Attenuated prefrontal activation during a verbal fluency task in remitted major depression

The aim of the present study was to investigate whether a functional abnormality in the left prefrontal cortex observed in patients with major depression performing a verbal fluency task is present after remission of depression. Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in eight remitted patients with major depression and 10 healthy control subjects during a verbal fluency task. Compared to the control subjects, the patients had a reduced response in the left prefrontal cortex (middle frontal gyrus, Brodmann area 10). These findings suggest the presence of dysfunction in the left prefrontal cortex during remission in major depression.     

Attenuated left prefrontal activation during a verbal fluency task in patients with depression

Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.     

Topographic analysis of individual activation patterns in medial frontal cortex in schizophrenia

Individual variability in the location of neural activations poses a unique problem for neuroimaging studies employing group averaging techniques to investigate the neural bases of cognitive and emotional functions. This may be especially challenging for studies examining patient groups, which often have limited sample sizes and increased intersubject variability. In particular, medial frontal cortex (MFC) dysfunction is thought to underlie performance monitoring dysfunction among patients with schizophrenia, yet previous studies using group averaging to compare schizophrenic patients to controls have yielded conflicting results. To examine individual activations in MFC associated with two aspects of performance monitoring, interference and error processing, functional magnetic resonance imaging data were acquired while 17 patients with schizophrenia and 21 healthy controls (HCs) performed an event-related version of the multisource interference task. Comparisons of averaged data revealed few differences between the groups. By contrast, topographic analysis of individual activations for errors showed that control subjects exhibited activations spanning across both posterior and anterior regions of MFC while patients primarily activated posterior MFC, possibly reflecting an impaired emotional response to errors in schizophrenia. This discrepancy between topographic and group-averaged results may be due to the significant dispersion among individual activations, particularly in HCs, highlighting the importance of considering intersubject variability when interpreting the medial frontal response to error commission.     

TNFB polymorphism may be associated with schizophrenia in the Korean population

This study was conducted to test the association between the tumor necrosis factor (TNF)-beta gene (B) polymorphism and schizophrenia in the Korean population. 127 patients with schizophrenia according to the DSM-IV criteria and 202 healthy controls were enrolled in this study. Patients and controls were biologically unrelated age and sex-matched native Koreans. Genotyping for the TNFB polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. Genotype and allele distributions of the TNFB polymorphism in patients with schizophrenia were significantly different from those of the controls. Subjects with the TNFB*2 allele had an increased risk for schizophrenia (Odds Ratio=1.76, 95% CI=1.27-2.45). The present study suggests that the TNFB polymorphism may confer susceptibility to schizophrenia in the Korean population.     

Attenuated prefrontal activation during decision-making under uncertainty in schizophrenia: A multi-center fMRI study

Decisions are called decisions under uncertainty when either prior information is incomplete or the outcomes of the decision are unclear. Alterations in these processes related to decisions under uncertainty have been linked to delusions. In patients with schizophrenia, the underlying neural networks have only rarely been studied. We aimed to disentangle the neural correlates of decision-making and relate them to neuropsychological and psychopathological parameters in a large sample of patients with schizophrenia and healthy subjects.Fifty-seven patients and fifty-seven healthy volunteers from six centers had to either indicate via button-press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or indicate whether eight red balls had been presented (baseline condition) while BOLD signal was measured with fMRI.Patients based their decisions on less conclusive evidence and had decreased activations in the underlying neural network, comprising of medial and lateral frontal as well as parietal areas, as compared to healthy subjects. While current psychopathology was not correlated with brain activation, positive symptoms led to longer decision latencies in patients.These results suggest that decision-making under uncertainty in schizophrenia is affected by a complex interplay of aberrant neural activation. Furthermore, reduced neuropsychological functioning in patients was related to impaired decision-making and task performance was modulated by distinct positive symptoms.     

Left frontal activation during a semantic categorization task: an fMRI-study.

In the present study we measured brain activation, with functional magnetic resonance imaging (fMRI) during the execution of a covert semantic categorization task. This involves activation of working memory and internal concept generation. Previous brain imaging studies of covert verbal fluency have shown widespread activation in the frontal and temporal lobes, and anterior cingulate. However, most of these studies have employed simple stimulus tasks with repetition of words e.g., beginning with a certain letter of the alphabet. Moreover, the subject is typically cued (either visually or auditory) every 2-5 second. In the present study we used a "single-cue" instruction at the beginning of each activation period where the subject was instructed to internally generate category specific names related to: "States in the USA," "UK Soccer clubs," and "Male names" during 54s periods. The three activation periods were compared to three baseline periods in which the subject was instructed to imagine mentally "lying on a beach and looking at the sky." Functional MRI was performed with a 1.5T Siemens Vision scanner. Initial TIW 3D FLASH scanning of anatomy was done, and thereafter, serial imaging with 60 BOLD sensitive echo planar whole brain measurements were done during the active and passive tasks. Main activation areas were found in the left middle frontal gyrus, partially overlapping with Brodmann area 9. This is in agreement with previous studies of increased activation in the left frontal lobe, and may indicate a left frontal neural network for accessing the mental lexicon.     

