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Papers by Roberta Rasetti
Proceedings of the National Academy of Sciences, 2001
A principle that regulates detailed architecture in the brain is that active terminals have a com... more A principle that regulates detailed architecture in the brain is that active terminals have a competitive advantage over less active terminals in establishing synaptic connections. This principle is known to apply to fibers within a single neuronal population competing for a common target domain. Here we uncover an additional rule that applies when two neuronal populations compete for two contiguous territories. The cerebellar Purkinje cell dendrites have two different synaptic domains with spines innervated by two separate excitatory inputs, parallel fibers (PFs) and climbing fibers (CFs). Glutamate ␦-2 receptors are normally present only on the PF spines where they are important for their innervation. After block of activity by tetrodotoxin, numerous new spines form in the CF domain and become innervated mainly by PFs; all spines, including those still innervated by the CFs, bear ␦-2 receptors. Thus, in the absence of activity, PFs gain a competitive advantage over CFs. The entire dendritic arbor becomes a uniform territory with the molecular cues associated with the PFs. To access their proper territory and maintain synaptic contacts, CFs must be active and locally repress the cues of the competitor afferents.
European Journal of Neuroscience, 2005
Previous experiments have shown that in the mature cerebellum both blocking of spontaneous electr... more Previous experiments have shown that in the mature cerebellum both blocking of spontaneous electrical activity and destruction of the climbing fibres by a lesion of the inferior olive have a similar profound effect on the spine distribution on the proximal dendrites of the Purkinje cells. Many new spines develop that are largely innervated by parallel fibers. Here we show that blocking electrical activity leads to a significant decrease in size of the spines on the branchlets. We have also compared the size of the spines of the proximal dendritic domain that appear during activity block and after an inferior olive lesion. In this region also, the spines in the absence of activity are significantly smaller. In the proximal dendritic domain, the new spines that develop in the absence of activity are innervated by parallel fibers and are not significantly different in size from those of the branchlets, although they are shorter. Thus, the spontaneous activity of the cerebellar cortex is necessary not only to maintain the physiological spine distribution profile in the Purkinje cell dendritic tree, but also acts as a signal that prevents spines from shrinking.
Aberrant activity in brain regions underlying various aspects of executive cognition has been rep... more Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ("flanker task") to identify brain activity and connectivity associated with response inhibition and conflict monitoring and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls.
Aberrant activity in brain regions underlying various aspects of executive cognition has been rep... more Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ("flanker task") to identify brain activity and connectivity associated with response inhibition and conflict monitoring and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls.
JAMA psychiatry, 2014
Declarative memory-the ability to learn, store, and retrieve information-has been consistently re... more Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and inc...
Arch Gen Psychiatry, 2011
Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connect... more Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. Research center. A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. Siblings and patients showed greater DLPFC "inefficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPFC activity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene.
Journal of Neuroscience, 2014
The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative suscep... more The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.
Schizophrenia Research, 2008
Psychiatry Research, 2002
Dysthymic disorder is a chronic depressive condition with considerable psychosocial impairment. E... more Dysthymic disorder is a chronic depressive condition with considerable psychosocial impairment. Even if DD patients respond to various antidepressant medications, there has been little systematic study on antidepressant-refractory DD. Only a few trials have evaluated the effects of treatment on psychosocial functioning of dysthymic patients. In this 3-month, open-label study, 60 outpatients with DSM-IV criteria for dysthymic disorder who failed to respond to 3-month treatment with paroxetine 20 mg/day were randomly assigned to treatment with paroxetine 40 mg/day or paroxetine 20 mg/day plus amisulpride 50 mg/day. The effects of the two treatments were assessed for both mood symptoms (21-item Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression, severity and improvement) and psychosocial outcomes (DSM-IV Global Assessment of Functioning, Social Adaptation Self-evaluation Scale). Analysis of variance on all rating scales showed that both treatments were effective over this observation period. Response and remission rates did not differ in the treatment groups. A significantly greater psychosocial improvement was observed in the group receiving combined treatment compared with patients receiving paroxetine alone. Both treatments appeared to be effective in our sample of dysthymic subjects. Combined treatment with paroxetine and amisulpride resulted in a better outcome in terms of social functioning.
