The importance of volitional behavior in neuroplasticity

It was postulated by Donald Hebb (1) and even earlier over a century ago by William James (2) that correlated activity between preand postsynaptic activity would lead to strengthening of the synaptic efficacy between the two neurons, and it is believed to form the basis for long-term memory formation. Long-term potentiation (LTP) induced by high-frequency stimulation of afferents to a neuron and by paired stimulation of preand postsynaptic neurons are Hebbian forms of plasticity that have been experimentally validated extensively beginning with the seminal work of Bliss and Lomo (3) in the hippocampus (4). Spike timing–dependent plasticity (STDP) has refined this idea by demonstrating that the precise timing between preand postsynaptic activity can result in either potentiation or depression of the synapse (5). Nevertheless, most studies that have induced LTP and STDP have focused on synaptic plasticity outside of the context of behavior. In PNAS, Moorjani et al. (6) have demonstrated a form of plasticity using electrical stimulation that depends critically on volitional behavior and have shown that changes in connectivity strength can be maintained and even enhanced following the induction phase for days or even longer as long as the appropriate volitional behavior occurs. The key insight in the study by Moorjani et al. (6) is the use of movement-gated intracortical microstimulation (ICMS) in motor cortex (M1) of nonhuman primates that primed the system for further enhancement of connectivity with ongoing motor behavior even after electrical stimulation ended. The approach involved identifying paired sites in M1 that exhibited reciprocal connectivity as assessed by stimulus-triggered evoked potentials (EPs) at one site due to a single test stimulation at the other site. One site was designated as the test site (referred to as Ntest), and monkeys were trained to perform wrist movements (flexion or extension) based on the evoked electromyographical (EMG) output at the Ntest site using high-frequency suprathreshold stimulation (Fig. 1A). For example, monkeys were required to volitionally flex their wrist if the evoked EMG output of that site was flexion. At the same time, another site (referred to as Nstim) that received a functional connection from Ntest was stimulated with ICMS at 10 Hz during the preferred movement of Ntest (e.g., flexion) such that neurons near the Ntest site were presumably firing, while induced firing occurred simultaneously among neurons near the Nstim site. Thus, the induction phase involved coactivation of neurons at Ntest and Nstim sites consistent with Hebbian plasticity. A strengthening in functional connectivity between Ntest and Nstim based on an amplitude increase of the EP occurred during movement-gated stimulation, which would be expected (Fig. 1B). What was striking, however, was that further increased connectivity strength occurred after stimulation ended as long as the monkeys continued to perform wrist movements associated with the preferred movement of Ntest (e.g., flexion) (Fig. 1 C and D). Appropriate controls were performed to demonstrate that movement-gated stimulation without further behavior or behavior without movement-gated stimulation did not result in increases in functional connectivity from Ntest to Nstim. Interestingly, there was no evidence of increased functional connectivity in the reverse direction from Nstim to Ntest. The role of behavior as a necessary component in inducing plasticity is not entirely novel. Using a different induction paradigm in the auditory cortex of nonhuman primates, a series of studies found that inferred connectivity between two neurons increased only when animals were engaging in an auditory discrimination task (7, 8). In those studies, the spiking of one neuron triggered an auditory stimulus that evoked a response in another neuron, resulting in correlated firing during the induction phase. This correlated firing as assessed with cross-correlation was maintained even after the induction phase ended but only when the animal was engaging in the task during induction. However, over minutes, this increase in inferred connectivity faded and returned to baseline. The study by Moorjani et al. (6), in contrast, demonstrated long-term maintenance and even enhancement of connectivity after the induction phase as long as the animal continued to engage in the appropriate voluntary movement. The mechanisms by which behavior acts to enable and even prime plasticity following induction are not known. Animals in the study by Moorjani et al. (6) performed a wrist task that was voluntary, goal directed, and rewarded, so a number of psychological processes may be at play, including attention, arousal, motivation, and even intentionality, which are associated with neuromodulation. A number of neuromodulator systems, such as dopamine, acetylcholine, neurepinephrin, and serotonin, have been shown to enhance plasticity, M1 motor maps, and motor learning through direct or indirect neuromodulator projections to M1 (4, 9–14). In particular, local cholinergic input to M1 has been shown to play a role in motor skill learning and to alter M1 output maps associated with learning (13). However, despite the fact that neuromodulation may play a critical role in Hebbian plasticity, it does not explain why continued behavior after the stimulation