Self-efficacy and neurocognition may be related to coping responses in recent-onset schizophrenia

Although stressful life events can trigger psychotic and depressive symptom exacerbation in schizophrenia, many patients who experience stressful events do not subsequently relapse. Models of vulnerability, stress, and protective factors in schizophrenia suggest that effective coping responses may serve as protective factors. Coping behavior, in turn, may be influenced by a schizophrenia patient's level of self-efficacy and neurocognitive functioning. Using the Coping Responses Inventory, we examined how 29 recent-onset schizophrenia outpatients and 24 demographically matched normal comparison subjects responded to a negative interpersonal life event. Approach oriented coping responses, such as "Think of different ways to deal with the problem" and "Make a plan of action and follow it," were used significantly more often by normal subjects (M=2.27) than by schizophrenia patients (M=1.89; p < 0.02). Among schizophrenia patients, greater use of approach, problem-focused coping strategies was associated with high self-efficacy (r=0.55, p < 0.01) and better performance on a measure of sustained attention emphasizing perceptual processing (r=0.42, p < 0.05). Multiple regression indicated that self-efficacy and sustained attention accounted for 56% of the variance in the use of problem-focused coping, strategies by schizophrenia patients.     

精神分裂症患者记忆围棋子位置时的脑激活区域

BACKGROUND： Go, a traditional Chinese chess-like game, requires many unknown functions of the brain including attention, imaging, problem solving and processing of spatial working memory. To date, it remains uncertain whether the intellectual activities required to play Go are related to the frontal lobe. OBJECTIVE： To investigate various patterns of brain region activity while schizophrenic patients and normal subjects engaged in memorizing piece placement in the Chinese game of Go. Spatial working memory was measured in order to validate whether the prefrontal lobe participates in this memory process.
DESIGN, TIME AND SETTING： Non-randomized, concurrent control trial was performed at Second Xiangya Hospital of Central South University, between May and December 2004.
PARTICIPANTS： A total of nine Chinese schizophrenic patients with no brain or bodily diseases and not undergoing electroshock treatment, who were in accordance with the DSM-Ⅳ criteria for schizophrenia, as well as thirteen healthy staffs and students with matched age, sex, and education were included. Patients and control subjects had no neurological disorders or mental retardation. In addition, all participants were right-handed. METHODS： The cognitive task for functional magnetic resonance imaging was a block design experiment. Both groups were asked to remember the placement of pieces in the Chinese game of Go on a computer screen. A brain activation map was analyzed in SPM99.
MAIN OUTCOME MEASURES： Brain responses were compared with regard to activation region size, volume, and asymmetry indices. RESULTS： Compared with the control group, the reaction time was significantly delayed in schizophrenics performing the working memory task （P 〈 0.05）. When performing the tasks, normal subjects showed significant activation of the bilateral dorsolateral prefrontal lobe with left dominance; the asymmetry indices were： frontal lobe, ＋0.32; temporal lobe, 0.58; parietal lobe, 0.41 ; and occipital lobe, 0.34. On the other hand, schizophrenics showed right dominance and had a broader activation region of the prefrontal lobe （asymmetry indices： frontal lobe, 0.10; temporal lobe, ＋0.38; parietal lobe, ＋0.24; and occipital lobe, 0.00）. When comparing the normal group subtracted with the schizophrenic group, no significant lateralization was found in the frontal lobes but significant activation was found in the left anterior central gyrus, left middle frontal gyrus and in both sides of the cingulate gyrus. Comparing the schizophrenic group subtracted with the normal group, there was significant right lateralization of the frontal lobe and abnormally activated regions on both sides of the anterior central gyrus, middle frontal gyrus, left inferior frontal gyrus, right medial frontal gyrus and the right insular lobe. CONCLUSION： Different brain activation regions are involved in memorizing the placement of pieces in Chinese Go between schizophrenia and healthy subjects. Schizophrenics showed right dominance and border activation range, indicating that the prefrontal cortex plays an important role in memory information processing and resource allocation when remembering piece placement in the game of Go.     

