Neural correlates of executive function and working memory in the 'at risk mental state'

Background and Aims: People with ‘prodromal’ symptoms have a very high risk of developing psychosis. We used functional MRI to examine the neurocognitive basis of this vulnerability. Method: Cross-sectional comparison of subjects with an ARMS (n=17), first episode schizophreniform psychosis (n=10) and healthy volunteers (n=15). Subjects were studied using functional MRI while they performed an overt verbal fluency task, a random movement generation paradigm and an N-Back working memory task. Results: During an N-Back task the ARMS group engaged inferior frontal and posterior parietal cortex less than controls but more than the first episode group. During a motor generation task, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than the first episode group. During verbal fluency using ‘Easy’ letters, the ARMS group demonstrated intermediate activation in the left inferior frontal cortex, with first episode groups showing least, and controls most, activation. When processing ‘Hard’ letters, differential activation was evident in two left inferior frontal regions. In its dorsolateral portion, the ARMS group showed less activation than controls but more than the first episode group, while in the opercular part of the left inferior frontal gyrus / anterior insula activation was greatest in the first episode group, weakest in controls and intermediate in the ARMS group. Conclusions: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have just developed psychosis but less severe

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making

Modulation of acute effects of delta-9-tetrahydrocannabinol on psychotomimetic effects, cognition and brain function by previous cannabis exposure

Cannabis use has been associated with psychosis and cognitive dysfunction. Some evidence suggests that the acute behavioral and neurocognitive effects of the main active ingredient in cannabis, (-)-trans-Delta 9-tetrahydrocannabinol (Delta 9-THC), might be modulated by previous cannabis exposure. However, this has not been investigated either using a control group of non-users, or following abstinence in modest cannabis users, who represent the majority of recreational users. Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, Delta 9-THC challenge study. Compared to non-users (N=12; <5 lifetime cannabis joints smoked), abstinent modest cannabis users (N=12; 24.5 +/- 9 lifetime cannabis joints smoked) showed worse performance and stronger right hemispheric activation during cognitive processing, independent of the acute challenge (all P=0.047). Acute Delta 9-THC administration produced transient anxiety and psychotomimetic symptoms (all P=0.02), the latter being greater in non-users compared to users (P=0.040). Non-users under placebo (control group) activated specific brain areas to perform the tasks, while deactivating others. An opposite pattern was found under acute (Delta 9-THC challenge in non-users) as well as residual (cannabis users under placebo) effect of Delta 9-THC. Under Delta 9-THC, cannabis users showed brain activity patterns intermediate between those in non-users under placebo (control group), and non-users under Delta 9-THC (acute effect) and cannabis users under placebo (residual effect). In non-users, the more severe the Delta 9-THC-induced psychotomimetic symptoms and cognitive impairments, the more pronounced was the neurophysiological alteration (all P=0.036). Previous modest cannabis use blunts the acute behavioral and neurophysiological effects of Delta 9-THC, which are more marked in people who have never used cannabis. (C) 2018 Elsevier B.V. and ECNP. All rights reserved

Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation.

The Iowa gambling task (IGT) is one of the most influential behavioral paradigms in reward-related decision making and has been, most notably, associated with ventromedial prefrontal cortex function. However, performance in the IGT relies on a complex set of cognitive subprocesses, in particular integrating information about the outcome of choices into a continuously updated decision strategy under ambiguous conditions. The complexity of the task has made it difficult for neuroimaging studies to disentangle the underlying neurocognitive processes. In this study, we used functional magnetic resonance imaging in combination with a novel adaptation of the task, which allowed us to examine separately activation associated with the moment of decision or the evaluation of decision outcomes. Importantly, using whole-brain regression analyses with individual performance, in combination with the choice/outcome history of individual subjects, we aimed to identify the neural overlap between areas that are involved in the evaluation of outcomes and in the progressive discrimination of the relative value of available choice options, thus mapping the two fundamental cognitive processes that lead to adaptive decision making. We show that activation in right ventromedial and dorsolateral prefrontal cortex was predictive of adaptive performance, in both discriminating disadvantageous from advantageous decisions and confirming negative decision outcomes. We propose that these two prefrontal areas mediate shifting away from disadvantageous choices through their sensitivity to accumulating negative outcomes. These findings provide functional evidence of the underlying processes by which these prefrontal subregions drive adaptive choice in the task, namely through contingency-sensitive outcome evaluation

Previous cannabis exposure modulates the acute effects of delta-9-tetrahydrocannabinol on attentional salience and fear processing

Cannabis can induce transient psychotic and anxiety symptoms and long-lasting disorders. The acute psychoactive effects of its main active ingredient, (-)-trans-Delta 9-tetrahydrocannabinol (Delta 9-THC), may be modulated by previous cannabis exposure. Secondary data analyses tested whether modest previous cannabis exposure modulated the acute effects of Delta 9-THC on attentional salience and emotional processing and their neurophysiological substrates. Twenty-four healthy men participated in a doubleblind, randomized, placebo-controlled, repeated-measures, within-subject, Delta 9-THC challenge study using fMRI. Compared with nonusers (NUs; n = 12; < 5 lifetime cannabis joints smoked), abstinent-modest cannabis users (CUs; n = 12; 24.5 +/- 9 lifetime cannabis joints smoked) showed less efficient attentional salience processing and recruited different/additional brain areas to process attentional salient and emotional stimuli (all ps < .01). The Delta 9-THC challenge disrupted attentional salience and emotional-processing-related brain activity and induced transient anxiety and psychotic symptoms (all ps <= .02). However, Delta 9-THC-induced psychotic symptoms and attentional salience behavioral impairment were more pronounced in NUs compared with CUs (all ps <= .04). Also, NUs under Delta 9-THC shifted toward recruitment of other brain areas to perform the tasks. Conversely, CUs were less affected by the acute challenge in an exposure-dependent manner, showing a neurophysiological pattern similar to that of NUs under placebo. Only in NUs, Delta 9-THC-induced psychotic symptom and cognitive impairment severity was associated with a more pronounced neurophysiological alteration (all ps <= .048). In conclusion, CUs displayed residual effects of cannabis exposure but more blunted responses to the acute symptomatic, behavioral, and neurophysiological effects of Delta 9-THC, which were more marked in NUs