See Kleen and Kirsch (doi:10.1093/awx178) for a scientific commentary on this article.Cognitive deficits are common among epilepsy patients. In these patients, interictal epileptiform discharges, also termed spikes, are seen routinely on electroencephalography and believed to be associated with transient cognitive impairments. In this study, we investigated the effect of spikes on memory encoding and retrieval, taking into account the spatial distribution of spikes in relation to the seizure onset zone as well as anatomical regions of the brain. Sixty-seven patients with medication refractory epilepsy undergoing continuous intracranial electroencephalography monitoring engaged in a delayed free recall task to test short-term memory. In this task, subjects were asked to memorize and recall lists of common nouns. We quantified the effect of each spike on the probability of successful recall using a generalized logistic mixed model. We found that in patients with left lateralized seizure onset zones, spikes outside the seizure onset zone impacted memory encoding, whereas those within the seizure onset zone did not. In addition, spikes in the left inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, and fusiform gyrus during memory encoding reduced odds of recall by as much as 15% per spike. Spikes also reduced the odds of word retrieval, an effect that was stronger with spikes outside of the seizure onset zone. These results suggest that seizure onset regions are dysfunctional at baseline, and support the idea that interictal spikes disrupt cognitive processes related to the underlying tissue.

Motor behavior requires selecting between potential actions. The role of inhibition in response selection has frequently been examined in tasks in which participants are engaged in some advance preparation prior to the presentation of an imperative signal. Under such conditions, inhibition could be related to processes associated with response selection, or to more general inhibitory processes that are engaged in high states of anticipation. In Experiment 1, we manipulated the degree of anticipatory preparation. Participants performed a choice reaction time task that required choosing between a movement of the left or right index finger, and used transcranial magnetic stimulation (TMS) to elicit motor evoked potentials (MEPs) in the left hand agonist. In high anticipation blocks, a non-informative cue (e.g., fixation marker) preceded the imperative; in low anticipation blocks, there was no cue and participants were required to divide their attention between two tasks to further reduce anticipation. MEPs were substantially reduced before the imperative signal in high anticipation blocks. In contrast, in low anticipation blocks, MEPs remained unchanged before the imperative signal but showed a marked suppression right after the onset of the imperative. This effect occurred regardless of whether the imperative had signaled a left or right hand response. After this initial inhibition, left MEPs increased when the left hand was selected and remained suppressed when the right hand was selected. We obtained similar results in Experiment 2 except that the persistent left MEP suppression when the left hand was not selected was attenuated when the alternative response involved a non-homologous effector (right foot). These results indicate that, even in the absence of an anticipatory period, inhibitory mechanisms are engaged during response selection, possibly to prevent the occurrence of premature and inappropriate responses during a competitive selection process.

Previous studies have identified two inhibitory mechanisms that operate during action selection and preparation. One mechanism, competition resolution, is manifest in the inhibition of the nonselected response and attributed to competition between candidate actions. The second mechanism, impulse control, is manifest in the inhibition of the selected response and is presumably invoked to prevent premature response. To identify constraints on the operation of these two inhibitory mechanisms, we manipulated the effectors used for the response alternatives, measuring changes in corticospinal excitability with motor-evoked potentials to TMS. Inhibition of the selected response (impulse control) was independent of the task context, consistent with a model in which this form of inhibition is automatically triggered as part of response preparation. In contrast, inhibition of the nonselected response (competition resolution) was context-dependent. Inhibition of the nonselected response was observed when the response alternatives involved movements of the upper limbs but was absent when one response alternative involved an upper limb and the other involved a lower limb. Interestingly, competition resolution for pairs of upper limbs did not require homologous effectors, observed when a left index finger response was pitted with either a nonhomologous right index finger movement or a right arm movement. These results argue against models in which competition resolution is viewed as a generic or fully flexible process, as well as models based on strong anatomical constraints. Rather, they are consistent with models in which inhibition for action selection is constrained by the similarity between the potential responses, perhaps reflecting an experience-dependent mechanism sensitive to the past history of competitive interactions.

