Working Memory In Schizophrenia Research Articles

Spatial and non-spatial feature binding impairments in visual working memory in schizophrenia

Working memory (WM) impairments are well recognized in schizophrenia patients (PSZ) and contribute to poor psycho-social outcomes in this population. Distinct neural networks underlay the ability to encode and recall visual and spatial information raising the possibility that profile of visual working memory performance may help pinpoint dysfunctional neural correlates in schizophrenia. This study assessed the resolution and associative aspects of visual working memory deficits in schizophrenia and whether these deficits arise during encoding or maintenance processes. A total of 60 participants (30 PSZ and 30 healthy controls) matched in age, gender and education assessed on a modified object in place (OiPT), a delayed non-match-to-sample (DNMST) and a delayed spatial estimation (DSET) task. Patients demonstrated lower accuracy than controls in binding visual features of the same object and recognizing novel objects as well as lower precision recalling the location of a memorized target. Moreover, response choice set size affected recognition accuracy more in PSZ than controls. However, delay duration affected spatial recall precisions, binding, and recognition accuracy equally in the two groups. Our results suggest that visual working memory (vWM) impairments in schizophrenia predominantly reflect spatial and non-spatial binding deficits, with largely preserved discrete feature information. Moreover, these impairments likely arise more during encoding than during maintenance. These binding deficits may reflect impaired effective neural functional connectivity observed in schizophrenia.

Left prefrontal transcranial direct-current stimulation reduces symptom-severity and acutely enhances working memory in schizophrenia

Recent studies indicated that left dorsolateral prefrontal cortex (DLPFC) transcranial direct current stimulation (tDCS) may improve clinical status and cognitive functioning in schizophrenia patients.The current study examined the effects of left prefrontal anodal tDCS on symptom-severity and on working memory performance in schizophrenia (SZ) patients. We conducted a double-blind, randomized sham-controlled parallel-group trial. Following baseline clinical and WM assessments, 19 chronic SZ patients were randomly assigned to receive 10 sessions of either active left dorsolateral prefrontal cortex (DLPFC) tDCS or sham DLPFC-tDCS across five consecutive days, followed by post-tDCS assessments every four weeks across 12 weeks. Active tDCS significantly alleviated symptom-severity versus baseline and versus sham tDCS. WM-performance improved versus baseline in the active tDCS group. Patients' symptom alleviation was maintained for four weeks after tDCS intervention. Patients' Post-tDCS WM scores were comparable to healthy controls' WM scores. The present findings highlight the benefits of left-prefrontal tDCS interventions and support the association between DLPFC dysfunction and symptom-severity in schizophrenia.

Alternations of the effective connectivity during working memory in Schizophrenia: Dynamic causal modeling of EEG

Alternations of the effective connectivity during working memory in Schizophrenia: Dynamic causal modeling of EEG

Brain Abnormalities in Different Phases of Working Memory in Schizophrenia

The current study aimed to examine both gray matter and functional activity changes in schizophrenia by combing both structural and task-related functional magnetic resonance imaging (fMRI). Nineteen patients with schizophrenia and 17 controls were recruited. The fMRI scan was performed while performing a working memory (WM) task. In terms of task performance, accuracy did not differ between groups, but there were significant differences in reaction time. Compared with controls, patients exhibited decreased functional activation in prefrontal areas, insula, lingual gyrus, and superior temporal gyrus during different phases of WM. The subcallosal cortex showed increased activation. Intriguingly, a structural-functional correlation was found in the left dorsolateral prefrontal cortex, anterior cingulate cortex, and subcallosal cortex in patients when performing high-load WM task. This study demonstrated both impaired gray matter volume and functional activation during WM in schizophrenia, suggesting structural and functional impairments. The structural-functional correlation in schizophrenia suggested that structural damage in schizophrenia might induce a decreased ability to modulate functional response in accordance with increasing task difficulty.

Effects of reward on spatial working memory in schizophrenia.

Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Improving working memory in schizophrenia: Effects of 1 mA and 2 mA transcranial direct current stimulation to the left DLPFC

Deficits in various cognitive processes, such as working memory, are characteristic for schizophrenia, lowering patients' functioning and quality of life. Recent research suggests that transcranial direct stimulation (tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) may be a potential therapeutic intervention for cognitive deficits in schizophrenia. Here, we examined the effects of online tDCS to the DLPFC on working memory (WM) performance in 40 schizophrenia patients in two separate experiments with a double blind, sham-controlled, cross-over design. Patients underwent single sessions of active and sham tDCS in a randomized order. Stimulation parameters were anode F3, cathode right deltoid muscle, 21 min tDCS duration, 1 mA tDCS in Experiment 1 (N = 20) and 2 mA tDCS in Experiment 2 (N = 20). Primary outcome was the change in WM performance as measured by a verbal n-back paradigm (1- to 3-back). Irrespective of the stimulation intensity, data analysis showed a significant higher WM accuracy during active tDCS than during sham tDCS (p = 0.019), but no main effect of stimulation intensity (p = 0.392). Subsequent separate analyses revealed a significantly improved WM performance only during 1 mA (p = 0.048). TDCS facilitated WM functioning in schizophrenia, with an advantage of 1 mA over 2 mA. Our results support the notion that tDCS may be a potential treatment for cognitive deficits in schizophrenia and emphasize the need for future research on the specific stimulation parameters.

