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1.
Schizophr Bull ; 37(1): 189-98, 2011 Jan.
Article in English | MEDLINE | ID: mdl-19666832

ABSTRACT

BACKGROUND: The prodromal phase of psychosis is characterized by impaired executive function and altered prefrontal activation. The extent to which the severity of these deficits at presentation predicts subsequent clinical outcomes is unclear. METHODS: We employed functional magnetic resonance imaging in a cohort of subjects at clinical risk for psychosis and in healthy controls. Images were acquired at clinical presentation and again after 1 year, using a 1.5-T Signa MRI scanner while subjects were performing a verbal fluency task. SPM5 was used for the analysis of imaging data. Psychopathological assessment of the "at-risk" symptoms was performed by using the Comprehensive Assessment for the At-Risk Mental State (CAARMS) and the Positive and Negative Symptom Scale (PANSS). RESULTS: In the at-risk mental state (ARMS) group, between presentation and follow-up, the CAARMS (perceptual disorder and thought disorder subscales) and the PANSS general scores decreased, while the Global Assessment of Functioning (GAF) score increased. Both the ARMS and control groups performed the verbal fluency task with a high degree of accuracy. The ARMS group showed greater activation in the left inferior frontal gyrus but less activation in the anterior cingulate gyrus than controls. Within the ARMS group, the longitudinal normalization of neurofunctional response in the left inferior frontal gyrus was positively correlated with the improvement in severity of hallucination-like experiences. CONCLUSIONS: The normalization of the abnormal prefrontal response during executive functioning is associated with 12-month psychopathological improvement of prodromal symptoms.


Subject(s)
Prefrontal Cortex/physiopathology , Psychotic Disorders/physiopathology , Adult , Cognition , Cohort Studies , Executive Function , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Psychotic Disorders/psychology , Risk Factors , Treatment Outcome , Verbal Learning
2.
Schizophr Res ; 123(1): 45-52, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20688479

ABSTRACT

BACKGROUND: Neurocognitive impairments in executive and mnemonic domains are already evident in the pre-psychotic phases. The longitudinal dynamic course of the neurofunctional abnormalities underlying liability to psychosis and their relation to clinical outcomes is unknown. METHODS: In this study we used functional magnetic resonance imaging (fMRI) in a cohort of subjects at ultra high clinical risk for psychosis (with an "At Risk Mental State", ARMS) and in healthy controls. Images were acquired at baseline and again after one year on a 1.5 Tesla Signa, while patients were performing a visuospatial working memory task. Psychopathological assessment of the prodromal symptoms was conducted at the same time points by using the CAARMS and the PANSS instruments. RESULTS: There were no significant differences between the ARMS and control groups with respect to age or IQ. Although both groups performed the PAL task with a high degree of accuracy, the ARMS showed an increased latency in answers during the most demanding level of the task. At baseline, such cognitive impairment was associated with reduced activation in the left precuneus, left superior parietal lobule, right middle temporal gyrus in the ARMS as compared to controls. In addition, the ARMS failed to activate parietal areas with increasing difficulty of the task. Between presentation and follow-up the overall clinical status of the ARMS sample improved, despite 2 out of the 15 subjects having developed a full-blown psychosis: the CAARMS (perceptual disorder and thought disorder subscales) and the PANNS general scores decreased, while the GAF score increased. Such clinical amelioration was associated with a longitudinal compensatory increase in occipitoparietal regions. CONCLUSIONS: The prodromal phase of psychosis is associated with functional alterations in parietal and temporal networks subserving visuospatial working memory which are more evident under high cognitive loads. The clinical improvement at one year is associated with a compensatory increase in occipitoparietal regions.


