Same task, different strategies: how brain networks can be influenced by memory strategy.

Previous functional neuroimaging studies demonstrated that different neural networks underlie different types of cognitive processing by engaging participants in particular tasks, such as verbal or spatial working memory (WM) tasks. However, we report here that even when a WM task is defined as verbal or spatial, different types of memory strategies may be used to complete it, with concomitant variations in brain activity. We developed a questionnaire to characterize the type of strategy used by individual members in a group of 28 young healthy participants (18-25 years) during a spatial WM task. A cluster analysis was performed to differentiate groups. We acquired functional magnetoencephalography and structural diffusion tensor imaging measures to characterize the brain networks associated with the use of different strategies. We found two types of strategies were used during the spatial WM task, a visuospatial and a verbal strategy, and brain regions and time courses of activation differed between participants who used each. Task performance also varied by type of strategy used with verbal strategies showing an advantage. In addition, performance on neuropsychological tests (indices from Wechsler Adult Intelligence Scale-IV, Rey Complex Figure Test) correlated significantly with fractional anisotropy measures for the visuospatial strategy group in white matter tracts implicated in other WM and attention studies. We conclude that differences in memory strategy can have a pronounced effect on the locations and timing of brain activation and that these differences need further investigation as a possible confounding factor for studies using group averaging as a means for summarizing results.

Bilateral hippocampal dysfunction in schizophrenia.

The hippocampus has long been known to be important for memory, with the right hippocampus particularly implicated in nonverbal/visuo-spatial memory and the left in verbal/narrative or episodic memory. Despite this hypothesized lateralized functional difference, there has not been a single task that has been shown to activate both the right and left hippocampi differentially, dissociating the two, using neuroimaging. The transverse patterning (TP) task is a strong candidate for this purpose, as it has been shown in human and nonhuman animal studies to theoretically and empirically depend on the hippocampus. In TP, participants choose between stimuli presented in pairs, with the correct choice being a function of the specific pairing. In this project, TP was used to assess lateralized hippocampal function by varying its dependence on verbal material, with the goal of dissociating the two hippocampi. Magnetoencephalographic (MEG) data were collected while controls performed verbal and nonverbal versions of TP in order to verify and validate lateralized activation within the hippocampi. Schizophrenia patients were evaluated to determine whether they exhibited a lateralized hippocampal deficit. As hypothesized, patients' mean level of behavioral performance was poorer than controls' on both verbal and nonverbal TP. In contrast, patients had no decrement in performance on a verbal and nonverbal non-hippocampal-dependent matched control task. Also, controls but not patients showed more right hippocampal activation during nonverbal TP and more left hippocampal activation during verbal TP. These data demonstrate the capacity to assess lateralized hippocampal function and suggest a bilateral hippocampal behavioral and activation deficit in schizophrenia.

Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating.

Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural network is not well understood. The present study used EEG and MEG to assess sensory gating and volumetric MRI to measure hippocampal volume to investigate relationships between them in 22 normal controls and 22 patients with schizophrenia. In the schizophrenia group, anterior but not posterior hippocampal volume was smaller, and both the P50 and M50 gating ratios were larger (worse) than in controls. Independent of group, left-hemisphere M50 gating ratio correlated negatively with left anterior hippocampal volume, and right-hemisphere M50 gating ratio correlated negatively with right anterior hippocampal volume. Schizophrenia diagnosis predicted M50 gating independent of hippocampal volume. These results are consistent with the finding that hippocampus is a critical part of a fronto-temporal circuit involved in auditory gating.

Prospective study to evaluate the efficacy of aripiprazole as a monotherapy in patients with severe chronic posttraumatic stress disorder: an open trial.

The objective of the study was to assess the efficacy and safety of aripiprazole in outpatients with posttraumatic stress disorder (PTSD) on a 12-week, open-label trial. Twenty-two subjects with DSM-IV diagnosis of PTSD participated; 16 were combat veterans. The primary outcome measure was PTSD symptom severity assessed with the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Positive and Negative Symptoms Scale and the Hamilton Depression and Anxiety Scales. All subjects had a CAPS score of > or = 60 at baseline. Lifetime history of psychotic disorders or bipolar illness was exclusionary. The overall analysis across time was Repeated Measures ANOVA, using Bonferroni corrections. Fourteen subjects completed 12 weeks of treatment. Eight subjects dropped-out due to side effects. For patients who discontinued, missing values were estimated using "the last observation carried forward" method. Significant improvements were seen on: CAPS total, all its subscales, positive symptoms, anxiety and depression scores. Fourteen participants were classified as responders, defined by 20% or greater improvement on CAPS total score. Of the 13 subjects who completed final ratings, CAPS total scores improved significantly (P = .011). Two subjects attained remission of PTSD (CAPS < 20), and three had a final CAPS < or = 26. The mean daily dose of aripiprazole was 12.95 mg. The most common side effects were somnolence (54.5%), restlessness (50%), insomnia (36.4%), and asthenia (31.8%). These results indicate that aripiprazole was effective in about two thirds of subjects that tolerated this medication. The initially high dropout rate may be related to intolerability due to a high starting dose (10 mg), suggesting beginning treatment at lower doses. These preliminary results are encouraging; a double blind study seems warranted.

Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1.

We report on our initial genetic linkage studies of schizophrenia in the genetically isolated population of the Afrikaners from South Africa. A 10-cM genomewide scan was performed on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. These results suggest that few genes of substantial effect exist for schizophrenia in the Afrikaner population, consistent with our previous genealogical tracing studies. The locus on chromosome 1 reached genomewide significance levels (nonparametric LOD score of 3.30 at marker D1S1612, corresponding to an empirical P value of.012) and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners.

Phenotypic characterization and genealogical tracing in an Afrikaner schizophrenia database.

Founder populations hold tremendous promise for mapping genes for complex traits, as they offer less genetic and environmental heterogeneity and greater potential for genealogical research. Not all founder populations are equally valuable, however. The Afrikaner population meets several criteria that make it an ideal population for mapping complex traits, including founding by a small number of initial founders that likely allowed for a relatively restricted set of mutations and a large current population size that allows identification of a sufficient number of cases. Here, we examine the potential to conduct genealogical research in this population and present initial results indicating that accurate genealogical tracing for up to 17 generations is feasible. We also examine the clinical similarities of schizophrenia cases diagnosed in South Africa and those diagnosed in other, heterogeneous populations, specifically the US. We find that, with regard to basic sample descriptors and cardinal symptoms of disease, the two populations are equivalent. It is, therefore, likely that results from our genetic study of schizophrenia will be applicable to other populations. Based on the results presented here, the history and current size of the population, as well as our previous analysis addressing the extent of background linkage disequilibrium (LD) in the Afrikaners, we conclude that the Afrikaner population is likely an appropriate founder population to map genes for schizophrenia using both linkage and LD approaches.