Abnormal cortical neural synchrony during working memory in schizophrenia

ObjectiveTo better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information. MethodsWe examined time–frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM−related hemodynamic responses and individualized structural head-models. ResultsCompared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM−load or duration. During encoding, PSZ had early theta and delta event-related synchrony (ERS) deficits in prefrontal and visual cortices which worsened with greater memory load and predicted WM performance. During prolonged maintenance of material, PSZ showed deficient beta event-related desynchrony (ERD) in dorsolateral prefrontal, posterior parietal, and visual cortices. In retrieval, PSZ showed reduced delta/theta ERS in the anterior prefrontal and ventral visual cortices and diminished gamma ERS in the premotor and posterior parietal cortices. ConclusionsAlthough beta/gamma cortical neural oscillatory deficits for maintenance/retrieval are evident during WM, the abnormal prefrontal theta-frequency ERS for encoding is most predictive of poor WM in schizophrenia. SignificanceTime-frequency-spatial analysis identified process- and frequency-specific neural synchrony abnormalities underlying WM deficits in schizophrenia.

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia.

Association of White Matter With Core Cognitive Deficits in Patients With Schizophrenia

Efforts to remediate the multiple cognitive function impairments in schizophrenia should consider white matter as one of the underlying neural mechanisms. To determine whether altered structural brain connectivity is responsible for 2 of the core cognitive deficits in schizophrenia- reduced information processing speed and impaired working memory. This cross-sectional study design took place in outpatient clinics from August 1, 2004, to August 31, 2015. Participants included 166 patients with schizophrenia and 213 healthy control individuals. These participants were from 3 independent cohorts, each of which had its own healthy control group. No participant had current or past neurological conditions or major medical conditions. Patients were diagnosed with either schizophrenia or schizoaffective disorder as defined by the DSM-IV. Controls had no Axis I psychiatric disorder. Mediation analyses and structural equation modeling were used to analyze the associations among processing speed, working memory, and white matter microstructures. Whole-brain and regional diffusion tensor imaging fractional anisotropy were used to measure white matter microstructures. Of the study participants, the 166 patients with schizophrenia had a mean (SD) age of 38.2 (13.3) years and the 213 healthy controls had a mean (SD) age of 39.2 (14.0) years. There were significantly more male patients than controls in each of the 3 cohorts (117 [70%] vs 91 [43%]), but there were no significant differences in sex composition among the 3 cohorts. Patients had significantly reduced processing speed (Cohen d = 1.24; P = 6.91 × 10-30) and working memory deficits (Cohen d = 0.83; P = 1.10 × 10-14) as well as a significant whole-brain fractional anisotropy deficit (Cohen d = 0.63; P = 2.20 × 10-9). In schizophrenia, working memory deficit was mostly accounted for by processing speed deficit, but this deficit remained when accounting for working memory (Cohen d = 0.89; P = 2.21 × 10-17). Mediation analyses showed a significant association pathway from fractional anisotropy to processing speed to working memory (P = 5.01 × 10-7). The strength of this brain-to-cognition pathway in different white matter tracts was strongly associated with the severity of schizophrenia-associated fractional anisotropy deficits in the corresponding white matter tracts as determined by a meta-analysis (r = 0.85-0.94; all P < .001). The same pattern was observed in patients and controls either jointly or independently. Study findings suggest that (1) processing speed contributes to the association between white matter microstructure and working memory in schizophrenia and (2) white matter impairment in schizophrenia is regional tract-specific, particularly in tracts normally supporting processing speed performance.

