Methylphenidate Enhances Early-Stage Sensory Processing and Rodent Performance of a Visual Signal Detection Task

Abstract

Methylphenidate (MPH) is used clinically to treat attention-deficit/hyperactivity disorder (ADHD) and off-label as a performance-enhancing agent in healthy individuals. MPH enhances catecholamine transmission via blockade of norepinephrine (NE) and dopamine (DA) reuptake transporters. However, it is not clear how this action affects neural circuits performing cognitive and sensorimotor functions driving performance enhancement. The dorsal lateral geniculate nucleus (dLGN) is the primary thalamic relay for visual information from the retina to the cortex and is densely innervated by NE-containing fibers from the locus coeruleus (LC), a pathway known to modulate state-dependent sensory processing. Here, MPH was evaluated for its potential to alter stimulus-driven sensory responses and behavioral outcomes during performance of a visual signal detection task. MPH enhanced activity within individual neurons, ensembles of neurons, and visually-evoked potentials (VEPs) in response to task light cues, while increasing coherence within theta and beta oscillatory frequency bands. MPH also improved reaction times to make correct responses, indicating more efficient behavioral performance. Improvements in reaction speed were highly correlated with faster VEP latencies. Finally, immunostaining revealed that catecholamine innervation of the dLGN is solely noradrenergic. This work suggests that MPH, acting via noradrenergic mechanisms, can substantially affect early-stage sensory signal processing and subsequent behavioral outcomes.

Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2

“…We conclude that lowering of glutamatergic excitability increases the use of resting periods, reduces distraction by concurrent environmental stimuli, reduces unnecessary exploratory behavior in favor or goal-directed behavior and allows for better selective attention and better performance in tasks requiring high attention and fast responses to visual light/ LED stimuli. The behavior of LPAR2 −/− mice has some similarity with mouse behavior under methylphenidate in models addressing attention or sensory processing [47][48][49]. Notably, glutamate overflow leads to attentional deficits [50] and the 5CSRT touchscreen task has indeed some predictive validity for selecting drugs effective for treating attentiondeficit/hyperactivity disorder [51].…”

P1‐223: Functional Markers for Cerebral Norepinephrine Deficiency in Alzheimer’s Disease

“…Beyond that, certain levels of NE contribute to the detection of environmental stimuli by priming sensory neurons. Application of pharmacological agents promoting the cortical NE supply provided evidence for facilitated processing of visual stimuli in primary sensory neurons (Borodovitsyna, Flamini, & Chandler, 2017;Navarra et al, 2017;Zitnik, Clark, & Waterhouse, 2014). Experiments with auditory signals (Manunta & Edeline, 2004) and those activating the gustatory sense (Heath et al, 2006) also demonstrated that NE increased the neuronal sensitivity for relevant information in the domain-specific cortical target regions.…”

Noradrenergic Modulation of Cognition in Health and Disease

“…Therefore, in addition to promoting waking, NE at particular levels might facilitate detection of sensory stimuli by priming sensory neurons. For example, LC stimulation and drugs that promote noradrenergic transmission have both been shown to increase responsiveness to visual stimulation in primary sensory neurons in the lateral geniculate nucleus [ 9 , 10 , 63 , 64 ]. Through these combined actions, NE may have procognitive effects simply by rendering animals more alert and more sensitive to salient sensory stimuli in their environments.…”