PAS-induced potentiation of cortical-evoked activity in the dorsolateral prefrontal cortex

Abstract

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ- and γ-activity and θ-phase-γ-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied.

Figures

Figure 1

Time series of potentiation. This figure illustrates the time frame for overall potentiation following transcranial magnetic stimulation (TMS) pulse. Using the ratio of cortical-evoked activity (CEA) post-paired associative stimulation (PAS)/CEA pre-PAS for every 100-ms window after TMS with increments of 1 ms, we identified two time-points after TMS: the first is the earliest time-point of the first 100-ms window when the mean ratio becomes significantly larger than 1 (horizontal blue dashed line) and it occurred at 44 ms after TMS. This 100-ms window is indicated by its midpoint (94 ms—left vertical blue dotted line) on the graph. The 50 ms cutoff that was used in calculating the area under the curve for overall potentiation and that was chosen to minimize TMS artifact falls within this window. The second time-point is the end of the last l00-ms window during which the mean ratio remains significantly >1 and it occurred at 275 ms after TMS. This 100-ms window is also indicated by its midpoint (225 ms—right vertical blue dotted line) on the graph. This second time-point is what we used as the second cutoff in calculating the area under the curve for overall potentiation. Each data point (solid red line) represents the midpoint of a 100-ms window and corresponding median CEA ratio for that window. Dotted red lines: ±1 SEM. Black double-arrow: timeframe in which CEA ratios for all contiguously sliding 100-ms windows were significantly higher than 1.

Figure 2

Time series of transcranial magnetic stimulation (TMS)-evoked response potential after paired associative stimulation (PAS) and paired associative stimulation—control condition (PAS-C). The upper panel illustrates the potentiation of the TMS-evoked response potential after PAS (Post) compared with pre-PAS (Pre). The lower panel illustrates the absence of this potentiation following the control condition, PAS-C.

Figure 3

Paired associative stimulation (PAS)-induced potentiation of cortical excitability: 25 vs 100 ms interstimulus interval (ISI). The upper panel illustrates that PAS with an ISI of 25 ms—but not 100 ms (paired associative stimulation—control condition (PAS-C))—between the peripheral nerve stimulation and transcranial magnetic stimulation (TMS) results in the potentiation of cortical excitability as indexed by maximum cortical-evoked activity (CEA) ratio significantly >1 (black line). The lower panel demonstrates the average topoplots of PAS and PAS-C. Circles: individual participants' data. Error bars: ±1 SEM.

Figure 4

Localization of potentiation. This figure illustrates that paired associative stimulation (PAS) results in significant potentiation (*) at the site of transcranial magnetic stimulation (TMS) stimulation over the left dorsolateral prefrontal cortex (DLPFC) (Target) and across the left frontal region (Left frontal) when mean cortical-evoked activity (CEA) ratio is compared with the reference value of 1 (black line) (p's<0.005). In contrast, no significant potentiation is observed in the contralateral frontal region (Right frontal) or over all electrodes (Global). Error bars: ±1 SEM.

Figure 5

Paired associative stimulation (PAS) effects on θ–γ coupling. This figure illustrates that PAS and not paired associative stimulation—control condition (PAS-C) increases the modulation index (MI) of θ-phase γ-amplitude coupling (θ–γ coupling) in the dorsolateral prefrontal cortex (DLPFC). MI in response to transcranial magnetic stimulation (TMS) is significantly greater than MI of surrogate data (black line) before and after PAS and PAS-C. However, following PAS and not PAS-C, MI significantly increases further. Error bars: ±1 SEM.