Functional genomics indicate that schizophrenia may be an adult vascular-ischemic disorder

In search for the elusive schizophrenia pathway, candidate genes for the disorder from a discovery sample were localized within the energy-delivering and ischemia protection pathway. To test the adult vascular-ischemic (AVIH) and the competing neurodevelopmental hypothesis (NDH), functional genomic analyses of practically all available schizophrenia-associated genes from candidate gene, genome-wide association and postmortem expression studies were performed. Our results indicate a significant overrepresentation of genes involved in vascular function (P<0.001), vasoregulation (that is, perivascular (P<0.001) and shear stress (P<0.01), cerebral ischemia (P<0.001), neurodevelopment (P<0.001) and postischemic repair (P<0.001) among schizophrenia-associated genes from genetic association studies. These findings support both the NDH and the AVIH. The genes from postmortem studies showed an upregulation of vascular-ischemic genes (P=0.020) combined with downregulated synaptic (P=0.005) genes, and ND/repair (P=0.003) genes. Evidence for the AVIH and the NDH is critically discussed. We conclude that schizophrenia is probably a mild adult vascular-ischemic and postischemic repair disorder. Adult postischemic repair involves ND genes for adult neurogenesis, synaptic plasticity, glutamate and increased long-term potentiation of excitatory neurotransmission (i-LTP). Schizophrenia might be caused by the cerebral analog of microvascular angina.     

The DSM-IV version of schizophrenia may be harmful to patients' health

The DSM-III, III-R and DSM-IV diagnostic systems required deterioration (functional loss) and duration (6 months) in the diagnosis of schizophrenia. These criteria made schizophrenia exceptional to an otherwise phenomenologically-based nosology, but their inclusion represented an effort to disentangle the diagnosis of schizophrenia from considerable historical baggage. Newer findings about the efforts of early detection and intervention in schizophrenia, however, are now calling into question the validity, utility and even the safety of these decisions. This communication will review the original reasons for including deterioration and duration as criteria. It will then argue that these reasons are now obsolete and potentially anti-therapeutic, and that a revised set of cross-sectional phenomenologic criteria for schizophrenia need to be utilized as soon as possible.     

Evidence for altered amygdala activation in schizophrenia in an adaptive emotion recognition task

Deficits in social cognition seem to present an intermediate phenotype for schizophrenia, and are known to be associated with an altered amygdala response to faces. However, current results are heterogeneous with respect to whether this altered amygdala response in schizophrenia is hypoactive or hyperactive in nature. The present study used functional magnetic resonance imaging to investigate emotion-specific amygdala activation in schizophrenia using a novel adaptive emotion recognition paradigm. Participants comprised 11 schizophrenia outpatients and 16 healthy controls who viewed face stimuli expressing emotions of anger, fear, happiness, and disgust, as well as neutral expressions. The adaptive emotion recognition approach allows the assessment of group differences in both emotion recognition performance and associated neuronal activity while also ensuring a comparable number of correctly recognized emotions between groups. Schizophrenia participants were slower and had a negative bias in emotion recognition. In addition, they showed reduced differential activation during recognition of emotional compared with neutral expressions. Correlation analyses revealed an association of a negative bias with amygdala activation for neutral facial expressions that was specific to the patient group. We replicated previous findings of affected emotion recognition in schizophrenia. Furthermore, we demonstrated that altered amygdala activation in the patient group was associated with the occurrence of a negative bias. These results provide further evidence for impaired social cognition in schizophrenia and point to a central role of the amygdala in negative misperceptions of facial stimuli in schizophrenia.     

The CLDN5 locus may be involved in the vulnerability to schizophrenia.

The present study was designed to detect three single nucleotide polymorphisms (SNPs) located on 22q11 that was thought as being of particularly importance for genetic research into schizophrenia. We recruited a total of 176 Chinese family trios of Han descent, consisting of mothers, fathers and affected offspring with schizophrenia for the genetic analysis. The transmission disequilibrium test (TDT) showed that of three SNPs, rs10314 in the 3'-untranslated region of the CLDN5 locus was associated with schizophrenia (chi(2) = 4.75, P = 0.029). The other two SNPs, rs1548359 present in the CDC45L locus centromeric of rs10314 and rs739371 in the 5'-flanking region of the CLDN5 locus, did not show such an association. The global chi-square (chi(2)) test showed that the 3-SNP haplotype system was not associated with schizophrenia although the 1-df test for individual haplotypes showed that the rs1548359(C)-rs10314(G)-rs739371(C) haplotype was excessively non-transmitted (chi(2) = 5.32, P = 0.02). Because the claudin proteins are a major component for barrier-forming tight junctions that could play a crucial role in response to changing natural, physiological and pathological conditions, the CLDN5 association with schizophrenia may be an important clue leading to look into a meeting point of genetic and environmental factors.     

