Isabel Valli

Elevated striatal dopamine function linked to prodromal signs of schizophrenia.

CONTEXT A major limitation on the development of biomarkers and novel interventions for schizophrenia is that its pathogenesis is unknown. Although elevated striatal dopamine activity is thought to be fundamental to schizophrenia, it is unclear when this neurochemical abnormality develops in relation to the onset of illness and how this relates to the symptoms and neurocognitive impairment seen in individuals with prodromal symptoms of schizophrenia. OBJECTIVES To determine whether striatal dopamine function is elevated in individuals with prodromal symptoms of schizophrenia before the onset of psychosis and to assess how this relates to the symptoms and neurocognitive impairment. DESIGN Case-control study of in vivo striatal dopaminergic function. SETTING Academic research. Patients Patients were recruited from a community mental health service. Twenty-four patients having prodromal symptoms of schizophrenia were compared with 7 patients having schizophrenia and with 12 matched healthy control subjects from the same community. Main Outcome Measure Striatal 6-fluoro-l-dopa F 18-dopa uptake measured using positron emission tomographic (18)F-dopa imaging. RESULTS Striatal (18)F-dopa uptake was elevated in patients with prodromal symptoms of schizophrenia (effect size, 0.75) to an intermediate degree compared with that in patients with schizophrenia (effect size, 1.25). The elevation was localized in the associative striatum in both groups. Moreover, striatal (18)F-dopa uptake in patients with prodromal symptoms of schizophrenia was correlated with the severity of prodromal psychopathologic and neuropsychological impairment but not with the severity of anxiety or depressive symptoms. CONCLUSIONS These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.

Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study.

CONTEXT Alterations in dopaminergic neurotransmission and function of the prefrontal cortex are thought to be central to the pathophysiology of schizophrenia, but the relationship between these factors in the development of psychosis is unclear. OBJECTIVE To investigate the relationship between striatal dopamine activity and prefrontal function in people at ultra high risk of psychosis. DESIGN Subjects were studied using functional magnetic resonance imaging while performing a working memory (N-back) task. Positron emission tomography with fluorine 18-labeled fluorodopa was used to investigate presynaptic striatal dopamine activity. SETTING Outpatient service for people with prodromal signs of psychosis. PATIENTS AND OTHER PARTICIPANTS Thirty-four subjects participated in the study: 14 healthy volunteers and 20 subjects with an at-risk mental state (ARMS). MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response), Ki for [(18)F]fluorodopa uptake, and objective ratings of psychopathology at the time of scanning. RESULTS In the associative part of the striatum, the Ki for [(18)F]fluorodopa was higher in the ARMS group than in the controls. During the N-back task, ARMS subjects displayed less activation in the right middle frontal gyrus, the medial frontal gyri, and the left superior parietal lobule than controls. The Ki for [(18)F]fluorodopa was positively correlated with activation in the right middle frontal gyrus in controls but negatively correlated with activation in this region in the ARMS group. CONCLUSIONS In people with prodromal signs of psychosis, there are direct correlations between altered prefrontal cortical function and subcortical dopamine synthesis capacity, consistent with the notion that frontostriatal interactions play a critical role in the pathoetiology of schizophrenia.

Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study

OBJECTIVE While there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. The authors addressed this issue by measuring dopamine synthesis capacity in individuals at ultra-high risk of psychosis and then following them to determine their clinical outcome. METHOD This prospective study included 30 patients who met standard criteria for being at ultra-high risk of psychosis and 29 healthy volunteers. Participants were scanned using [(18)F]6-fluoro-L-dopa positron emission tomography. The ultra-high-risk patients were scanned at presentation and followed up for at least 3 years to determine their clinical outcome. Six patients had comorbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining patients, nine developed a psychotic disorder (psychotic transition group) and 15 did not (nontransition group). RESULTS There was a significant effect of group on striatal dopamine synthesis capacity. The psychotic transition group had greater dopamine synthesis capacity in the striatum (effect size=1.18) and its associative subdivision (effect size=1.24) than did the healthy comparison subjects and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition group than in the nontransition group. CONCLUSIONS These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further research is needed to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.

Neuroanatomical Abnormalities That Predate the Onset of Psychosis: A Multicenter Study

CONTEXT People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent. OBJECTIVE To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites. DESIGN Case-control study. SETTING Multisite. PARTICIPANTS A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not. MAIN OUTCOME MEASURES Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry. RESULTS The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not. CONCLUSIONS Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.

Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis

Schizophrenia is characterized by altered prefrontal activity and elevated striatal dopaminergic function. To investigate the relationship between these abnormalities in the prodromal phase of the illness, we combined functional Magnetic Resonance Imaging and 18F-Dopa Positron Emission Tomography. When performing a verbal fluency task, subjects with an At-Risk Mental State showed greater activation in the inferior frontal cortex than controls. Striatal dopamine function was greater in the At-Risk group than in controls. Within the At-Risk group, but not the control group, there was a direct correlation between the degree of left inferior frontal activation and the level of striatal dopamine function. Altered prefrontal activation in subjects with an At-Risk Mental State for psychosis is related to elevated striatal dopamine function. These changes reflect an increased vulnerability to psychosis and predate the first episode of frank psychosis.

Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study

Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study

Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis.

CONTEXT Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. OBJECTIVE To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). DESIGN Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. SETTING Maudsley Hospital, London, England. PATIENTS AND OTHER PARTICIPANTS A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. RESULTS During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. CONCLUSIONS Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls.

Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals

BACKGROUND People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not. METHODS Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years. RESULTS Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region. CONCLUSIONS In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.

Effect of BDNF val66met polymorphism on declarative memory and its neural substrate: A meta-analysis

Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders.

Altered Prefrontal and Hippocampal Function During Verbal Encoding and Recognition in People With Prodromal Symptoms of Psychosis

Despite robust evidence of hippocampal abnormalities in schizophrenia, it is unclear whether hippocampal dysfunction predates the onset of psychosis. We used functional magnetic resonance imaging to investigate hippocampal function in subjects with an at-risk mental state (ARMS). Eighteen subjects meeting criteria for an ARMS and 22 healthy controls, matched for age, gender, and premorbid IQ, were scanned while performing a version of the Deese-Roediger-McDermott false memory task. During an encoding phase, subjects read lists of words aloud. Following a delay, they were presented with 24 target words, 24 semantically related lure words, and 24 novel words and required to indicate if each had been presented before. Behaviorally, the ARMS group made more false alarm responses for novel words than controls (P = .04) and had a lower discrimination accuracy for target words (P = .02). During encoding, ARMS subjects showed less activation than healthy controls in the left middle frontal gyrus, the bilateral medial frontal gyri, and the left parahippocampal gyrus. Correct recognition relative to false alarms was associated with differential engagement of the hippocampus bilaterally in healthy controls, but this difference was absent in the ARMS group. The ARMS was associated with altered function in the medial temporal cortex, as well as in the prefrontal regions, during both verbal encoding and recognition. These neurofunctional differences were associated with diminished recognition performance and may reflect the greatly increased risk of psychosis associated with the ARMS.