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

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.     

Abnormal cortical neural synchrony during working memory in schizophrenia

Objective

To 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.

Transient and executive function working memory in schizophrenia

Transient working memory requires attention and temporary storage of information, whereas executive function working memory requires additional mental manipulation of that information. Working memory impairment is common in schizophrenia patients, but only some studies have found differential impairment in executive function working memory compared to transient working memory. We measured both types of working memory using the Digit Span forward (DF) and backward (DB) tasks in a large sample of schizophrenia patients (n=267) and normal comparison subjects (n=82); in the patients, we also examined associations between performance on the Digit Span tasks and Letter-Number Sequencing (LNS), a putative executive function working memory test. Compared to healthy subjects, the schizophrenia patients showed impairment in the medium effect size range on both DF (d=-0.55) and DB (d=-0.68). DB scores predicted LNS performance, whereas DF scores did not. Worse negative symptoms were associated with worse performance on DF, DB and LNS. These results do not reflect differential executive function working memory dysfunction in schizophrenia, but appear to support transient and executive function working memory as separable constructs.     

Cooperative processing in primary somatosensory cortex and posterior parietal cortex during tactile working memory

In the present study, causal roles of both the primary somatosensory cortex (SI) and the posterior parietal cortex (PPC) were investigated in a tactile unimodal working memory (WM) task. Individual magnetic resonance imaging‐based single‐pulse transcranial magnetic stimulation (spTMS) was applied, respectively, to the left SI (ipsilateral to tactile stimuli), right SI (contralateral to tactile stimuli) and right PPC (contralateral to tactile stimuli), while human participants were performing a tactile‐tactile unimodal delayed matching‐to‐sample task. The time points of spTMS were 300, 600 and 900 ms after the onset of the tactile sample stimulus (duration: 200 ms). Compared with ipsilateral SI, application of spTMS over either contralateral SI or contralateral PPC at those time points significantly impaired the accuracy of task performance. Meanwhile, the deterioration in accuracy did not vary with the stimulating time points. Together, these results indicate that the tactile information is processed cooperatively by SI and PPC in the same hemisphere, starting from the early delay of the tactile unimodal WM task. This pattern of processing of tactile information is different from the pattern in tactile‐visual cross‐modal WM. In a tactile‐visual cross‐modal WM task, SI and PPC contribute to the processing sequentially, suggesting a process of sensory information transfer during the early delay between modalities.     

Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex

Neuroimaging studies in humans have shown that different working memory (WM) tasks recruit a common bilateral fronto-parietal cortical network. Animal studies as well as neuroimaging studies in humans have suggested that this network, in particular the prefrontal cortex, is preferentially recruited when material from different domains (e.g. spatial information or verbal/object information) has to be memorized. Early imaging studies have suggested qualitative dissociations in the prefrontal cortex for spatial and object/verbal WM, either in a left-right or a ventral-dorsal dimension. However, results from different studies are inconsistent. Moreover, recent fMRI studies have failed to find evidence for domain dependent dissociations of WM-related activity in prefrontal cortex. Here we present evidence from two independent fMRI studies using physically identical stimuli in a verbal and spatial WM task showing that domain dominance for WM does indeed exist, although only in the form of quantitative differences in activation and not in the form of a dissociation with different prefrontal regions showing mutually exclusive activation in different domains. Our results support a mixed dimension model of domain dominance for WM within the prefrontal cortex, with left ventral prefrontal cortex (PFC) supporting preferentially verbal WM and right dorsal PFC supporting preferentially spatial WM. The concept of domain dominance is discussed in the light of recent theories of prefrontal cortex function.     

Abnormal frontal and parietal activity during working memory updating in post-traumatic stress disorder

This study used event-related potentials (ERPs) to investigate the timing and scalp topography of working memory in post-traumatic stress disorder (PTSD). This study was designed to investigate ERPs associated with a specific working memory updating process. ERPs were recorded from 10 patients and 10 controls during two visual tasks where (a) targets were a specific word or (b) targets were consecutive matching words. In the first task, nontarget words are not retained in working memory. In the second task, as in delay-match-to-sample tasks, a non-target word defines a new target identity, so these words are retained in working memory. This working memory updating process was related to large positive ERPs over frontal and parietal areas at 400-800 ms, which were smaller in PTSD. Estimation of cortical source activity indicated abnormal patterns of frontal and parietal activity in PTSD, which were also observed in regional cerebral blood flow [Clark, C.R., McFarlane, A.C., Morris, P., Weber, D.L., Sonkkilla, C., Shaw, M., Marcina, J., Tochon-Danguy, H., Egan, G., 2003. Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study. Biological Psychiatry 53, 474-481]. Frontal and parietal cortex are known to be involved in distributed networks for working memory processes, interacting with medial temporal areas during episodic memory processes. Abnormal function in these brain networks helps to explain everyday concentration and memory difficulties in PTSD.     

