ANÁLISIS DE LOS PROCESOS Y TIEMPOS DE PRODUCCIÓN

As highlighted above, lesioning the STN leads to evidence of impulsive response selection behaviour, which supports the assertion that STN enables us to “hold our horses” by providing deliberative potential in decision making, perhaps by raising the response threshold to allow time for information gathering (Frank, 2006; Jahanshahi et al., 2014). Impulsivity can manifest many forms, such as responding without deliberation (impulsive action), aversion to delayed gratification, the inability to withhold a prepotent response (motor inhibition), along with engaging in more risky decision making (for reviews Evenden, 1999; Dalley, Everitt, & Robbins, 2011; but also Eagle & Baunez, 2010). In the case of decision making, and particularly decisions made under high-conflict conditions (i.e., choosing the best response under two positively associated responses), inhibition of responding is crucial; it is posited that the STN may play a large role in the ‘stopping’ and

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‘integration’ of information prior to response selection, which consequently prevents impulsive or premature responding (Frank, 2006; Jahanshahi et al., 2014).

In humans, this behaviour is typically modeled in a gambling task, such as the Iowa Gambling Task (IGT; see Bechara, 2003), which presents real-world contingencies of reward and punishment (i.e., winning and losing money), and creates a ‘decision conflict’

between an immediate large reward, yet at the cost of a delayed, and inevitable, punishment. Subjects are typically presented with four decks of cards with high-paying (decks A & B) or low-paying (decks C & D) options; the punishment is also higher in the high-paying decks and lower in the low-paying decks, and the task is designed such that the high-paying decks cost more in the long run, and are therefore disadvantageous (Bechara, 2003). Individuals who select riskier options in these tasks tend to accept short-term gains in lieu

of longer-term objectives, and therefore this task has become a useful diagnostic tool in detecting drug addiction, compulsive binge-eating, and pathological gambling (Bechara, 2003; Dalley, Everitt, & Robbins, 2011).

There is also growing evidence that patients with Parkinson’s disease are at increased risk for developing pathological gambling, along with other impulse control disorders such as hypersexuality, overeating and punding (14% of clinical population), and that furthermore, the likelihood of developing these disorders may be predicted by dopamine agonist therapy (Jahanshahi, 2013). This predisposition in Parkinson’s patients undergoing dopamine agonist therapy may in part be due to a reduction in activation in brain areas implicated in impulse control and response inhibition (OFC, rostral cingulate area, amygdala, & GPe), which results in riskier choices, and may be mediated by outcome devaluation, or reward prediction errors; essentially an interference in the ability to learn from losses (van Eimeren et al., 2009; 2010). It has also been found that Parkinson’s patients who are undergoing STN-HFS respond more impulsively, and are consequently impaired in tasks which require conflict resolution, or response selection under conflict (Frank, Samanta, Moustafa, & Sherman, 2007; Zaghloul et al., 2012; Zénon et al., 2016). It is postulated that the OFC, DMS and STN form a network of regions that may be critical in impulsive/compulsive behaviour, and that dysregulating this network results in increased

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impulsive action, premature responding and perseveration, and thus contribute to this impairment in decision making (Eagle & Baunez, 2010; Baunez & Lardeux, 2011).

There is evidence that inactivation of the STN with HFS in Parkinson’s patients selectively interferes with the ability slow down, or ‘apply the brakes’, when faced with a decision conflict (Frank et al., 2007). Furthermore, when faced with decision conflict, patients undergoing HFS demonstrate increased spiking activity in the STN, and that as decision conflict increases, so too does the level of the spiking activity (Zaghloul et al., 2012). More recent research by Zénon et al. (2016) has revealed that patients who are undergoing HFS therapy – both on and off L-DOPA – exhibit low-frequency neuronal activity in the STN, and instead of signalling conflict, this activity may indicate the encoding of cost-benefit comparisons. Zénon et al. (2016) tested patients on an effort-based decision task, providing monetary incentive for effortful activity (e.g., squeezing a handgrip in varying intensity); behaviourally, the probability of engaging in an effortful task increases with reward and decreases with required effort level. L-DOPA+HFS treatment increased the rate of acceptance for efforts associated with lower rewards, and that when off L-DOPA treatment, this effect was weakened. The authors also found synchronised activity in populations of STN neurons that may reflect the subjective value of reward and the subjective cost of effort, which is postulated by Zénon et al. to be the net subjective value of a trial during decision making. These findings indicate that the STN plays a critical role in the mediation of action selection during decision making, and that furthermore this may be mediated by the STN encoding the information required to make cost-benefit comparisons, rather than signalling conflict, which may also implicate the STN in motivational behaviour.

