Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings

doi:10.1016/S0920-9964(02)00294-3

Schizophrenia Research

Volume 60, Issues 2–3, 1 April 2003, Pages 285-298

https://doi.org/10.1016/S0920-9964(02)00294-3 Get rights and content

Abstract

Working memory (WM) deficits are a persistent, disabling and relatively treatment-resistant feature of schizophrenia that may underlie many cognitive deficits and symptoms. They are associated with prefrontal cortex dysfunction. While most neuroimaging studies of WM demonstrate “task-related hypofrontality” in schizophrenic relative to healthy subjects, several recent studies have reported equal or increased prefrontal activity. These findings challenge central assumptions regarding cognitive deficits and prefrontal cortex dysfunction in schizophrenia. The goal of this review is to reconcile these seemingly discrepant findings. Methodological factors addressed include the use of intersubject averaging, WM task parameters and the reliability of the measures. Factors intrinsic to schizophrenia and their relevance to the selection of experimental methods and the interpretation of group data are also discussed. Both hypo- and hyperfrontality are hypothesized to be valid and informative reflections of prefrontal cortex dysfunction in schizophrenia. Due to the heterogeneity and variability of both performance and regional recruitment in schizophrenia, whether individual data is considered, the level and type of WM demands and the composition of the sample with regard to performance deficits all influence study outcome and contribute to discrepancies. Although the prefrontal cortex is consistently implicated in WM deficits, the basis of its dysfunction and its exact contribution remain unclear. Future work might focus on delineating the exact WM processes, domains and components that are deficient. In addition, variability in behavior and activation might best be regarded as intrinsic to schizophrenia and having a neural basis that requires explanation. In combination with other techniques, neuroimaging can identify the neural circuitry responsible for WM deficits and elucidate the contribution of each anatomical component.

Section snippets

Technical issues in neuroimaging: group averaging

Findings of hypofrontality may be an artifact of methodologies that require group averaging and for this reason mask possible structural and functional heterogeneity of the DLPFC. Group comparisons in neuroimaging studies often rely on data that is averaged across the individuals within each group. Averaging is used to enhance the signal-to-noise properties of the images. Using the averaged group data, images obtained during an experimental or task state are statistically compared to those

Choice of tasks: processes, domains and components

The seminal studies that established a direct link between deficient cognition and reduced activity of the prefrontal cortex employed the Wisconsin Card Sort Test (WCST), a standard neuropsychological instrument that is sensitive to prefrontal cortex dysfunction Berman et al., 1986, Berman et al., 1992, Weinberger et al., 1986, Weinberger et al., 1988. The WCST is the most widely employed measure of executive function in schizophrenia (Green, 1998). In addition to WM, successful performance of

Performance differences: motivation and capacity

Amotivation is a prominent feature of schizophrenia and represents a possible confound in studies of cognitive performance (Schmand et al., 1994). When a subject performs poorly, it is often difficult to determine whether this reflects a true information processing deficit or that the subject was unwilling or unable to exert the effort necessary for optimal performance. In addition, tasks differ in the amount of effort required and suboptimal motivation may be more detrimental to some tasks

Measurement issues: reliability and heterogeneity

Discrepant findings call into question the reliability of fMRI findings of prefrontal cortex dysfunction in schizophrenia. Demonstrating reliability has become particularly important since some atypical antipsychotic medications (e.g., Risperidone) purportedly improve WM deficits (Green et al., 1997) and associated prefrontal dysfunction as measured by repeated fMRI studies (Honey et al., 1999) (literature reviews and commentary on the differential effects of atypical antipsychotic drugs on

A theory of WM deficits in schizophrenia: deficient automation

One speculative explanation of reduced capacity and increased variability is that schizophrenics fail to automate WM task performance. Automation refers to using experience to shape the optimal spatiotemporal pattern of activity in neural circuitry. Automation leads to increased efficiency and decreased variability of behavior. In the motor system, the DLPFC and striatum are activated while learning a task (Jueptner and Weiller, 1998). DLPFC activation is no longer present after the task

Conclusions

Findings of both hypo- and hyperfrontality during WM performance are likely valid and informative reflections of prefrontal dysfunction in schizophrenia. They are consistent with clinical and neuropsychological studies that implicate the prefrontal cortex in a range of symptoms and cognitive deficits. Whether a particular study finds hypo- or hyperfrontality may depend on a number of variables. Methodological factors include: whether individual as well as group data is considered; WM task

Acknowledgements

The author thanks Stephan Heckers, James C. Houk, Daniel Z. Press and an anonymous reviewer for their perceptive remarks and Kristen A. Lindgren for her technical assistance. Support is given by NIMH K23MH01829-01 and National Alliance for Research on Schizophrenia and Depression.