Dimensions of working memory dysfunction in schizophrenia

The aim of this study was to investigate the underlying structure of eight working memory tests used to assess prefrontal dysfunction in schizophrenia research [Letter-Number Span (LNS), Digit-Symbol Test (DST), Trail-Making Test B (TMT-B), Delayed Response Task (DRT) for spatial working memory, Subject Ordered Pointing Task (SOPT), Dual Tasking (DUAL), Continuous Performance Test (CPT)-Identical Pairs, Wisconsin Card Sorting Test (WCST)]. Sixty-six patients with schizophrenia showed significant working memory performance deficits in all tests when compared with 45 healthy controls. Performance was not systematically related to psychopathology. When differences in IQ were controlled, working memory deficits remained stable except in the WCST. Principal components analyses yielded three components for healthy controls: a comparator function of the central executive defined by a comparison of working memory content with information from the environment, an allocation of attentional resources function, and a maximum storage capacity function. The comparator and maximum storage functions could be replicated in the schizophrenia sample. However, the allocation function did not emerge as an independent component and was replaced by a component defined by the WCST. These findings suggest that working memory is not a unitary concept but rather should be conceptually differentiated as functions of transient storage/active rehearsal capacity and central executive manipulation supporting a previous suggestion proposed by Perry et al. [Schizophr. Bull. 27 (2001) 157].     

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.     

Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia.

BACKGROUND: Schizophrenic patients show deficits in working memory (WM) and inhibition of prepotent responses. We examined brain activity while subjects performed tasks that placed demands on WM and overriding prepotent response tendencies, testing predictions that both processes engage overlapping prefrontal cortical (PFC) regions and that schizophrenic patients show reduced PFC activity and performance deficits reflecting both processes. METHODS: Functional magnetic resonance imaging data were acquired while 16 schizophrenic and 15 healthy subjects performed the N-Back task that varied WM load and a version of the AX-CPT that required overriding a prepotent response tendency. RESULTS: Both tasks engaged overlapping cortical networks (e.g., bilateral dorsolateral PFC, Broca's area, parietal cortex). Increased WM load monotonically increased activity; preparation to override a prepotent response produced greater and more enduring activity. Group differences on each task emerged in a right dorsolateral PFC region: schizophrenic subjects showed lesser magnitude increases under conditions of high WM and prepotent response override demands, with concomitant performance impairments. CONCLUSIONS: Schizophrenic patients exhibit PFC-mediated deficits in WM and preparation to override prepotent responses. Findings are consistent with the operation of a single underlying PFC-mediated cognitive control mechanism and with physiologic dysfunction of the dorsolateral PFC in schizophrenic patients reflecting impairments in this mechanism.     

Differential activation of ventrolateral prefrontal cortex during working memory retrieval

Brain imaging studies have suggested a predominant involvement of prefrontal areas during retrieval of information from working memory (WM). This study used event-related functional magnetic resonance imaging to assess the gradual recruitment of brain areas during verbal WM-retrieval with a parametrically varied modified version of the Sternberg Item Recognition Paradigm. In particular, we were interested in activation differences during retrieval of negative and positive probes. Fifteen subjects performed a WM-task which required the retrieval of a probe letter from a set of a maximum of three letters. The analysis of the retrieval period regardless of probe type revealed bilateral VLPFC activation during retrieval from a single remembered item. These initially activated regions showed a gradual activation increase of left VLPFC (BA 47) and anterior PFC (BA 10) as well as and bilateral DLPFC (BA 9) with increasing retrieval demand, i.e. during retrieval of two and three previously remembered letters. The comparison of negative and positive probes (non-targets versus targets) revealed greater activity in VLPFC (BA 47) in response to negative than to positive probes. These findings demonstrate that ventral areas of prefrontal cortex seem to be differentially engaged during the discrimination of a non-target from a previously manipulated set.     