In order to investigate how the STN integrates reward information and to what extent such integration correlates with behaviour, Espinosa-Parrilla, Baunez, & Apicella (2015) conducted electrophysiology recordings of the monkey STN during a two-choice target-reaching task, in which selection of a visual cue (target) from a touch-screen led to the delivery of a higher or lower value reward (e.g., juice vs water). Two variants of the task were employed: the standard task, and the choice task. The standard task presented monkeys with an instruction cue (e.g., either a green or yellow circle, on either the left or

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right side of the screen), which provided advanced information regarding the nature of the upcoming reward (e.g., green = juice, yellow = water), followed by a 1 seconds waiting period before presented with one trigger stimulus (e.g., red circle) in the same spatial location as the instruction cue, and the animals were permitted to make a selection to receive the designated reward. The information gathered from this standard task helped investigate how the type of reward expected may influence neuronal activity during preparation, initiation and execution of the reaching movement. The choice condition task was formally similar to the standard condition, except it provided two instruction cues (one denoting juice, and the other water), and thereby it permitted the animal to choose its reward when presented with the trigger stimulus. Neuronal recordings were assessed over three time periods: the cue-trigger delay period, the movement period and the reward period. The authors found that when no choice was allowed (i.e., during the standard task), the activity of STN neurons was rarely modulated by adjustments of behaviour, although there was evidence that animals responded faster in juice trials, compared to water trials, therefore indicating a discriminative ability for reward-predictive cues. Conversely, when given a choice in selecting actions that lead to reward (i.e., during the choice task), STN activity was sensitive to the reward type, resulting in an increase STN neuronal activity at the outcome phase (when receiving reward), when the less-preferred reward was chosen (Espinosa-Parrilla, Baunez, & Apicella, 2015). These findings also indicate that the STN may encode whether or not a preferred reward has been received when alternative choices are available, which sheds new light on how the STN may mediate decision making processes.

In studies with rats, our ability to infer complex decision making processes are more limited than in humans (e.g., clinical populations), and therefore we must rely on inference from overt behaviours in modified gambling tasks or delay discounting tasks in operant chambers (Winstanley, Baunez, Theobald, & Robbins, 2005; Uslaner & Robinson, 2006; Aleksandrova et al., 2013). The delay discounting task used by Winstanley et al. (2005) assessed impulsive choice behaviour, which defines impulsivity as the selection of a small immediate reward over a larger delayed reward, and can be contrasted with impulsive action behaviour (i.e., motoric disinhibition). Winstanley et al. (2005) tested rats in an

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operant box which required rats to sustain a nose-poke in a central hole in order to commence a trial; subsequently, two levers were presented, in which one lever provided an immediate food reward of one pellet (delay: 0 seconds), whilst the other lever would produce a reward of four pellets with increasing delays between lever-press and reward delivery as testing proceeded (delay: 0, 10, 20, 30, 40 and 60 seconds). The authors found that preoperatively, rats demonstrated the typical delay-dependant choice behaviour: initially preferring a larger reward when delivery is immediate, but eventually shifting to a smaller reward as delay is increased. Postoperatively, STN-lesioned rats chose the larger reward more frequently than sham-operated controls, which suggests that STN-lesioned rats were less impulsive in this delay-discounting task. Furthermore the evidence that STN lesions results in increased impulsive action (Baunez & Robbins, 1997; Baunez et al., 2001) without increasing impulsive choice may suggest that these behaviours may be subject to independent regulatory mechanisms that operate in concert or an ‘impulsive/compulsive network’ (for reviews see Eagle & Baunez, 2010; Baunez & Lardeux, 2011). In a follow-up study by Uslaner & Robinson (2006), the authors replicated the findings of Winstanley et al. (2005), and found in a delay-discounting task, STN- lesioned rats selected the lever which led to delayed gratification more frequently than control rats, but only in the longest delay condition, which supports that lesioning the STN may in fact decrease impulsive choice behaviour. It is also possible that the incentive of the larger reward is more difficult to inhibit, particularly following lesioning, and owing to the task sensitivity of the delay-discounting task we are able to obtain different findings than an impulsive action task (i.e., the 5CSRTT). These findings also align with the studies in human Parkinson’s patient and monkeys presented above, in which the STN may play a critical role in outcome evaluation.

In a recent study by Adams et al. (2017), the authors investigated the effects of STN-HFS in rats completing the Rat Gambling Task (rGT) – the rodent analogue of the IGT. Similar to the IGT and delay-discounting tasks, the rGT creates a decision conflict in rats by forcing them to decide the most efficient strategy to maximise food reward by training them to poke their nose in one of four holes which differ in reward volume (1, 2, 3, or 4 pellets given per trial) and with corresponding punishments in the form of a ‘time-out’

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(5, 10, 30, or 40 seconds), with larger rewards leading to a higher likelihood of punishment. In typical fashion, the most advantageous option maximised reward, yet limited punishment; essentially, smaller per-trial gains but lower time-out penalties. Adams et al. (2017) found that STN-HFS did not influence performance for those rats identified as ‘optimal decision makers’ in the baseline assessment, but that HFS significantly improved choice responding for ‘risk-preferring’ rats (‘high risk, high reward’; roughly 25% of rats from baseline). It is worth noting that the behavioural effects of HFS for this population were progressive, in that improvement in decision making was not apparent until the fourth treatment session. This effect has been seen in the past (see Baunez et al., 2007), which has led Adams et al. (2017) to postulate that perhaps HFS itself may not reliably induce changes in decision making, and that perhaps repeated stimulation is required to trigger neuroplasticity, which in turn, results in cognitive change. Ultimately, more work is needed, as it has also been demonstrated that HFS of the STN does not truly mimic the inactivation obtained from lesioning (Baunez et al., 2007; Baunez & Lardeux, 2011), but global evidence from both HFS and lesioning, and across humans, monkeys and rats suggests that STN may play a pivotal role in the processes contributing to decision making.