Medication may be required for the development of automatic information processing in schizophrenia

Medicated and unmedicated schizophrenic patients and normal subjects (n's = 4) were examined on the extent to which their information-processing performance became automated over time, as reflected by increased competence in dual task performance. The central task was a computerized version of the Continuous Performance Test, and the secondary task was a word-list shadowing task. Normal subjects and medicated schizophrenic patients became much more efficient at performing both tasks simultaneously with practice, with unmedicated patients showing no improvement over time.     

Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task

Townsend JD, Bookheimer SY, Foland‐Ross LC, Moody TD, Eisenberger NI, Fischer JS, Cohen MS, Sugar CA, Altshuler LL. Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task.
Bipolar Disord 2012: 14: 442–450. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: The inferior frontal cortical–striatal network plays an integral role in response inhibition in normal populations. While inferior frontal cortex (IFC) impairment has been reported in mania, this study explored whether this dysfunction persists in euthymia. Methods: Functional magnetic resonance imaging (fMRI) activation was evaluated in 32 euthymic patients with bipolar I disorder and 30 healthy subjects while performing the Go/NoGo response inhibition task. Behavioral data were collected to evaluate accuracy and response time. Within‐group and between‐group comparisons of activation were conducted using whole‐brain analyses to probe significant group differences in neural function. Results: Both groups activated bilateral IFC. However, between‐group comparisons showed a significantly reduced activation in this brain region in euthymic patients with bipolar disorder compared to healthy subjects. Other frontal and basal ganglia regions involved in response inhibition were additionally significantly reduced in bipolar disorder patients, in both the medicated and the unmedicated subgroups. No areas of greater activation were observed in bipolar disorder patients versus healthy subjects. Conclusions: Bipolar disorder patients, even during euthymia, have a persistent reduction in activation of brain regions involved in response inhibition, suggesting that reduced activation in the orbitofrontal cortex and striatum is not solely related to the state of mania. These findings may represent underlying trait abnormalities in bipolar disorder.     

Changes over time in frontotemporal activation during a working memory task in patients with schizophrenia

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including prefrontal and temporal cortex. Longitudinal studies have shown changes in prefrontal activation during treatment. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in healthy subjects and medicated patients with schizophrenia with an acute symptom exacerbation. Patients were scanned twice: within the first week after admission to the hospital and after 7-8 weeks of a multimodal treatment including atypical antipsychotic agents. There were no differences in activation of lateral prefrontal regions in patients relative to healthy controls neither at baseline nor after 7-8 weeks. Controls showed relatively more activation in parietal, striatal and cerebellar regions. In patients with schizophrenia, frontotemporal function was bilaterally enhanced after 7-8 weeks. This activation change was associated with improved accuracy in a verbal WM task, improved verbal WM-span and symptom reduction as measured by the BPRS global score and the BPRS factor for thought disturbance. Although we could not replicate findings of functional hypofrontality in the patients with schizophrenia, frontotemporal activation changed with treatment and was associated with verbal WM performance and significant reduction of psychopathology.     

Alterations in functional activation in euthymic bipolar disorder and schizophrenia during a working memory task

Dysfunctions in prefrontal cortical networks are thought to underlie working memory (WM) impairments consistently observed in both subjects with bipolar disorder and schizophrenia. It remains unclear, however, whether patterns of WM‐related hemodynamic responses are similar in bipolar and schizophrenia subjects compared to controls. We used fMRI to investigate differences in blood oxygen level dependent activation during a WM task in 21 patients with euthymic bipolar I, 20 patients with schizophrenia, and 38 healthy controls. Subjects were presented with four stimuli (abstract designs) followed by a fifth stimulus and required to recall whether the last stimulus was among the four presented previously. Task‐related brain activity was compared within and across groups. All groups activated prefrontal cortex (PFC), primary and supplementary motor cortex, and visual cortex during the WM task. There were no significant differences in PFC activation between controls and euthymic bipolar subjects, but controls exhibited significantly increased activation (cluster‐corrected P < 0.05) compared to patients with schizophrenia in prefrontal regions including dorsolateral prefrontal cortex (DLPFC). Although the bipolar group exhibited intermediate percent signal change in a functionally defined DLPFC region of interest with respect to the schizophrenia and control groups, effects remained significant only between patients with schizophrenia and controls. Schizophrenia and bipolar disorder may share some behavioral, diagnostic, and genetic features. Differences in the patterns of WM‐related brain activity across groups, however, suggest some diagnostic specificity. Both patient groups showed some regional task‐related hypoactivation compared to controls across the brain. Within DLPFC specifically, patients with schizophrenia exhibited more severe WM‐related dysfunction than bipolar subjects. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Paranoid schizophrenia may be caused by dopamine hyperactivity of CA1 hippocampus.