Subject(s)
Brain/blood supply , Cognition Disorders/etiology , Magnetic Resonance Imaging/methods , Memory, Short-Term/physiology , Psychotic Disorders/complications , Adult , Analysis of Variance , Brain/pathology , Brain Mapping , Cognition Disorders/pathology , Female , Humans , Image Processing, Computer-Assisted/methods , Longitudinal Studies , Male , Mental Status Schedule , Neuropsychological Tests , Oxygen/blood , Psychotic Disorders/pathology , Risk Factors , Young Adult
3.
Psychol Med ; 40(12): 1987-99, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20214840

ABSTRACT

BACKGROUND: Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. METHOD: fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object-location paired-associate memory task, with experimental manipulation of mnemonic load. RESULTS: In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. CONCLUSIONS: Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.


Subject(s)
Frontal Lobe/physiopathology , Memory, Short-Term/physiology , Parietal Lobe/physiopathology , Schizophrenia/physiopathology , Schizophrenic Psychology , Adult , Case-Control Studies , Female , Humans , Magnetic Resonance Imaging , Male , Task Performance and Analysis , Young Adult
4.
Acta Psychiatr Scand ; 122(4): 295-301, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20064129

ABSTRACT

OBJECTIVE: People with 'prodromal' symptoms have a very high risk of developing psychosis. We examined the neurocognitive basis of this vulnerability by using functional MRI to study subjects with an at-risk mental state (ARMS) while they performed a random movement generation task. METHOD: Cross-sectional comparison of individuals with an ARMS (n = 17), patients with first episode schizophreniform psychosis (n = 10) and healthy volunteers (n = 15). Subjects were studied using functional MRI while they performed a random movement generation paradigm. RESULTS: During random movement generation, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than in the first episode group. CONCLUSION: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have recently presented with psychosis but less severe.


Subject(s)
Cerebral Cortex/pathology , Psychotic Disorders , Adult , Antipsychotic Agents/therapeutic use , Causality , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Cross-Sectional Studies , Disease Susceptibility , Humans , Magnetic Resonance Imaging , Mental Health , Motor Activity , Psychotic Disorders/diagnosis , Psychotic Disorders/epidemiology , Psychotic Disorders/physiopathology , Psychotic Disorders/therapy , Schizophrenia/diagnosis , Schizophrenia/epidemiology , Schizophrenia/physiopathology , Schizophrenia/therapy , Task Performance and Analysis
5.
Horm Behav ; 53(1): 61-8, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17956758

ABSTRACT

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT(2A) receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT(2A) receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT(2A) receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT(2A) receptor ligand (123)I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT(2A) receptor availability. Never-users had significantly higher 5-HT(2A) receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p=0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT(2A) receptor availability correlated negatively with verbal and general memory and delayed recall (r=-0.45, p=0.01; r=-0.40, p=0.02; r=-0.36, p=0.04). Right superior temporal 5-HT(2A) receptor availability correlated negatively with verbal memory (r=-0.36, p=0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory (r=-0.70, p=0.002; r=-0.69, p=0.002); and in never-users, receptor availability negatively correlated with attention and concentration (r=-0.54, p=0.02). Long-term ET may be associated with lower 5-HT(2A) receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT(2A) receptor in hippocampus is associated with poorer memory function.


Subject(s)
Brain Mapping , Estrogen Replacement Therapy , Hippocampus/metabolism , Postmenopause/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Aged , Analysis of Variance , Cross-Sectional Studies , Female , Humans , Matched-Pair Analysis , Memory/physiology , Middle Aged , Postmenopause/drug effects , Reference Values , Temporal Lobe/metabolism , Time Factors , Tomography, Emission-Computed, Single-Photon
6.
Eur Neuropsychopharmacol ; 17(6-7): 492-500, 2007.
Article in English | MEDLINE | ID: mdl-17337340

ABSTRACT

This study aimed to assess the neurophysiological effects of acute atypical antipsychotic treatment on cognitive functioning in subjects presenting with a first episode of psychosis. We used functional MRI to examine the modulatory effects of acute psychopharmacological intervention on brain activation during four different cognitive tasks: overt verbal fluency, random movement generation, n-back and a spatial object memory task. Treatment with atypical antipsychotics was associated with alterations in regional activation during each task and also when task demands were manipulated within paradigms. The initial treatment of psychosis with atypical antipsychotics thus appears to be associated with modifications of the neurofunctional correlates of executive and mnemonic functions. These effects need to be considered when interpreting group differences in activation between medicated patients and controls.


