All psychiatric disorders have suffered from a dearth of truly novel pharmacological interventions. In bipolar disorder, lithium remains a mainstay of treatment, six decades since its effects were serendipitously discovered. The lack of progress reflects several factors, including ignorance of the disorder's pathophysiology and the complexities of the clinical phenotype. After reviewing the current status, we discuss some ways forward. First, we highlight the need for a richer characterization of the clinical profile, facilitated by novel devices and new forms of data capture and analysis; such data are already promoting a reevaluation of the phenotype, with an emphasis on mood instability rather than on discrete clinical episodes. Second, experimental medicine can provide early indications of target engagement and therapeutic response, reducing the time, cost, and risk involved in evaluating potential mood stabilizers. Third, genomic data can inform target identification and validation, such as the increasing evidence for involvement of calcium channel genes in bipolar disorder. Finally, new methods and models relevant to bipolar disorder, including stem cells and genetically modified mice, are being used to study key pathways and drug effects. A combination of these approaches has real potential to break the impasse and deliver genuinely new treatments.
Our ability to hold information in mind is limited, requires a high degree of cognitive control, and is necessary for many subsequent cognitive processes. Children, in particular, are highly variable in how, trial-by-trial, they manage to recruit cognitive control in service of memory. Fronto-parietal networks, typically recruited under conditions where this cognitive control is needed, undergo protracted development. We explored, for the first time, whether dynamic changes in fronto-parietal activity could account for children's variability in tests of visual short-term memory (VSTM). We recorded oscillatory brain activity using magnetoencephalography (MEG) as 9- to 12-year-old children and adults performed a VSTM task. We combined temporal independent component analysis (ICA) with general linear modeling to test whether the strength of fronto-parietal activity correlated with VSTM performance on a trial-by-trial basis. In children, but not adults, slow frequency theta (4-7 Hz) activity within a right lateralized fronto-parietal network in anticipation of the memoranda predicted the accuracy with which those memory items were subsequently retrieved. These findings suggest that inconsistent use of anticipatory control mechanism contributes significantly to trial-to-trial variability in VSTM maintenance performance.
Abstract Despite the intuition that we can shift cognitive set on instruction, some behavioral studies have suggested that set shifting might only be accomplished once we engage in performance of the new task. It is possible that set switching consists of more than one component cognitive process and that the component processes might segregated in time. We recorded event-related potentials (ERPs) during two set-switching tasks to test whether different component processes were responsible for (i) set initiation and reconfiguration when presented with the instruction to switch, and (ii) the implementation of the new set once subjects engaged in performing the new task. The response switching (RS) task required shifts of intentional set; subjects selected between responses according to one of two conflicting intentional sets. The results demonstrated the existence of more than one constituent process. Some of the processes were linked to the initiation and reconfiguration of the set prior to actual performance of the new task. Other processes were time locked to performance of new task items. Set initiation started with modulation of medial frontal ERPs and was followed by modulation over parietal electrodes. Implementation of intentional set was associated with modulation of response-related ERPs.
During visual search we quickly learn to attend to an object’s probable location, efficiently sifting through clutter from the visual world to find our target. Research has supported that this process is facilitated when target-location learning is based on hippocampal-dependent spatial contextual associations (CC, contextual cueing) or striatal-based probabilistic regularities (LPL, location probability learning). Here, we tested how these different types of learning aid the utilization of established memories. In two online experiments, participants searched for targets within scenes. Depending on the scene category, the target consistently appeared at a specific location (CC), within a hemifield (LPL), or was unpredictable (random). In Experiment 1, 54 participants were subsequently tested on their memory for the hemifield and the specific location of the learned targets. Participants showed enhanced recall accuracy for target hemifield and specific target location in both LPL and CC conditions. However, when learning performance was low (low accuracy/high reaction time), predominantly LPL facilitated memory for target hemifields, and when learning performance was high, CC facilitated memory for specific target locations. In Experiment 2, after learning, 54 participants were tested on their ability to orient attention to targets flashed either in a learned specific location or hemifield. We found greater orienting benefits for CC compared to LPL, as measured by reaction time. Together, we demonstrate that contextual and probabilistic learning systems provide utility for future retrieval of learned associations, but how these systems promote memory retrieval may be related to the quality of encoding. Further, after comparable learning conditions, attentional orienting seems more profoundly guided by contextual, compared to probabilistic regularities. Our work suggests that a more nuanced view of how these memory systems cooperate and/or compete to guide adaptive behavior is necessary.
