Dissecting Neural Responses to Temporal Prediction, Attention, and Memory: Effects of Reward Learning and Interoception on Time Perception

Cerebral Cortex, October 2015;25: 3856–3867 doi: 10.1093/cercor/bhu269 Advance Access Publication Date: 11 November 2014 Original Article ORIGINAL ARTICLE Dissecting Neural Responses to Temporal Prediction, Dardo Tomasi1, Gene-Jack Wang1, Yana Studentsova1 and Nora D. Volkow1,2 1 National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA, and 2National Institute on Drug Abuse, Bethesda, MD 20892, USA Address correspondence to Dardo Tomasi, PhD, 10 Center Dr, Rm B2L304, Bethesda, MD 20892-1013, USA. Email: Abstract Temporal prediction (TP) is needed to anticipate future events and is essential for survival. Our sense of time is modulated by emotional and interoceptive (corporal) states that are hypothesized to rely on a dopamine (DA)-modulated “internal clock” in the basal ganglia. However, the neurobiological substrates for TP in the human brain have not been identified. We tested the hypothesis that TP involves DA striato-cortical pathways, and that accurate responses are reinforcing in themselves and activate the nucleus accumbens (NAc). Functional magnetic resonance imaging revealed the involvement of the NAc and anterior insula in the temporal precision of the responses, and of the ventral tegmental area in error processing. Moreover, NAc showed higher activation for successful than for unsuccessful trials, indicating that accurate TP per se is rewarding. Inasmuch as activation of the NAc is associated with drug-induced addictive behaviors, its activation by accurate TP could help explain why video games that rely on TP can trigger compulsive behaviors. Key words: dopamine, fMRI, reward, timekeeping Introduction Adaptive organisms must predict future events in time scales that are useful for survival. Temporal prediction (TP), the ability to estimate the short-term evolution of future events, is continuously shaped by reward/aversion learning processes as a function of sensory information (Schultz et al. 1997; Nobre et al. 2007) as well as emotional and interoceptive states (Pollatos et al. 2014). Our sense of time and the temporal relationships between previous events help us to anticipate future events and to make faster responses (Jazayeri and Shadlen 2010). Multiple processes seem to determine our subjective perception of time in the range of hundreds of milliseconds to several seconds, including interoceptive signals in the insular cortex and an “internal clock” or internal timekeeper, presumably located in the basal ganglia and modulated by DA (Buhusi 2003; Coull et al. 2011; Merchant et al. 2013). Specifically, it is hypothesized that interval timing is encoded by coincident activity of cortical neurons that are detected by striatal neurons and conveyed through the thalamus into the cortex (Matell and Meck 2004). Since dopamine (DA) regulates striato-thalamo-cortical circuits, this could explain how DA signaling could modulate time perception (Meck 1986, 2006; Drew et al. 2007; Wiener et al. 2014). However, the neural bases of TP, including its cortical representations, are still poorly understood. Behavioral and neuroimaging studies have shown that the sense of time is slower in elders and in psychiatric disorders of abnormal basal ganglia function (schizophrenia, Parkinson’s disease, attention deficit hyperactivity disorder, and addiction; Allman and Meck 2012; Allman et al. 2014), which is consistent with DA’s role in timekeeping operations (Bäckman et al. 2006; Dreher et al. 2008). Similarly, pharmacological studies in animals also support DA’s role in timekeeping operations in the striatum (Maricq and Church 1983; Meck 1986; Oprisan and Buhusi 2011). These include the effects of drugs of abuse such as stimulants, Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US. Attention, and Memory: Effects of Reward Learning and Interoception on Time Perception The Neural Basis of Temporal Prediction Tomasi et al. Materials and Methods Subjects The 36 healthy participants (age: 27 ± 6 years, mean ± SD; 34 right handed and 2 left handed; 18 females) in this study were recruited from advertisements in local newspapers. Written informed consent was obtained from all participants prior to the study. Participants were excluded from the study if they had 1) history of major psychiatric or neurological disease; 2) medical conditions that may alter cerebral function (i.e., cardiovascular, endocrinological, oncological, or autoimmune diseases), 3) head trauma with loss of consciousness for >30 min, or 4) use prescribed psychoactive medications. The participants were instructed to discontinue any over the counter medication 2 weeks prior to the study. Food and beverages (except for water) were discontinued at least 4 h prior and cigarettes for at least 2 h prior to the study. Females were scanned in their midfollicular phase. The study was approved by the Committee on Research in Human Subjects at Stony Brook University. Prediction Learning Paradigm During functional scans, participants engaged in 4 consecutive tasks (Supplementary Fig. 1A) involving SM coupling, TOP, spatial WM, and SA. The tasks had identical duration (4 min), number of trials (20), and intertrial interval (ITI = 12 s; 2 s jittering). Button press responses were recorded to determine reaction time (RT; average time difference between targets and responses) and performance accuracy ( percentage of successful events relative to the total number of events). In addition, the subject’s responses were used for general linear modeling (GLM) of brain activation responses during successful prediction as well as during prediction errors. The next paragraphs describe the trials for each of the 4 tasks in this paradigm. The SM task involves visual perception and measures the RT required for the subjects to respond to the presence of a target, an open circle covering 10% and 12% of the horizontal and vertical visual fields (Supplementary Fig. 1B). A static white fixation cross was shown at the center of the black screen during 96% of the ITI. During each trial, the target was randomly flashed for 200 ms at 1 of the 4 corners of the screen in the peripheral visual field. The subjects’ task was to respond to the appearance of the target by pushing an in-house MRI-compatible response button with their right index finger as quickly as possible upon target presentation. The 600-ms response window that followed the target was used to classify a button press response as successful (RT ≤ 600 ms) or unsuccessful (RT > 600 ms). After an expectation period of 1.3 s, an outcome message, “$” for a hit or “X” for a miss, briefly (500 ms) replaced the fixation cross at the center of the visual field as a feedback, to inform the subjects about their accuracy during the trial; after the outcome only the fixation cross was displayed for 9–11 s, until the onset of the next target. The TOP task is based on the observation that subse (...truncated)