Verbal working memory dysfunction in schizophrenia: an FMRI investigation

Impaired processing of working memory information is one of the cognitive deficits seen in patients with schizophrenia. This study aims at corroborating the differences in the brain activities involved in the process of working memory between patients with schizophrenia and the controls. Twelve patients with schizophrenia and 11 controls participated in the study. Functional magnetic resonance imaging (fMRI) was used to assess cortical activities during the performance of a two-back verbal working memory paradigm using the Korean alphabet as mnemonic content. Group analysis revealed that inferior fontal, middle frontal, and superior temporal region showed decreased cortical activities in the patient group compared to those of the controls. This study showed a decreased activation in inferior fontal (BA 47), middle frontal (BA 6), and superior temporal (BA 22/38) neural networks from the patient group and confirmed the earlier findings on the impaired working memory of schizophrenic patients in the fMRI investigation.     

Lateral inferotemporal cortex maintains conceptual-semantic representations in verbal working memory

Verbal working memory, that is, the temporary maintenance of linguistic information in an activated state, is typically assumed to rely on phonological representations. Recent evidence from behavioral, neuropsychological, and electrophysiological studies, however, suggests that conceptual-semantic representations may also be maintained in an activated state. We developed a new semantic working memory task that involves the maintenance of a novel conceptual combination. Functional magnetic resonance imaging data acquired during the maintenance of conceptual combinations, relative to an item recognition task without the possibility of conceptual combination, demonstrate increased activation in the posterior left middle and inferior temporal gyri (known to be involved in conceptual representations) and left inferior frontal gyrus (known to be involved in semantic control processes). We suggest that this temporo-frontal system supports maintenance of conceptual information in working memory, with the frontal regions controlling the sustained activation of heteromodal conceptual representations in the inferior temporal cortex.     

Brain activation during executive processes in schizophrenia

Schizophrenia patients show some deficits in executive processes (impaired behavioural performance and abnormal brain functioning). The aim of this study is to explore the brain activity of schizophrenia patients during different inhibitory tasks. We used functional magnetic resonance imaging to investigate to investigate the restraint and deletion aspects of inhibition in 19 patients with schizophrenia and 12 normal subjects during the performance of the Hayling and the N-back tasks. The patients demonstrated impaired performance (more errors and longer reaction times) in the Hayling task. Schizophrenia subjects activated the same fronto-parietal network as the control subjects but demonstrated stronger parietal activations. For the N-back task, the deficit shown by the patients was limited to the number of target omissions. The reaction times and the number of false alarms did not differ in the two groups. We interpret this pattern of deficit as an alteration of working memory processes (and unaltered inhibition). Schizophrenia subjects showed higher activations in a fronto-parietal network. Since schizophrenia patients reached normal inhibitory performances in the N-back task and not in the Hayling task, the frontal hyperactivation may reflect an increased effort or a compensatory mechanism that facilitates the performance of executive tasks. During the Hayling task, this frontal hyperactivation was not achieved, and its absence was associated with a performance deficit relative to the performance of normal subjects.     

Abnormal neural response to phonological working memory demands in persistent developmental stuttering

Persistent developmental stuttering is a neurological disorder that commonly manifests as a motor problem. Cognitive theories, however, hold that poorly developed cognitive skills are the origins of stuttering. Working memory (WM), a multicomponent cognitive system that mediates information maintenance and manipulation, is known to play an important role in speech production, leading us to postulate that the neurophysiological mechanisms underlying stuttering may be associated with a WM deficit. Using functional magnetic resonance imaging, we aimed to elucidate brain mechanisms in a phonological WM task in adults who stutter and controls. A right‐lateralized compensatory mechanism for a deficit in the rehearsal process and neural disconnections associated with the central executive dysfunction were found. Furthermore, the neural abnormalities underlying the phonological WM were independent of memory load. This study demonstrates for the first time the atypical neural responses to phonological WM in PWS, shedding new light on the underlying cause of stuttering.     

Diagnosis-specific effect of familial loading on verbal working memory in schizophrenia

Background  Working memory disturbances are a frequently replicated finding in schizophrenia and less consistent also in schizoaffective disorder. Working memory dysfunctions have been shown to be heritable and have been proposed to represent a promising endophenotype of schizophrenic psychoses. Methods   In the present study, we investigated the effects of familial loading on performance rates in circuit-specific verbal and visuospatial working memory tasks in matched samples of schizophrenic patients (from multiply affected or uniaffected families), schizoaffective patients (from multiply affected or uniaffected families), and healthy subjects. Results  We found a significant interaction effect between familial loading and diagnosis in terms of a diagnosis-specific detrimental effect of familial loading on the performance of schizophrenic (but not schizoaffective) patients in the articulatory rehearsal task. Conclusion  This finding of a circuit-specific verbal working memory deficit in schizophrenic patients with additional familial loading is consistent with prior studies, which provided evidence for the existence of specific subgroups of schizophrenic patients with selective working memory impairments and for diagnosis-specific dysfunctions of the articulatory rehearsal mechanism in schizophrenic, but not in schizoaffective patients. Together, these findings suggest that the genetic risk for (a subtype of) schizophrenia may be associated with dysfunctions of the brain system, which underlies the articulatory rehearsal mechanism, the probably phylogenetically youngest part of human working memory.     

