The Effects of Methylphenidate (Ritalin) on the Neurophysiology of the Monkey Caudal Prefrontal Cortex

Abstract

Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task (N = 2811 neuronal recordings). Over different recording sessions (N = 55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain.

Keywords: Ritalin; attention; methylphenidate; multielectrode array; prefrontal cortex; primates.

Figure 1.

Behavioral task and performance. A, Behavioral task with the three randomly interleaved trial types. Blue dashed circles represent the focus of covert attention. Pink dashed circles indicate orientation change(s). Pink arrows indicate saccadic eye movements. Blue dot represents gaze position. B, Average behavioral performance of each subject under placebo sessions only. The colors indicate the proportion of each trial outcome in a behavioral session. Fixation break represents errors where the subject would respond before a Go signal was given. Sac. to distractor represents errors where the subject would respond to a distracting stimulus. No response represents trials where the subject would not provide a response. C, D, Line plots representing the change in overall hit rate relative to matched placebo sessions in the attention task following various doses of MPH. Hit rate is considered a proportion (Hit/Hit+Errors). Differences in proportion (hit rate) across treatment conditions are computed with χ² tests. Asterisks represent statistically significant changes in hit rate relative to placebo sessions (χ² test, p < 0.05). E, F, Same format as C, D but representing the proportion of specific error types across treatment conditions. Up means more errors. Refer to Materials and Methods for definitions. Error bars represent the SE of the sample proportion estimate.

Figure 2.

Neurophysiological recordings. A, Location of chronically implanted multielectrode Utah array within the left caudal LPFC. The shaded pink area roughly represents area 8A in the macaque brain. The blue square represents implant location. P: principal sulcus. AS: arcuate sulcus superior. AI: arcuate sulcus inferior. B, Implant location based on intra-operative photography for both monkey “F” and monkey “JL” in reference to major sulci. Each small square represents one of the 96 microelectrodes on the array. Colors represent the spatial attentional tuning of the neurons recorded at each electrode site as a function of the four quadrant locations (inset). Note tuned stands for neurons that do not show attentional modulation. Inactive represents reference electrodes and grounds.

Figure 3.

Qualitative effects of MPH on the average single neuron response. A, Attentional modulation of single neuron activity averaged over the entire sample of tuned cells and trials (sample size reported with N in figure). The trial-averaged SDFs are displayed separately for MPH and placebo (PLB) sessions. The light blue and red SDFs depict the average single neuron response on trials where attention is allocated inside, or opposite to the neuron’s preferred location (i.e., RF), respectively. The abscissa represents the time from trial onset and the ordinate the population neuronal firing rate (z-scored). Shaded areas represent SEM. The average responses during all MPH sessions are overlaid on top of the average response during placebo sessions to illustrate the near-perfect overlap in single neuron responses across treatment conditions. B, Same as in A but for monkey “JL.” C, D, Same as A, B but only including the MPH sessions showing the best behavioral improvement due to treatment (best-dose analysis; 0.86 mg/kg for monkey “F,” 0.67 mg/kg for monkey “JL”). The same absence of difference in this best-dose analysis is demonstrated by the overlap of the MPH and PLB curves in C, D.

Figure 4.

Effects of MPH on 19 single neuron response metrics. A, Visual response metrics for visually-selective neurons as a function of drug dose. Refer to Materials and Methods for the meaning of each metric. The x-axis depicts MPH drug dose using arbitrary units (a.u.), from the smallest dose to the biggest for each monkey. These are 0.43, 0.86, 1.08, 1.29, or 1.72 mg/kg for monkey “F,” and 0.33, 0.67, 0.83, 1.00, or 1.33 mg/kg for monkey “JL.” The y-axis is relative to the particular metric being plotted. Blue and green lines are for monkey “F” and monkey “JL,” respectively. The top-leftmost subplot includes the size of single neurons samples included for the computation of all the visual metrics. The red error bars correspond to the best-dose of MPH according to behavioral performance. The colored numbers to the right of each line represent the p values for the ANOVA test ran for each metric, uncorrected (top), and corrected for multiple comparisons (bottom). B, Same as in A but for the attentional response metrics of attention-selective neurons. C, Same as in A but for the saccadic response metrics of saccade-selective neurons. All error bars represent SEM.

Figure 5.

Effects of MPH on noise correlations. Each line illustrates the median noise correlation coefficient separately for positive and negative noise correlations (blue and red, respectively) as a function of drug dose (x-axis). The x-axis uses arbitrary units, from the smallest dose of MPH to the biggest for each monkey. These are 0.43, 0.86, 1.08, 1.29, or 1.72 mg/kg for monkey “F,” and 0.33, 0.67, 0.83, 1.00, or 1.33 mg/kg for monkey “JL.” The left column presents results from analyses including all recorded neurons, independent of their selectivity. The right column includes only neurons that were selective (i.e., tuned) for the corresponding epoch. Since no tuning can be measured during the baseline fixation epoch, visual tuning was used as a replacement in this analysis. Each column presents results for each monkey independently.

Figure 6.

Effects of MPH on noise correlation structure. A, Relationship between the signal correlation (i.e., tuning similarity) and noise correlation between every possible pairs of simultaneously recorded neurons, presented for each drug dose (colored lines). As expected, the more similar is the tuning between two neurons, the more noise they share through common inputs. B, Same as in A, although for monkey “JL.” Best dose of MPH based on behavioral performance is in bold in the legend. Error bars represent SEM.

Figure 7.

Effects of MPH on neuronal ensemble decoding of task-related information. A, Decoding accuracy of a SVM algorithm extracting single-trial information about the visual, attentional, and saccadic representations in the neuronal ensemble activity of simultaneously recorded neurons. Decoding accuracy, used as a proxy for neuronal coding accuracy, is presented as a function of drug dose (x-axis), as in preceding figures. The purple line represents the achieved chance performance using permutation testing and overlaps roughly with the theoretical chance performance of 25%. B, Same as A but for monkey “JL.” Error bars represent SEM.