Biological markers of the effects of intravenous methylphenidate on improving inhibitory control in cocaine-dependent patients

Abstract

Prior research points to the importance of psychostimulants in improving self-control. However, the neural substrates underlying such improvement remain unclear. Here, in a pharmacological functional MRI study of the stop signal task, we show that methylphenidate (as compared with placebo) robustly decreased stop signal reaction time (SSRT), an index of improved control, in cocaine-dependent patients (a population in which inhibitory control is impaired). Methylphenidate-induced decreases in SSRT were positively correlated with inhibition-related activation of left middle frontal cortex (MFC) and negatively with activation of the ventromedial prefrontal cortex (vmPFC) in whole brain linear regressions. Inhibition-related MFC but not vmPFC activation distinguished individuals with short and long SSRT in 36 demographically matched healthy individuals, whereas vmPFC but not MFC activation, along with improvement in SSRT, was correlated with a previously implicated biomarker of methylphenidate response (systolic blood pressure). These results implicate a specific neural (i.e., vmPFC) mechanism whereby stimulants improve inhibitory control. Altered ventromedial prefrontal activation and increased blood pressure may represent useful CNS and peripheral biomarkers in individualized treatment with methylphenidate for patients with cocaine dependence.D eficits in cognitive control have been implicated in the pathophysiology of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and cocaine dependence (1-5), and a wide literature supports the utility of stimulants, including methylphenidate, in improving cognitive control (6-9, see ref. 10 for review). For example, studies have shown that stimulants alter cerebral activation and influence cognitive functions, including improving inhibitory control, in healthy individuals (11-21). Similarly, Overtoom et al. (22) reported that methylphenidate improved stopping performance and restored the electrophysiological potential of stopping in a stop signal task, whereas it did not affect go trial reaction time, in adult patients with ADHD. Although neuroimaging studies have examined the effects of stimulants on regional brain activation and connectivity, the neural substrates underlying stimulant-mediated improvements in inhibitory control remain unclear. A more complete understanding of the neural mechanisms whereby stimulants improve cognitive control will be critically important, not only for an improved understanding of its biological basis but also for understanding the pathophysiology and treatment of conditions associated with its impairment. Using a stop signal task, we (and others) have demonstrated that patients with cocaine (and other stimulant) misuse display impaired inhibitory control and prefrontal activation during a stop signal task (5, 23-27). Whereas prior research has examined stimulants in clinical trials of therapeutic efficacy (28-33) and neuroimaging studies of regional brain activation and connectivity in cocaine user...

The effects of methylphenidate on resting-state striatal, thalamic and global functional connectivity in healthy adults

“…Furthermore, methylphenidate increased negative global connectivity of the fronto-parietal cortices. These findings in healthy adults are in contrast with many previous studies of clinical populations, where methylphenidate increased regional activations and connectivities in association with executive functioning (Scheres et al, 2003; Kim et al, 2006; Jonkman et al, 2007; Pollak et al, 2007; Li et al, 2010; Tye et al, 2010; Nandam et al, 2011; Tomasi et al, 2011). For instance, methylphenidate improved working memory and visuospatial attention in patients with traumatic brain injury (Kim et al, 2006), and increased prefrontal activations for cognitive control in cocaine-addicted adults (Li et al, 2010).…”

“…These findings in healthy adults are in contrast with many previous studies of clinical populations, where methylphenidate increased regional activations and connectivities in association with executive functioning (Scheres et al, 2003; Kim et al, 2006; Jonkman et al, 2007; Pollak et al, 2007; Li et al, 2010; Tye et al, 2010; Nandam et al, 2011; Tomasi et al, 2011). For instance, methylphenidate improved working memory and visuospatial attention in patients with traumatic brain injury (Kim et al, 2006), and increased prefrontal activations for cognitive control in cocaine-addicted adults (Li et al, 2010). Although speculative, this contrasting pattern of the effects of methylphe-nidate may reflect the inverted U relationship between level of catecholaminergic signalling and cognitive performance, as postulated earlier (Birnbaum et al, 1999; Arnsten, 2009; Berridge et al, 2012; Rajala et al, 2012).…”

Neurochemical Enhancement of Conscious Error Awareness

“…These groups are known to demonstrate impaired error awareness O'Connell et al, 2009) and diminished error-related neural activity in regions including the dACC (Kaufman et al, 2003;Rubia et al, 2005), with the level of impairment associated with increased symptom severity (Moeller et al, 2010). Recent evidence suggests that MPH significantly increases ACC activity in ADHD and cocaine dependence (Jonkman et al, 2007;Goldstein et al, 2010;Li et al, 2010). It is not known, however, whether chronic use of MPH during typical treatment regimens has beneficial effects for error awareness or clinical symptomatology.…”

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

“…These results are also consistent with two recent studies in CUD: an fMRI study showed that i.v. MPH compared with placebo improved inhibitory control on a neutral cognitive task (30), and a positron emission tomography study showed that oral MPH (20 mg) attenuated the inhibition of metabolism in limbic brain regions that followed cocaine-cues exposure (31). Our fMRI study shows that a therapeutic dose of the feasibly administered oral MPH (20 mg) improved cognitive performance (decreased errors of commission, a measure of impulsivity) both in CUD and control participants during performance of a salient cognitive task as associated with enhanced activation of the ACC in the CUD.…”