Impact of executive dysfunction on verbal memory performance in patients with Alzheimer's disease

It is currently accepted that there is a subset of patients diagnosed with Alzheimer's disease (AD) who show executive functioning (EF) impairments even in the earlier stages. These patients have been shown to present distinct psychiatric, behavioral, occupational, and even histopathological profiles. We assessed thirty patients with AD on two tasks of verbal memory (Logical Memory - LM, and the Rey Auditory-Verbal Learning Task - RAVLT), as well as classical tests of EF. AD patients were classified into either a spared EF (SEF) group if they showed impaired performance (z < -1.5 SD) in none or only one of the executive tests, or into an impaired EF (IEF) group if they showed impaired performance on two or more tasks of EF. Their performance was compared with fourteen healthy controls. SEF showed significantly more years of education than IEF, but the groups did not differ significantly on age, gender, mood symptoms, or performance on general screening tests or attentional tasks. With education as a covariate, both AD groups differed from controls on all measures of memory, but a significant difference was found between SEF and IEF patients only on the recognition phases of both logical memory (p < 0.01) and RAVLT (p = 0.02). Recognition scores significantly correlated with performance on executive tasks. Early AD patients who preserve their EF seem to have an advantage in their ability to recognize information that has been previously presented over patients with impaired EF. Such advantage seems to be strongly associated with executive performance.     

Abnormal medial temporal activity for bound information during working memory maintenance in patients with schizophrenia

Alterations of binding in long‐term memory in schizophrenia are well established and occur as a result of aberrant activity in the medial temporal lobe (MTL). In working memory (WM), such a deficit is less clear and the pathophysiological bases remain unstudied. Seventeen patients with schizophrenia and 17 matched healthy controls performed a WM binding task while undergoing functional magnetic resonance imaging. Binding was assessed by contrasting two conditions comprising an equal amount of verbal and spatial information (i.e., three letters and three spatial locations), but differing in the absence or presence of a link between them. In healthy controls, MTL activation was observed for encoding and maintenance of bound information but not for its retrieval. Between‐group comparisons revealed that patients with schizophrenia showed MTL hypoactivation during the maintenance phase only. In addition, BOLD signals correlated with behavioral performance in controls but not in patients with schizophrenia. Our results confirm the major role that the MTL plays in the pathophysiology of schizophrenia. Short‐term and long‐term relational memory deficits in schizophrenia may share common cognitive and functional pathological bases. Our results provide additional information about the episodic buffer that represents an integrative interface between WM and long‐term memory. © 2009 Wiley‐Liss, Inc.     

Spatial working memory span,delayed response and executive function in schizophrenia

This study investigated the spatial working memory span (SWMS) as well as the immediate memory span of schizophrenic patients, and examined the contribution of each span to the patients’ executive function deficit in the visuospatial domain. SWMS measured the visuospatial working memory capacity that simultaneously processes and stores visuospatial information. Immediate memory span was measured with the spatial span (SS), a variant of Corsi's block-tapping test. A total of 16 patients diagnosed with schizophrenia and 16 normal control subjects participated in the study. SWMS, as well as the forward and backward SS, was significantly reduced in schizophrenia. The SWMS deficit observed in this study and previous findings of deficit in verbal working memory spans suggest that impairment in working memory capacity in schizophrenia is general, and not limited to the verbal domain. Executive function as assessed with the self-ordered pointing task (SOPT) was also impaired in the patients, which is consistent with clinical observations of self-monitoring impairment in schizophrenia. SWMS was able to account for the performance on the SOPT, but its contribution in the patients’ impairment did not reach statistical significance. Backward span deficit explained this executive function impairment. SWMS was effective in explaining schizophrenic patients’ impaired performance on the spatial delayed response, a prefrontal function task. Implications of the relations observed between the spans and the prefrontal function tasks are discussed.