Verbal working memory in schizophrenia: The role of syntax in facilitating serial recall

BackgroundDeficits in verbal working memory (VWM) have consistently been observed in schizophrenia, ranging from impairments in capacity, encoding, to irregular semantic organisation. However, syntactic deficits are less well-characterised, despite its crucial role in language construction. This study examines the role of simple syntactic structure (basis of the “sentence superiority effect”) in VWM of patients with psychotic disorders. MethodsPatients with schizophrenia-spectrum disorders (n=40) and healthy controls matched on age, sex and education (n=40) were administered an auditory serial recall task containing word lists with low semantic coherence and either syntactically familiar structure (noun-verb-noun sequence) or syntactically unfamiliar structure. Other neurocognitive measures, symptoms and social functioning of patients were also assessed. ResultsA 4-way analysis of variance (group×version×list type×serial position) indicated that patients had significantly worse performance overall, suggesting a generalised verbal memory impairment. In addition, a significant interaction was found for list type and Group, demonstrating that healthy controls, but not patients, had superior performance in syntactically familiar word lists. A subgroup analysis of high-performing patients revealed that the interaction was not an artefact of poor verbal memory, but a selective deficit in syntactic facilitation. ConclusionsOur findings may suggest segregated mechanisms for maintenance and computational aspects of VWM, and show that even simple syntactic structure facilitates recall of syntactically unfamiliar words lists. Additionally, schizophrenic patients show difficulty utilising syntactic information, which highlights the need to understand the neuropsychological basis of working memory and linguistic impairments in psychosis.

Prefrontal dysconnectivity links to working memory deficit in first-episode schizophrenia.

Working memory (WM) deficit is a core feature of schizophrenia and is characterized by abnormal functional integration in the prefrontal cortex, including the dorsolateral prefrontal cortex (dLPFC), dorsal anterior cingulate cortex (dACC), and ventrolateral prefrontal cortex (vLPFC). However, the specific mechanism by which the abnormal neuronal circuits that involve these brain regions contribute to this deficit is still unclear. Therefore, this study focused on these regions and sought to answer which abnormal causal relationships in these regions can be linked to impaired WM in schizophrenia. We used spectral dynamic causal modeling to estimate directed (effective) connectivity between these regions based on resting-state functional magnetic resonance imaging data from healthy control (HC) subjects and patients with first-episode schizophrenia (FES). By comparing these effective connections in the controls and patients, we found that the effective connectivity from the dACC to the dLPFC and from the right dLPFC to the left vLPFC was weaker in the FES group than in the HC group. Furthermore, these effective connections displayed a positive correlation with WM performance in the HCs. However, in the FES patients, the effective connectivity from the dACC to the dLPFC was not correlated with WM performance, and the effective connectivity from the right dLPFC to the left vLPFC was negatively correlated with WM performance. These results could be explained by an aberrant top-down mechanism of WM processing and provide new evidence for the dysconnectivity hypothesis of schizophrenia.

Impaired retrieval processes evident during visual working memory in schizophrenia

Prominent working memory (WM) deficits have been observed in people with schizophrenia (PSZ) across multiple sensory modalities, including the visuospatial realm. Electrophysiological abnormalities noted during early visual processing as well as later cognitive functions in PSZ may underlie deficiencies in WM ability, though the mechanisms linking behavior to neural responses are not well understood. WM dysfunction has also been observed in biological relatives of PSZ (REL) and therefore may be a manifestation of genetic liability for the disorder. We administered a delayed response visuospatial WM task to 23 PSZ, 30 of their REL, and 37 healthy controls (CTRL) to better understand the contributions of neural abnormalities to WM performance deficits associated with schizophrenia. PSZ performed more poorly on the WM task and failed to effectively process distractor stimuli as well as CTRL and REL. N1 electrophysiological responses to probes during retrieval differentiated the type and locations of stimuli presented during encoding in CTRL. Retrieval N1 responses in PSZ, however, failed to do so, while retrieval responses in REL showed more pronounced differentiation of stimulus features during encoding. Furthermore, neural responses during retrieval predicted behavioral performance in PSZ and REL, but not CTRL. These results suggest that retrieval processes are particularly important to efficient visuospatial WM function in PSZ and REL, and support further investigation of WM retrieval as a potential target for improving overall WM function through clinical intervention.

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.

Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia. The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia.

The effect of transcranial Direct Current Stimulation on gamma activity and working memory in schizophrenia

Working memory impairments in schizophrenia have been strongly associated with abnormalities in gamma oscillations within the dorsolateral prefrontal cortex (DLFPC). We recently published the first ever study showing that anodal transcranial Direct Current Stimulation (tDCS) to the left DLPFC was able to significantly improve working memory performance in schizophrenia. In the current paper we present a secondary analysis from this study, specifically looking at the effect of tDCS on gamma activity and its relationship to working memory. In a repeated measures design we assessed the impact of anodal tDCS (1mA, 2mA, sham) on gamma activity in the left DLPFC at three time-points post-stimulation (0min, 20min, 40min). EEG data was available for 16 participants in the 2mA condition, 13 in the 1mA condition and 12 in the sham condition. Following 2mA stimulation we found a significant increase in gamma event-related synchronisation in the left DLPFC, this was in the context of a significantly improved working memory performance. There was also a significant decrease in gamma event-related synchronisation, with no changes in working memory, following sham stimulation. The current study provides preliminary evidence that tDCS may enhance working memory in schizophrenia by restoring normal gamma oscillatory function.