References (99)

D.M. Barch et al.
Dissociating working memory from task difficulty in human prefrontal cortex
Neuropsychologia
(1997)
T.S. Braver et al.
A parametric study of prefrontal cortex involvement in human working memory
NeuroImage
(1997)
J.H. Callicott et al.
Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia
Neuropsychopharmacology
(1998)
C. Carter et al.
Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenia patients
Biol. Psychiatry
(1996)
M. D'Esposito et al.
Functional MRI studies of spatial and nonspatial working memory
Cogn. Brain Res.
(1998)
M. D'Esposito et al.
Maintenance versus manipulation of information held in working memory: an event-related fMRI study
Brain Cogn.
(1999)
T.E. Goldberg et al.
Uncoupling cognitive workload and prefrontal cortical physiology: a PET rCBF study
NeuroImage
(1998)
J.V. Haxby et al.
Distinguishing the functional roles of multiple regions in distributed neural systems for visual working memory
NeuroImage
(2000)
S.G. Hellman et al.
Monetary reinforcement and Wisconsin Card Sorting performance in schizophrenia: why show me the money?
Schizophr. Res.
(1998)
G.D. Honey et al.
De-coupling of cognitive performance and cerebral functional response during working memory in schizophrenia
Schizophr. Res.
(2002)

K.F. Berman et al.

Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia

Arch. Gen. Psychiatry

(1992)

M.S. Buchsbaum et al.

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics

Arch. Gen. Psychiatry

(1992)

J.H. Callicott

Functional brain imaging in psychiatry

J.H. Callicott et al.

Physiological characteristics of capacity constraints in working memory as revealed by functional MRI

Cereb. Cortex

(1999)

J.H. Callicott et al.

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited

Cereb. Cortex

(2000)

C.S. Carter et al.

Functional hypofrontality and working memory dysfunction in schizophrenia

Am. J. Psychiatry

(1998)

J.D. Cohen et al.

A computational approach to prefrontal cortex, cognitive control and schizophrenia: recent developments and current challenges

Philos. Trans. R. Soc. Lond.

(1996)

J.D. Cohen et al.

Temporal dynamics of brain activation during a working memory task

Nature

(1997)

K.P. Ebmeier et al.

Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia

J. Neurol. Neurosurg. Psychiatry

(1995)

M.F. Egan et al.

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

Proc. Natl. Acad. Sci. U. S. A.

(2001)

P.C. Fletcher et al.

Frontal lobes and human memory: insights from functional neuroimaging

Brain

(2001)

H.R. Friedman et al.

Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey

J. Neurosci.

(1994)

C.D. Frith et al.

Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task

Br. J. Psychiatry

(1995)

H. Garavan et al.

Practice-related functional activation changes in a working memory task

Microsc. Res. Tech.

(2000)

T.E. Goldberg et al.

Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies

J. Clin. Psychiatry

(1996)

P. Goldman-Rakic

Prefrontal cortical dysfuntion in schizophrenia: the relevance of working memory

M.F. Green

Schizophrenia from a Neurocognitive Perspective

(1998)

M.F. Green et al.

Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit

Am. J. Psychiatry

(1992)

M.F. Green et al.

Does risperidone improve verbal working memory in treatment-resistant schizophrenia?

Am. J. Psychiatry

(1997)

M.F. Green et al.

Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”?

Schizophr. Bull.

(2000)

J.L. Holt et al.

