Ivan J. Torres

Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable.

Functional neuroimaging studies in schizophrenia have demonstrated abnormal activation of dorsolateral prefrontal cortex (DLPFC) during working memory (WM) performance. However, findings of increased and decreased activity have been reported. The authors used meta-analysis to investigate whether diverging results arise as a function of differential WM task performance between patients and control participants. Results indicate that the magnitude of the group difference in WM performance is a moderator of DLPFC activation differences, and concepts such as hypo- or hyperfrontality do not universally characterize WM findings in schizophrenia. Thus, the variability in the WM activation findings between participants with schizophrenia and control participants reflects the specific conditions under which WM functions are evaluated, not just the WM construct per se.

Auditory and visual attention assessed with PET.

Brain mechanisms involved in the maintenance of attention to auditory and visual stimuli at different spatial locations were assessed using positron emission tomography with [15O]water to measure regional cerebral blood flow (rCBF) changes in 13 normal volunteers. Simultaneous auditory [dichotically presented consonant‐vowel‐consonants (CVCs)] and visual stimuli (vertically oriented, CVCs presented to the left and right of fixation) were presented on every trial. In different conditions subjects attended for targets in a specified stimulus channel (left or right ears or left or right visual fields) while maintaining fixation on a central x. Attending left or right for auditory stimuli increased rCBF in primary auditory cortex in Heschls gyrus and in temporal lobe auditory association cortices in both hemispheres. Attending left or right for visual stimuli did not change rCBF in primary visual cortex, and only attention to the right significantly increased rCBF in contralateral occipital cortex. Visual attention caused significant rCBF changes in a widespread network that included frontal, parietal, and temporal cortical regions as well as the cerebellum, whereas rCBF changes due to auditory attention were largely localized in the temporal lobes. The results suggest that spatially directed attention is mediated by different mechanisms in the auditory and visual modalities. Hum. Brain Mapping 5:422–436, 1997.

Unawareness of deficits in Alzheimer's disease and other dementias: operational definitions and empirical findings.

Individuals with dementia frequently demonstrate decreased awareness of their cognitive difficulties. Empirical research examining this phenomenon has addressed a number of aspects of unawareness in Alzheimers disease and other dementias, including occurrence in various disorders; possible neuroanatomical substrates; relationship to general cognitive functioning, executive functioning, and psychiatric symptomatology; and progression over time and across cognitive domains. Limitations of the current research literature are discussed, particularly issues surrounding operational definitions of unawareness and the current limited understanding of the role of the frontal lobes. A number of conclusions regarding unawareness that appear to be supported by the current body of empirical research and possible future directions are discussed.

Symptomatic determinants of insight in schizophrenia spectrum disorders

Impaired insight in schizophrenia spectrum disorders has been linked to several psychopathologic features including positive symptoms, although not all dimensions of psychopathology have been studied and confounds from other symptoms have not been ruled out. In addition, the nature of the association between insight and specific positive symptoms, in particular delusions, remains unclear. The present investigation examined whether, in patients with schizophrenia spectrum disorders insight is associated with specific symptom dimensions including delusional severity. The factor structure was determined from scores of 151 patients rated on the Signs and Symptoms of Psychotic Illness scale. Associations of the Signs and Symptoms of Psychotic Illness insight item with the resulting components and delusions were assessed using regression-based methodology. Principal component analysis revealed 4 orthogonal symptom clusters. Correlational analyses demonstrated that only depression/anxiety and psychomotor excitation were significantly related to insight. Hierarchical regression indicated that delusions explained unique variance in insight over and above depression/anxiety and psychomotor excitation. These results suggest that depression/anxiety is associated with better insight and that psychomotor excitation and delusions are associated with poorer insight.

Effects of retroactive and proactive interference on word list recall in schizophrenia

Schizophrenia spectrum patients (N = 143) and healthy controls (N = 160) were administered the Rey Auditory Verbal Learning Test (RAVLT) and tests of executive functioning to directly investigate the effects of proactive interference (PI) and retroactive interference (RI) on word list recall. It was hypothesized that by virtue of the predicted preferential association between executive functioning and RI (relative to PI), patients would demonstrate increased susceptibility to RI in their ability to recall word lists. Results indicated that patients show increased susceptibility to RI relative to PI. Furthermore, this difference appeared to be related to the frontally-mediated central executive functions that were preferentially associated with RI but not PI susceptibility.

Structural pathology underlying neuroendocrine dysfunction in schizophrenia

Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.

Symptoms and interference from memory in schizophrenia: evaluation of Frith's model of willed action

The present study was undertaken to test Friths [The Cognitive Neuropsychology of Schizophrenia, 1992. Erlbaum (UK) Taylor and Francis, East Sussex] model which states that certain symptoms of schizophrenia arise from diminished capacity to regulate willed (goal-directed) and stimulus-driven action systems. A total of 107 patients were administered the Rey Auditory Verbal Learning Test (RAVLT), a task that on interference trials requires individuals to recall target material while suppressing non-target distracting stimuli from memory. Symptom ratings were obtained using the SANS/SAPS [Andreasen, N.C., 1984. Scale for the Assessment of Negative Symptoms/Scale for the Assessment of Positive Symptoms [Manual] University of Iowa Press, Iowa City]. It was predicted that (1) negative symptoms would result in diminished recall, reflecting compromised activation of the willed action system, and (2) disorganized symptoms would be associated with heightened interference susceptibility resulting from diminished ability to suppress the stimulus-driven action system. Results revealed that diminished recall was related to negative, but not disorganized or positive symptoms. Symptom ratings were also evaluated in a subset of patients with intrusion error data (n=38). In this subset, it was found that patients who committed intrusion errors on the interference trials evidenced more disorganized, but not negative or positive symptoms, than individuals failing to commit such errors. These findings provide some support for Friths hypothesis that impaired regulation of action systems may underlie some of the specific symptoms and cognitive impairments of this illness.