Background: A significant component of ethanol (EtOH) dependence is the disruption to decision-making processes. Prior work has shown EtOH dependence biases habitual seeking of EtOH and disrupts neural mechanisms supporting decision-making. This has contributed to the hypothesis that habitual EtOH seeking in EtOH dependence may promote excessive habitual or compulsive EtOH consumption. However, decision-making and behavioral processes underlying seeking and consummatory behaviors differ. Here, we examine the microstructure of EtOH consummatory behavior in the context of habitual EtOH seeking.Methods: Following home cage pre-exposure to EtOH, C57Bl/6J mice underwent 4 rounds of chronic intermittent EtOH (CIE) or air exposure. Following acute withdrawal, mice began training for operant self-administration of 15% EtOH. Training consisted of 16-hour sessions in which mice were trained in a random ratio (RR) schedule of reinforcement for 30-second access to the EtOH sipper. To test for CIE-induced changes in action control, we used sensory-specific satiation and assessed the effect of outcome devaluation on EtOH seeking. Importantly, the use of a lickometer during operant training allowed us to measure the microstructure of lick behavior.Results: Prior induction of EtOH dependence led to increased EtOH seeking, consumption, and an insensitivity to outcome devaluation, the latter indicative of habitual EtOH seeking. We also found altered consummatory lick patterns in CIE-exposed mice compared to Air controls. While CIE mice had significantly more licks in a burst and a longer burst duration, there were no differences in the total number of bursts compared to Air controls. Furthermore, these EtOH consummatory behaviors correlated with blood EtOH concentrations (BECs), while EtOH-seeking responses did not.Conclusions: Our results confirm that EtOH dependence can produce habitual EtOH seeking and suggests the increased EtOH consummatory behaviors following EtOH dependence are separable from decision-making processes controlling EtOH seeking.

Motor-evoked potentials (MEPs), elicited by transcranial magnetic stimulation (TMS) over the motor cortex, are reduced during the preparatory period in delayed response tasks. In this study we examined how MEP suppression varies as a function of the anatomical organization of the motor cortex. MEPs were recorded from a left index muscle while participants prepared a hand or leg movement in experiment 1 or prepared an eye or mouth movement in experiment 2. In this manner, we assessed if the level of MEP suppression in a hand muscle varied as a function of the anatomical distance between the agonist for the forthcoming movement and the muscle targeted by TMS. MEP suppression was attenuated when the cued effector was anatomically distant from the hand (e.g., leg or facial movement compared with finger movement). A similar effect was observed in experiment 3 in which MEPs were recorded from a muscle in the leg and the forthcoming movement involved the upper limb or face. These results demonstrate an important constraint on preparatory inhibition: it is sufficiently broad to be manifest in a muscle that is not involved in the task, but it is not global, showing a marked attenuation when the agonist muscle belongs to a different segment of the body. NEW & NOTEWORTHY Using transcranial magnetic stimulation, we examined changes in corticospinal excitability as people prepared to move. Consistent with previous work, we observed a reduction in excitability during the preparatory period, an effect observed in both task-relevant and task-irrelevant muscles. However, this preparatory inhibition is anatomically constrained, attenuated in muscles belonging to a different body segment than the agonist of the forthcoming movement.

Decision-making is a continuous and dynamic process with prior experience reflected in and used by the brain to guide adaptive behavior. However, most neurobiological studies constrain behavior and/or analyses to task-related variables, not accounting for the continuous internal and temporal space in which they occur. We show mice rely on information learned through recent and longer-term experience beyond just prior actions and reward - including checking behavior and the passage of time - to guide self-initiated, self-paced, and self-generated actions. These experiences are represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrates this information to bias strategy-level decision-making, and DMS projections reflect specific aspects of this recent experience to guide actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity in alcohol exposed mice.

Subjective experience is a powerful driver of decision-making and continuously accrues. However, most neurobiological studies constrain analyses to task-related variables and ignore how continuously and individually experienced internal, temporal, and contextual factors influence adaptive behavior during decision-making and the associated neural mechanisms. We show mice rely on learned information about recent and longer-term subjective experience of variables above and beyond prior actions and reward, including checking behavior and the passage of time, to guide self-initiated, self-paced, and self-generated actions. These experiential variables were represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrated this information to bias strategy-level decision-making, and DMS projections used specific aspects of this recent experience to plan upcoming actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.