Variability in functional neuroanatomy in schizophrenia: group vs. single-subject PET activation data

Cited by (588)

Exploratory` study on driving ability of people with schizophrenia: Relationships among cognitive function, symptoms, and brain activity
2024, Schizophrenia Research
This study aimed to examine the relationships among cognitive function, symptoms, prefrontal activation, basic driving skills, and collision risk factors using a hazard prediction task in simulated driving.
Participants included 42 people with schizophrenia aged 20–50 years who had actual experience of driving. The Trail making test (TMT) A and TMTB, Wechsler Memory Test–Revised (WMS-R), and Zoo Map test (ZMT) were used to evaluate cognitive function. Positive and negative syndrome scale was used to assess symptoms, and brain activity was assessed by evaluating cerebral blood flow during a visual working memory task using functional near-infrared spectroscopy. Driving tasks that tested basic skills, such as brake reaction, steering wheel skills, and standard deviation of lateral position, were analyzed using multiple regression analysis. Three hazard prediction tasks were performed using discriminant analysis.
Brake reaction associated with cerebral blood flow and TMT-A. Steering wheel skills associated with WMS-R, driving experience and depression. Significant differences were found between the collision and noncollision groups in the hazard prediction task, as shown by the ZMT, driving experience, and brake reaction.
Brain activity in the frontal lobe during a desk task may be useful data for driving assessment. Assessment of processing speed and learning ability may be particularly important in the evaluation of basic skills for safe driving. In addition, for people with schizophrenia, foresight, as represented by proactive planning, experience, and quick braking may be an essential characteristic to anticipate danger and react quickly enough to avoid collisions.
Effect of anticholinergic burden on brain activity during Working Memory and real-world functioning in patients with schizophrenia
2023, Schizophrenia Research
Cognitive impairment has been associated with poor real-world functioning in patients with Schizophrenia. Previous studies have shown that pharmacological treatment with anticholinergic properties may contribute to cognitive impairment in Schizophrenia. We investigated the effect of the anticholinergic burden (ACB) on brain activity, cognition, and real-world functioning in Schizophrenia. We hypothesized that greater ACB would be associated with altered brain activity along with poorer cognitive performance and lower real-world functioning. A sample of 100 patients with a diagnosis of schizophrenia or schizoaffective disorder was recruited in the naturalistic multicenter study of the Italian Network for Research on Psychoses (NIRP) across 7 centres. For each participant, ACB was evaluated using the Anticholinergic Cognitive Burden scale. The association of ACB with brain function was assessed using BOLD fMRI during the N-Back Working Memory (WM) task in a nested cohort (N = 31). Real-world functioning was assessed using the Specific Level of Functioning (SLOF) scale. Patients with high ACB scores (≥3) showed lower brain activity in the WM frontoparietal network (TFCE corrected alpha <0.05) and poorer cognitive performance (p = 0.05) than patients with low ACB scores (<3). Both effects were unaffected by demographic characteristics, clinical severity, and antipsychotic dosage. Moreover, patients with high ACB showed poorer real-world functioning than patients with lower ACB (p = 0.03). Our results suggest that ACB in Schizophrenia is associated with impaired WM and abnormal underlying brain function along with reduced real-world functioning. Clinical practice should consider the potential adverse cognitive effects of ACB in the treatment decision-making process.
Medial Prefrontal Cortex Dysfunction Mediates Working Memory Deficits in Patients With Schizophrenia
2023, Biological Psychiatry Global Open Science
Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release.
Patients with SCZ (n = 41) and healthy control participants (HCs) (n = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [¹¹C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release.
mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients.
Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC.
Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia
2023, Schizophrenia Research
Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n = 54 total, n = 28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.
Axonal transport deficits in neuropsychiatric disorders
2022, Molecular and Cellular Neuroscience
Axonal transport is a major cellular process that mediates bidirectional signaling between the soma and synapse, enabling both intracellular and intercellular communications. Cellular materials, such as proteins, RNAs, and organelles, are transported by molecular motor proteins along cytoskeletal highways in a highly regulated manner. Several studies have demonstrated that axonal transport is central to normal neuronal function, plasticity, and memory storage. Importantly, disruptions in axonal transport result in neuronal dysfunction and are associated with several neurodegenerative disorders. However, we do not know much about axonal transport deficits in neuropsychiatric disorders. Here, we briefly discuss our current understanding of the role of axonal transport in schizophrenia, bipolar and autism.
Neurohemodynamic correlates of BDNF gene expression in schizophrenia patients with working memory deficits: A functional MRI study
2022, Asian Journal of Psychiatry
Brain-derived neurotrophic factor (BDNF) is involved in neuroplasticity underlying cognitive deficits, including working memory deficits (WMD), in schizophrenia. Methodological challenges and inconsistencies are reported with peripheral BDNF levels. Left dorsolateral prefrontal cortex (DLPFC) is proposed to underlie WMD, though inconsistently. We aimed to explore the correlations between brain activation during working memory task-based functional Magnetic Resonance Imaging (fMRI) and BDNF gene expression in schizophrenia patients with WMD.
26 patients with schizophrenia with established WMD were recruited for the study. Blood samples were collected to study lymphocyte BDNF gene expression. Patients underwent task-based fMRI to examine the working memory performance and related brain activation. Whole-brain analysis was performed with 2-back > 0-back and 2-back > rest contrast. The peak intensity values of the activation were used for correlation analysis.
Whole brain analysis with 2-back > rest contrast revealed maximum activation in left DLPFC, Brodmann area 9 (t = 10.54, FWE corrected p < 0.05). The baseline BDNF gene expression correlated positively with the peak intensity of brain activation in left DLPFC (r = 0.365, p = 0.033). Negative symptom score negatively correlated with BDNF gene expression (r = −0.499, p = 0.005) and left DLPFC fMRI activation (r = −0.393, p = 0.023) respectively.
We found a significant positive association between BDNF gene expression and the activation of the DLPFC during the working memory task. This novel observation needs further systematic evaluation to establish the potential role of peripheral BDNF expression in WMD in schizophrenia.