Explicit consolidation of memory, or fixation of declarative belief, appears to be physically represented in changes of synaptic conductances of neurons in the parietal-temporal-occipital association cortex (PTO) of the mammalian forebrain. This fixation of belief in PTO is postulated to be critically dependent on a diffuse reinforcement signal via the inferior temporal cortex (ITC) ultimately caused by an increased output of the CA1 pyramidal cells of hippocampus. Analogous to the reinforcing mechanisms of other forebrain systems, this updating of the connection weights of the neural nets in PTO by the output of the critical neurons in CA1 is directly related to concentrations of dopamine (DA). We propose that the delusions (i.e., unreasonable beliefs) of paranoid schizophrenia are caused by a hyperactivity of the same DA-sensitive CA1 neurons that are responsible for the fixation of normal beliefs. The dramatic reduction in delusions with administration of neuroleptics, as DA D2 blockers, in schizophrenics may thus be explained by their acting to ameliorate the hyperactivity of these CA1 DA D2 receptors.     

Examination by near-infrared spectroscopy for evaluation of piano performance as a frontal lobe activation task

The purpose of this study was to reveal the activation of the frontal lobe in piano performance by the use of near-infrared spectroscopy. Participants wereseven healthy volunteer music college students. The results of the examination showed a tendency towards an increase in total hemoglobin volume over a wider area in the frontal part of the brain during an appropriate piano task compared with an easy piano task or the Keio version of the Wisconsin Card Sorting Test. The results suggest that piano performance is recognized as a frontal lobe-activating task and that performance of an appropriate piano task can be expected to elicit wider activation of the frontal lobe than an easy one.     

Low‐fat oxidation may be a factor in obesity among men with schizophrenia

Objective: Obesity associated with atypical antipsychotic medications is an important clinical issue for people with schizophrenia. The purpose of this project was to determine whether there were any differences in resting energy expenditure (REE) and respiratory quotient (RQ) between men with schizophrenia and controls. Method: Thirty‐one men with schizophrenia were individually matched for age and relative body weight with healthy, sedentary controls. Deuterium dilution was used to determine total body water and subsequently fat‐free mass (FFM). Indirect calorimetry using a Deltatrac metabolic cart was used to determine REE and RQ. Results: When corrected for FFM, there was no significant difference in REE between the groups. However, fasting RQ was significantly higher in the men with schizophrenia than the controls. Conclusion: Men with schizophrenia oxidised proportionally less fat and more carbohydrate under resting conditions than healthy controls. These differences in substrate utilisation at rest may be an important consideration in obesity in this clinical group.     

Reduced frontopolar activation during verbal fluency task in schizophrenia: a multi-channel near-infrared spectroscopy study

Functional neuroimaging studies to date have shown prefrontal dysfunction during executive tasks in schizophrenia. However, relationships between hemodynamic response in prefrontal sub-regions and clinical characteristics have been unclear. The objective of this study is to evaluate prefrontal hemodynamic response related to an executive task in schizophrenia and to assess the relationship between activation in the prefrontal sub-regions and clinical status. Fifty-five subjects with schizophrenia and age- and gender-matched 70 healthy subjects were recruited for this case-control study in a medical school affiliated hospital in the Tokyo metropolitan area, Japan. We measured hemoglobin concentration changes in the prefrontal (dorsolateral, ventrolateral, and frontopolar regions) and superior temporal cortical surface area during verbal fluency test using 52-channel near-infrared spectroscopy, which enables real-time monitoring of cerebral blood volumes in the cortical surface area under a more restraint-free environment than positron emission tomography or functional magnetic resonance imaging. The two groups showed distinct spatiotemporal pattern of oxy-hemoglobin concentration change during verbal fluency test. Schizophrenia patients were associated with slower and reduced increase in prefrontal activation than healthy controls. In particular, reduced activations of the frontopolar region, rather than lateral prefrontal or superior temporal regions, showed significant positive correlations with lower global assessment of functioning scores in the patient group, although task performance was not significantly associated with the scores. These results suggest that reduced frontopolar cortical activation is associated with functional impairment in patients with schizophrenia and that near-infrared spectroscopy may be an efficient clinical tool for monitoring these characteristics.