Cholinergic and Anticholinergic Balances Affect Working Memory in Schizophrenia

Impaired working memory, a core feature of schizophrenia, is not significantly improved by clozapine or other antipsychotics and is hypothesized to

Hippocampal place cell and inhibitory neuron activity in disrupted-in-schizophrenia-1 mutant mice: implications for working memory deficits.

Background:Despite the prevalence of working memory deficits in schizophrenia, the neuronal mechanisms mediating these deficits are not fully understood. Importantly, deficits in spatial working memory are identified in numerous mouse models that exhibit schizophrenia-like endophenotypes. The hippocampus is one of the major brain regions that actively encodes spatial location, possessing pyramidal neurons, commonly referred to as ‘place cells’, that fire in a location-specific manner. This study tests the hypothesis that mice with a schizophrenia-like endophenotype exhibit impaired encoding of spatial location in the hippocampus.Aims:To characterize hippocampal place cell activity in mice that exhibit a schizophrenia-like endophenotype.Methods:We recorded CA1 place cell activity in six control mice and six mice that carry a point mutation in the disrupted-in-schizophrenia-1 gene (Disc1-L100P) and have previously been shown to exhibit deficits in spatial working memory.Results:The spatial specificity and stability of Disc1-L100P place cells were similar to wild-type place cells. Importantly, however, Disc1-L100P place cells exhibited a higher propensity to increase their firing rate in a single, large location of the environment, rather than multiple smaller locations, indicating a generalization in their spatial selectivity. Alterations in the signaling and numbers of CA1 putative inhibitory interneurons and decreased hippocampal theta (5–12 Hz) power were also identified in the Disc1-L100P mice.Conclusions:The generalized spatial selectivity of Disc1-L100P place cells suggests a simplification of the ensemble place codes that encode individual locations and subserve spatial working memory. Moreover, these results suggest that deficient working memory in schizophrenia results from an impaired ability to uniquely code the individual components of a memory sequence.Supplementary informationThe online version of this article (doi:10.1038/npjschz.2015.11) contains supplementary material, which is available to authorized users.

Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study: The moderating role of smoking status and antipsychotic medications

ObjectivesWorking memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. MethodsFrom 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter–number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. ResultsSchizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. ConclusionsResults confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke.

Is there a binding deficit in working memory in patients with schizophrenia? A meta-analysis

In schizophrenia (SZ), a specific binding deficit in working memory (WM) has not yet been demonstrated, given that studies with various methodologies were conducted and the results obtained were heterogeneous. Thus, a meta-analysis of 10 WM studies was performed. Effect sizes were calculated for binding and control conditions. Analyses disclosed significantly lower scores in SZ patients relative to controls for both binding and control conditions. In addition, analyses revealed no greater impairments for the binding condition than for the control condition in SZ patients. Our meta-analysis suggests that there is no specific deficit of binding in WM in SZ.

Differential impairments of episodic and working memory in schizophrenia, bipolar disorder and ADHD

Differential impairments of episodic and working memory in schizophrenia, bipolar disorder and ADHD

Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.

Early in development, GABA, an inhibitory neurotransmitter in adults, is excitatory. NKCC1 (SLC12A2) encodes one of two cation chloride cotransporters mediating the conversion of GABA from excitatory to inhibitory. Using 3' and 5' RACE and PCR, we verified previously characterized alternative transcripts of NKCC1a (1-27) and NKCC1b (1-27(Δ21)), identified new NKCC1 transcripts, and explored their expression patterns during human prefrontal cortical development. A novel ultra-short transcript (1-2a) was expressed preferentially in the fetus. Expression of NKCC1b and 1-2a were decreased in schizophrenia compared with controls (NKCC1b: 0.8-fold decrease, p = 0.013; 1-2a: 0.8-fold decrease, p = 0.006). Furthermore, the expression of NKCC1b was associated with NKCC1 polymorphism rs3087889. The minor allele at rs3087889, associated with reduced NKCC1b expression (homozygous for major allele: N = 37; homozygous for minor allele: N = 15; 1.5-fold decrease; p < 0.01), was also associated with a modest increase in schizophrenia risk in a case-control sample (controls: N = 435; cases: N = 397, OR = 1.5). This same allele was then found associated with cognitive (n = 369) and fMRI (n = 313) intermediate phenotypes associated with schizophrenia-working memory (Cohen's d = 0.35), global cognition or g (d = 0.18), and prefrontal inefficiency (d = 0.36) as measured by BOLD fMRI during a working memory task. Together, these preclinical and clinical results suggest that variation in NKCC1 may increase risk for schizophrenia via alterations of mRNA expression at the molecular level and impairment of optimal prefrontal function at the macro or systems level.