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Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

Verbal Working memory (vWM) capacity measures the ability to maintain and manipulate verbal information for a short period of time. The specific neural correlates of this construct are still a matter of debate. The aim of this study was to conduct a coordinate-based meta-analysis of 42 fMRI studies on visual vWM in healthy subjects ( = 795, males = 459, females = 325, unknown = 11; age range: 18-75). The studies were obtained after an exhaustive literature search on PubMed, Scopus, Web of Science, and Brainmap database. We analyzed regional activation differences during fMRI tasks with the anisotropic effect-size version of seed-based d mapping software (ES-SDM). The results were further validated by performing jackknife sensitivity analyses and heterogeneity analyses. We investigated the effect of numerous relevant influencing factors by fitting corresponding linear regression models. We isolated consistent activation in a network containing fronto-parietal areas, right cerebellum, and basal ganglia structures. Regarding lateralization, the results pointed toward a bilateral frontal activation, a left-lateralization of parietal regions and a right-lateralization of the cerebellum, indicating that the left-hemisphere concept of vWM should be reconsidered. We also isolated activation in regions important for response inhibition, emphasizing the role of attentional control in vWM. Moreover, we found a significant influence of mean reaction time, load, and age on activation associated with vWM. Activation in left medial frontal gyrus, left precentral gyrus, and left precentral gyrus turned out to be positively associated with mean reaction time whereas load was associated with activation across the PFC, fusiform gyrus, parietal cortex, and parts of the cerebellum. In the latter case activation was mainly detectable in both hemispheres whereas the influence of age became manifest predominantly in the left hemisphere. This led us to conclude that future vWM studies should take these factors into consideration.

Initially inspired by the Atkinson and Shiffrin model, researchers have spent a half century investigating whether actively maintaining an item in working memory (WM) leads to improved subsequent long-term memory (LTM). Empirical results have been inconsistent, and thus the answer to the question remains unclear. We present evidence from 13 new experiments as well as a meta-analysis of 61 published experiments. Both the new experiments and meta-analysis show clear evidence that increased WM maintenance of a stimulus leads to superior recognition for that stimulus in subsequent LTM tests. This effect appears robust across a variety of experimental design parameters, suggesting that the variability in prior results in the literature is probably due to low power and random chance. The results support theories on which there is a close link between WM and LTM mechanisms, while challenging claims that this relationship is specific to verbal memory and evolved to support language acquisition.

When trying to remember verbal information from memory, people look at spatial locations that have been associated with visual stimuli during encoding, even when the visual stimuli are no longer present. It has been shown that such “eye movements to nothing” can influence retrieval performance for verbal information, but the mechanism underlying this functional relationship is unclear. More precisely, covert in comparison to overt shifts of attention could be sufficient to elicit the observed differences in retrieval performance. To test if covert shifts of attention explain the functional role of the looking-at-nothing phenomenon, we asked participants to remember verbal information that had been associated with a spatial location during an encoding phase. Additionally, during the retrieval phase, all participants solved an unrelated visual tracking task that appeared in either an associated (congruent) or an incongruent spatial location. Half the participants were instructed to look at the tracking task, half to shift their attention covertly (while keeping the eyes fixed). In two experiments, we found that memory retrieval depended on the location to which participants shifted their attention covertly. Thus, covert shifts of attention seem to be sufficient to cause differences in retrieval performance. The results extend the literature on the relationship between visuospatial attention, eye movements, and verbal memory retrieval and provide deep insights into the nature of the looking-at-nothing phenomenon.

To date, the evidence regarding the effect of bilingualism/multilingualism on short-term memory (STM) and working memory (WM) capacity is inconclusive. This study investigates whether multilingualism has a positive effect on the verbal STM and WM capacity of neurotypical middle-aged and older individuals. Eighty-two L1-Norwegian sequential bilingual/multilingual academics were tested with tasks measuring verbal STM/WM capacity. Degree of bilingualism/multilingualism for each participant was estimated based on a comprehensive questionnaire. Different measures of bilingualism/multilingualism were used. Data on potentially influencing non-linguistic factors were also collected. Correlation and regression analyses showed that multilingualism impacts both verbal STM and verbal WM. In particular, all analyses showed that number of known foreign languages was the strongest predictor of verbal STM and WM capacity. The results are discussed in light of recent studies on the impact of bilingualism on STM/WM and on recent proposals regarding the mechanism underlying so-called bilingual advantage.