Neuropsychological Impairment in Patients With Schizophrenia and Evidence of Hyponatremia and Polydipsia

Patients with schizophrenia and water imbalance may represent a subset of patients with distinct pathophysiological abnormalities and susceptibility to cognitive impairment. Specifically, patients with polydipsia and hyponatremia have been shown to have smaller anterior hippocampal volumes, which are also associated with various impairments in neuroendocrine function. To determine whether abnormalities in patients with water imbalance extend to the cognitive realm, the present study evaluated neuropsychological functioning in three groups of patients with schizophrenia: polydipsic hyponatremic, polydipsic normonatremic, and nonpolydipsic normonatremic. Participants were administered cognitive tests assessing intelligence, attention, learning/memory (verbal, nonverbal, emotional), and facial discrimination. Hyponatremic patients showed poorer overall neuropsychological functioning relative to all other patients, and polydipsic normonatremic patients performed intermediate to the other two groups. Results indicate that patients with schizophrenia and polydipsia, and particularly those with hyponatremia, show prominent cognitive deficits relative to patients without water imbalance. The clinical, neuroendocrine, and cognitive abnormalities in these patients may arise from pathology within the anterior hippocampus and associated prefrontal/limbic brain regions.

Preferential semantic fluency impairment is related to hallucinations, but not formal thought disorder

Semantic memory dysfunction in schizophrenia spectrum disorders has been theoretically linked primarily to formal thought disorder (FTD) and, to a lesser extent, hallucinations. Although past studies have demonstrated associations between FTD and semantic memory dysfunction, the potential influence of hallucinations and other symptoms on this association has not previously been evaluated. We investigated the relationship between semantic dysfunction and levels of schizophrenic symptoms in 75 patients with a DSM-IV diagnosis of schizophrenia/schizoaffective disorder. Symptoms were rated on a 0-5 scale using the Scale for Assessment of Positive Symptoms/Scale for Assessment of Negative Symptoms. Semantic dysfunction was quantified through a semantic/phonological fluency difference score. The vocabulary test from the Shipley Institute of Living Scale was included as a measure of pre-morbid IQ. We hypothesized a relationship between FTD and semantic dysfunction, with an alternative hypothesis being that semantic dysfunction would be related to hallucinations. The measure of semantic dysfunction was significantly correlated with level of hallucinations (r=-.35, p=.002), but not level of FTD (r=.05, p=.67). The relationship between hallucinations and semantic dysfunction remained significant after control for age and verbal intellectual ability, and after controlling for the influence of other symptoms. This finding supports theories linking a breakdown in semantic associative networks to the production of hallucinations, and suggests that past associations between formal thought disorder and semantic dysfunction may have been at least partly driven by differential levels of hallucinations between groups.

Verbal memory improvement in first-episode psychosis APOE- ε4 carriers: a pleiotropic effect?

Background Verbal memory impairment is a core feature in schizophrenia even at early stages of the disease, but its etiopathogenesis is not fully understood. The APOE-ε4 is the main genetic risk factor for late-onset Alzheimer’s disease. Our primary goal was to ascertain whether APOE-ε4 status had a pleiotropic effect in early stages of the illness. Participants and methods A total of 86 first-episode psychosis (FEP) outpatients and 39 healthy volunteers were recruited. Demographic and clinical data, APOE genotyping, and a neuropsychological test battery including the California Verbal Learning Test – second edition (CVLT-II) were administered and assessed at study entry and at 1-year follow-up. Data were analyzed using mixed-model repeated measures, where the dependent variable was verbal memory indexed by California Verbal Learning Test (CVLT) Trials 1–5 total recall score. Results FEP-APOE-ε4 carriers and FEP-APOE-ε4 noncarriers had similar symptom severity, clinical outcomes, premorbid and current intelligence quotient, and exposure to antipsychotics. There was a main effect of group on CVLT 1–5 (FEP =43.30 vs control =58.25; F[1, 119.7]=42.97; P<0.001) as well as an APOE-ε4 by group by time (F[4, 116.2]=2.73, P=0.033) interaction with only FEP-APOE-ε4 carriers showing improved verbal memory at follow-up. Conclusion Our study is the first to report improvement in verbal memory in persons afflicted by FEP who are APOE-ε4 carriers and replicates the prominent verbal memory deficits present in FEP. Our work provides further evidence pointing to an antagonistic pleiotropic effect of APOE-ε4 in neuropsychiatric disorders. Our results merit further research into antagonistic pleiotropic effects in schizophrenia.