Subject(s)
Antipsychotic Agents/pharmacology , Association Learning/physiology , Brain/drug effects , Brain/physiopathology , Psychotic Disorders/drug therapy , Psychotic Disorders/psychology , Adult , Association Learning/drug effects , Brain/pathology , Brain Mapping , Cognition/drug effects , Humans , Imagination/drug effects , Imagination/physiology , Magnetic Resonance Imaging , Memory/drug effects , Memory/physiology , Motor Activity/drug effects , Movement/drug effects , Movement/physiology , Psychotic Disorders/physiopathology , Reaction Time/drug effects , Space Perception/drug effects , Speech/drug effects , Verbal Learning/drug effects , Verbal Learning/physiology
7.
Acta Psychiatr Scand ; 110(4): 292-8, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15352931

ABSTRACT

OBJECTIVE: Treatment options are very limited for individuals with schizophrenia resistant to clozapine. We tested the hypothesis that amisulpride augmentation would lead to an improvement in these patients. METHOD: This was an open non-randomized study. Thirty-three patients with sub-optimal response to clozapine were commenced on amisulpride in addition to clozapine. Clinical status was evaluated at baseline, 3 and 6 months using the Positive And Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Calgary Depression Scale, Calgary Anxiety Scale and various side effect rating scales. RESULTS: Twenty-eight subjects completed 6 months treatment on clozapine and amisulpride. There was a statistically significant improvement in the mean scores for PANSS, SANS and GAS at follow-up and no significant changes in side effect ratings. CONCLUSION: Co-administration of amisulpride, in a group of patients partially or non-responsive to clozapine, may lead to a substantial improvement in positive and negative symptoms, without worsening the side effect burden.


Subject(s)
Antipsychotic Agents/therapeutic use , Clozapine/therapeutic use , Schizophrenia/drug therapy , Sulpiride/analogs & derivatives , Sulpiride/therapeutic use , Amisulpride , Brief Psychiatric Rating Scale , Diagnostic and Statistical Manual of Mental Disorders , Drug Synergism , Drug Therapy, Combination , Female , Humans , Male , Schizophrenia/diagnosis
8.
Schizophr Res ; 58(1): 93-7, 2002 Nov 01.
Article in English | MEDLINE | ID: mdl-12363396

ABSTRACT

Clozapine is a potent antagonist of 5-HT3 receptors, which are ligand-gated ion channels that mediate rapid excitatory responses in the central nervous system. Two different isoforms of 5-HT3 receptor subunit genes (HTR3A and HTR3B) have been identified. They have been assigned to chromosome 11q23.1-q23.2, a region which in the past has been linked to schizophrenia and bipolar disorder. In this study, we performed a systematic mutation screening of the 5-HT3A and 5-HT3B receptor genes and tested the variants for association with clozapine response in a sample of 266 clozapine-treated patients. Two polymorphisms at the 5-HT3A gene and five new variants in the 5-HT3B gene were finally detected. Of these, only the more frequent mutations (178-C/T and 1596-A/G in 5-HT3A and a CA-repeat in 5-HT3B) were genotyped in our clozapine sample. Association analysis showed similar allele and genotype distributions among clozapine responders and nonresponders. These results make unlikely the possibility that 5-HT3A and 5-HT3B receptor genes underlie variation in clinical response to clozapine. However, the promoter regions of both genes have yet to be investigated.


Subject(s)
Antipsychotic Agents/therapeutic use , Clozapine/therapeutic use , Receptors, Serotonin/genetics , Schizophrenia/genetics , Chi-Square Distribution , DNA Mutational Analysis/methods , Gene Frequency , Genotype , Humans , Mutation , Polymerase Chain Reaction , Polymorphism, Genetic , Receptors, Serotonin, 5-HT3 , Schizophrenia/drug therapy , Treatment Outcome
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