Our goal was to determine whether anserine/carnosine supplementation (ACS) suppresses chemokine levels in elderly people. In a double-blind randomized controlled trial, volunteers were assigned to the ACS or placebo group (1:1). Sixty healthy elderly volunteers (active, n = 30; placebo, n = 30) completed the study. The ACS group was administered 1.0 g of anserine/carnosine (3:1) for 3 months. A microarray analysis and subsequent quantitative real-time polymerase chain reaction (qRT-PCR) analysis of peripheral blood mononuclear cells (PBMCs) showed decreased expression of CCL24, an inflammatory chemokine (p < 0.05). Verbal memory, assessed using the Wechsler memory scale–logical memory, was preserved in the ACS group. An age-restricted sub-analysis showed significant verbal memory preservation by ACS in participants who were in their 60s (active, n = 12; placebo, n = 9; p = 0.048) and 70s (active, n = 7; placebo, n = 11; p = 0.017). The suppression of CCL24 expression was greatest in people who were in their 70s (p < 0.01). There was a significant correlation between the preservation of verbal memory and suppression of CCL24 expression in the group that was in the 70s (Poisson correlation, r = 0.46, p < 0.05). These results suggest that ACS may preserve verbal episodic memory, probably owing to CCL24 suppression in the blood, especially in elderly participants.

The problem of how the mind can retain sequentially organized information has a long research tradition that remains unresolved. While various computational models propose a mechanism of binding serial order information to position markers, the representational nature and processes that operate on these position markers are not clear. Recent behavioral work suggests that space is used to mark positions in serial order and that this process is governed by spatial attention. Based on the assumption that brain areas controlling spatial attention are also involved in saccadic planning, we continuously tracked the eye-movements as a direct measure of the spatial attention during retrieval from a verbal WM sequence. Participants memorized a sequence of auditory numbers. During retention, they heard a number-cue that did or did not belong to the memorized set. After this number-cue, a target-beep could be presented to which they had to respond if the number-cue belonged to the memorized sequence. In Experiment 1, the target-beep was either presented to the left or right ear, and in Experiment 2 bilaterally (removing any spatial aspect). We tested the hypothesis that systematic eye-movements are made when people retrieve items of sequences of auditory words and found that the retrieval of begin items resulted in leftward eye-movements and the retrieval of end items in rightward eye-movements. These observations indicate that the oculomotor system is also involved in the serial order processes in verbal WM thereby providing a promising novel approach to get insight into abstract cognitive processes.

We test predictions from the language emergent perspective on verbal working memory that lexico-syntactic constraints should support both item and order memory. In natural language, long-term knowledge of lexico-syntactic patterns involving part of speech, verb biases, and noun animacy support language comprehension and production. In three experiments, participants were presented with randomly generated dative-like sentences or lists in which part of speech, verb biases, and animacy of a single word were manipulated. Participants were more likely to recall words in the correct position when presented with a verb over a noun in the verb position, a good dative verb over an intransitive verb in the verb position, and an animate noun over an inanimate noun in the subject noun position. These results demonstrate that interactions between words and their context in the form of lexico-syntactic constraints influence verbal working memory.

Previous studies have shown that psycholinguistic effects such as lexico-semantic knowledge effects mainly determine item recall in verbal working memory (WM). However, we may expect that syntactic knowledge, involving knowledge about word-level sequential aspects of language, should also impact serial-order aspects of recall in WM. Evidence for this assumption is scarce and inconsistent and has been conducted in language with deterministic syntactic rules. In languages such as French, word position is determined in a probabilistic manner: an adjective is placed before or after a noun, depending on its lexico-semantic properties. We exploited this specificity of the French language for examining the impact of syntactic positional knowledge on both item and serial order recall in verbal WM. We presented lists with adjective–noun pairs for immediate serial recall, the adjectives being in regular or irregular position relative to the nouns. We observed increased recall performance when adjectives occurred in regular position; this effect was observed for item recall but not order recall scores. We propose an integration of verbal WM and syntactic processing models to account for this finding by assuming that the impact of syntactic knowledge on serial-order WM recall is indirect and mediated via syntax-dependent item-retrieval processes.

In this study, we examined the impact of concurrent verbal and visuospatial working memory demands on performance of a visuospatial successive target detection task. Three hundred and four participants performed a visuospatial vigilance task while simultaneously performing either a spatial or verbal working memory task that either required a memory load during the vigil or did not require a memory load during the vigil. Perceptual sensitivity A ′ to vigilance target stimuli was reduced by concurrent memory load, both verbal and visuospatial. The decline in perceptual sensitivity to vigilance targets, the vigilance decrement, was steeper for a visuospatial memory task than a verbal memory task, regardless of concurrent memory load. Memory performance after vigilance detection trials was much lower for visuospatial than verbal items, even though memory performance before vigilance detection trials was higher for visuospatial than verbal items. Together, this indicates increased interference when a visuospatial vigilance task is paired with a visuospatial memory task, than when paired with a verbal memory task. Overall, the visuospatial and verbal working memory loads both impacted vigilance target detection, suggesting utilization of common executive resources. There may, however, be domain specific interference, and this may be exacerbated for two visuospatial tasks.