Being able to orient our attention to moments in time is crucial for optimizing behavioral performance. In young adults, flexible cue-based temporal expectations have been shown to modulate perceptual functions and enhance behavioral performance. Recent studies with older individuals have reported significant deficits in cued temporal orienting. To investigate the extent of these deficits, the authors conducted 3 studies in healthy old and young adults. For each study, participants completed 2 tasks: a reaction time (RT) task that emphasized speeded responding and a nonspeeded rapid-serial-visual-presentation task that emphasized visual discrimination. Auditory cues indicated the likelihood of a target item occurring after a short or long temporal interval (foreperiod; 75% validity). In the first study, cues indicating a short or a long foreperiod were manipulated across blocks. The second study was designed to replicate and extend the first study by manipulating the predictive temporal cues on a trial-by-trial basis. The third study extended the findings by including neutral cues so that it was possible to separate cueing validity benefits and invalidity costs. In all 3 studies, cued temporal expectation conferred significant performance advantages for target stimuli occurring after the short foreperiod for both old and young participants. Contrary to previous findings, these results suggest that the ability to allocate attention to moments in time can be preserved in healthy aging. Further research is needed to ascertain whether similar neural networks are used to orient attention in time as we age, and/or whether compensatory mechanisms are at work in older individuals. (PsycINFO Database Record
Memory plays an important role in orchestrating cognition. Memories across different timescales have been shown to support separate, discrete cognitive operations; for example, attentional sampling (encoding), attentional guidance, and working memory. However, during free-flowing natural behaviour, memories provide the scaffolding for these discrete operations in a continuous and interconnected way. In three virtual reality (VR) experiments, we embraced the interconnected nature of these hallmark cognitive operations. We tracked head, hand, and eye movements as well as free-flowing interactions with the environment while participants copied a Model display by selecting realistic objects from a Resource pool and placing them into a Workspace. Using our novel VR protocol, we segmented continuous temporally extended behaviour into tractable sub-units: attentional sampling (encoding), attentional guidance during visual search, and working memory usage. By repeating selected arrangements within the environment (Exp1: Model, Exp2: Resource, Exp3: both) and using non-repeated/novel arrangements as a baseline, we show how different types of memories guide the interlinked processes of encoding, search, and working memory use during continuous natural behaviour. First, overall task performance increased for repeated vs novel arrangements. Next, we demonstrate that reliance on information in memory – compared to gathering information from the external environment – increased when Model arrangements were repeated. Further, search times improved for repeated Resource arrangements. We also found high performance in a subsequent recognition memory task for repeated Model and Resource arrangements, suggesting that the incidentally formed representation during the task were durable and accessible. Overall, we find memories help guide not only overall performance, but also differentially affect segmented cognitive operations during complex behaviour. Our work provides a novel framework for investigating naturally unfolding memory-guided behaviour and sheds new light on the coordination between vision, memory, and action.
High-speed magnetic resonance (MR) imaging was used to detect activation in the human prefrontal cortex induced by a spatial working memory task modeled on those used to elucidate neuronal circuits in nonhuman primates. Subjects were required to judge whether the location occupied by the current stimulus had been occupied previously over a sequence of 14 or 15 stimuli presented in various locations. Control tasks were similar in all essential respects, except that the subject's task was to detect when one of the stimuli presented was colored red (color detection) or when a dot briefly appeared within the stimulus (dot detection). In all tasks, two to three target events occurred randomly. The MR signal increased in an area of the middle frontal gyrus corresponding to Brodmann's area 46 in all eight subjects performing the spatial working memory task. Right hemisphere activation was greater and more consistent than left. The MR signal change occurred within 6-9 sec of task onset and declined within a similar period after task completion. An increase in MR signal was also noted in the control tasks, but the magnitude of change was less than that recorded in the working memory task. These differences were replicated when testing was repeated in five of the original subjects. The localization of spatial working memory function in humans to a circumscribed area of the middle frontal gyrus supports the compartmentalization of working memory functions in the human prefrontal cortex and the localization of spatial memory processes to comparable areas in humans and nonhuman primates.
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