View all citing articles on Scopus

View full text

Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings

Abstract

Section snippets

Technical issues in neuroimaging: group averaging

Choice of tasks: processes, domains and components

Performance differences: motivation and capacity

Measurement issues: reliability and heterogeneity

A theory of WM deficits in schizophrenia: deficient automation

Conclusions

Acknowledgements

Neuropsychologia

NeuroImage

Neuropsychopharmacology

Biol. Psychiatry

Cogn. Brain Res.

Brain Cogn.

NeuroImage

NeuroImage

Schizophr. Res.

Schizophr. Res.

Prog. Brain Res.

Biol. Psychiatry

Biol. Psychiatry

NeuroImage

NeuroImage

Biol. Psychiatry

NeuroImage

NeuroImage

NeuroImage

Psychiatry Res.

NeuroImage

Brain Res. Cogn. Brain Res.

Parallel organization of functionally segregated circuits linking basal ganglia and cortex

Annu. Rev. Neurosci.

Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia

Arch. Gen. Psychiatry

Rehearsal in spatial working memory: evidence from neuroimaging

Psychol. Sci.

Working memory

Science

Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia

Arch. Gen. Psychiatry

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: II. Role of neuroleptic treatment, attention, and mental effort [see comments]

Arch. Gen. Psychiatry

Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia

Arch. Gen. Psychiatry

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics

Arch. Gen. Psychiatry

Functional brain imaging in psychiatry

Physiological characteristics of capacity constraints in working memory as revealed by functional MRI

Cereb. Cortex

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited

Cereb. Cortex

Functional hypofrontality and working memory dysfunction in schizophrenia

Am. J. Psychiatry

A computational approach to prefrontal cortex, cognitive control and schizophrenia: recent developments and current challenges

Philos. Trans. R. Soc. Lond.

Temporal dynamics of brain activation during a working memory task

Nature

Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia

J. Neurol. Neurosurg. Psychiatry

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

Proc. Natl. Acad. Sci. U. S. A.

Frontal lobes and human memory: insights from functional neuroimaging

Brain

Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey

J. Neurosci.

Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task

Br. J. Psychiatry

Practice-related functional activation changes in a working memory task

Microsc. Res. Tech.

Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies

J. Clin. Psychiatry

Prefrontal cortical dysfuntion in schizophrenia: the relevance of working memory

Schizophrenia from a Neurocognitive Perspective

Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit

Am. J. Psychiatry

Does risperidone improve verbal working memory in treatment-resistant schizophrenia?

Am. J. Psychiatry

Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”?