prospective inhibition and error processing from reactive inhibition obscures the nature of neural correlates of these processes. In a series of experiments, I use a novel imaging approach to study the neural correlates of prospective inhibition, reactive inhibition and error processing. Children and adolescents with a diagnosis of ADHD are 101-­‐Gar 101 786 Gar-­‐O-­‐Gar, Behram Yazad, Yatha tauri madad, Sarosh tauri panah iii compared to normal controls and to children with either OCD or ASD in order to identify atypical and unique neural correlates of these processes. Methods: Three fMRI studies were conducted using a modified version of the stop signal task (SST) and a novel analytical approach that permitted the separation of the hemodynamic response generated by prospective inhibition, reactive inhibition and error processing. In the first study, twelve ADHD and twelve normal controls were compared during prospective and reactive inhibition. In the second study, fourteen ADHD and fourteen controls were compared during error detection and modification. The third study compared nine ADHD children and adolescents, ten OCD and ten ASD participants on prospective and reactive inhibition. Results: Children with ADHD showed less activation of task specific preparatory networks and a failure to deactivate the default mode network relative to controls during prospective inhibition. Both groups activated the right inferior frontal gyrus (IFG) during reactive inhibition. We also showed that the normal controls deactivated bilateral dorsal striatum and multiple regions in ACC during error detection whereas the ADHD group showed deactivation that was limited to the left dorsal striatum and a single location in the ACC. The control group deactivated the ventral striatum and OFG while the ADHD displayed positive activity in the same location during modification. The OCD group’s impairment was mitigated by activation in task specific preparatory networks that was absent in ADHD children. The ASD group’s neural activity in the right IFG and MPFC appeared to be very similar to what was observed in normal controls during prospective inhibition. I argue that these results indicate that all three disorders have specific and unique mechanisms underlying response inhibition. 101-­‐Gar 101 786 Gar-­‐O-­‐Gar, Behram Yazad, Yatha tauri madad, Sarosh tauri panah iv Conclusion: This is the first attempt to address the neural substrates of different aspects of the response inhibition process in clinical samples. Identification of the neural correlates of prospective inhibition, reactive inhibition, error detection and modification offers new insight into the nature of the inhibition process and the unique nature of ADHD, OCD and ASD. This knowledge could serve as biomarkers for assessment, diagnostic, predictive and therapeutic research and practice. 101-­‐Gar 101 786 Gar-­‐O-­‐Gar, Behram Yazad, Yatha tauri madad, Sarosh tauri panah