Psychiatry Research, 2006
The present study aims at exploring the relationship between content-related aspects of delusions... more The present study aims at exploring the relationship between content-related aspects of delusions and hallucinations in schizophrenia and the basic domains of cognition, controlling for the other clinical and demographic variables that could produce bias in the interpretation of the results. Seventy stable schizophrenic patients were evaluated through psychiatric assessment and a neuropsychological battery including tests on attention, memory, perceptual-motor speed and executive functions. We found that the severity of negative symptoms was strongly correlated with poor performance in almost all domains of cognitive functions, while only the attentional deficit was correlated with positive symptoms. The relationships between different cognitive domains and specific types of delusions and hallucinations showed that thought insertion, guilt, grandiose, religious and somatic delusions were associated with impairment in different cognitive functions (verbal and visual memory, attention and executive functions). Voices arguing and tactile hallucinations were correlated to delay-recall memory function. Our results suggest that no specific cognitive pattern is associated with typical-content delusions and hallucinations. On the basis of our findings, cognitive impairments associated with delusions and hallucinations, as measured by our battery, seem not to play a central role in the genesis and the maintenance of these symptoms, suggesting a more complex model of pathogenesis. D
Proceedings of the National Academy of Sciences, 2001
A principle that regulates detailed architecture in the brain is that active terminals have a com... more A principle that regulates detailed architecture in the brain is that active terminals have a competitive advantage over less active terminals in establishing synaptic connections. This principle is known to apply to fibers within a single neuronal population competing for a common target domain. Here we uncover an additional rule that applies when two neuronal populations compete for two contiguous territories. The cerebellar Purkinje cell dendrites have two different synaptic domains with spines innervated by two separate excitatory inputs, parallel fibers (PFs) and climbing fibers (CFs). Glutamate ␦-2 receptors are normally present only on the PF spines where they are important for their innervation. After block of activity by tetrodotoxin, numerous new spines form in the CF domain and become innervated mainly by PFs; all spines, including those still innervated by the CFs, bear ␦-2 receptors. Thus, in the absence of activity, PFs gain a competitive advantage over CFs. The entire dendritic arbor becomes a uniform territory with the molecular cues associated with the PFs. To access their proper territory and maintain synaptic contacts, CFs must be active and locally repress the cues of the competitor afferents.
European Journal of Neuroscience, 2005
Previous experiments have shown that in the mature cerebellum both blocking of spontaneous electr... more Previous experiments have shown that in the mature cerebellum both blocking of spontaneous electrical activity and destruction of the climbing fibres by a lesion of the inferior olive have a similar profound effect on the spine distribution on the proximal dendrites of the Purkinje cells. Many new spines develop that are largely innervated by parallel fibers. Here we show that blocking electrical activity leads to a significant decrease in size of the spines on the branchlets. We have also compared the size of the spines of the proximal dendritic domain that appear during activity block and after an inferior olive lesion. In this region also, the spines in the absence of activity are significantly smaller. In the proximal dendritic domain, the new spines that develop in the absence of activity are innervated by parallel fibers and are not significantly different in size from those of the branchlets, although they are shorter. Thus, the spontaneous activity of the cerebellar cortex is necessary not only to maintain the physiological spine distribution profile in the Purkinje cell dendritic tree, but also acts as a signal that prevents spines from shrinking.
Aberrant activity in brain regions underlying various aspects of executive cognition has been rep... more Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ("flanker task") to identify brain activity and connectivity associated with response inhibition and conflict monitoring and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls.
Aberrant activity in brain regions underlying various aspects of executive cognition has been rep... more Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task ("flanker task") to identify brain activity and connectivity associated with response inhibition and conflict monitoring and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls.
JAMA psychiatry, 2014
Declarative memory-the ability to learn, store, and retrieve information-has been consistently re... more Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and inc...
Arch Gen Psychiatry, 2011
Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connect... more Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. Research center. A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. Siblings and patients showed greater DLPFC "inefficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPFC activity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene.
Journal of Neuroscience, 2014
The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative suscep... more The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.
Schizophrenia Research, 2008
Psychiatry Research, 2002
Dysthymic disorder is a chronic depressive condition with considerable psychosocial impairment. E... more Dysthymic disorder is a chronic depressive condition with considerable psychosocial impairment. Even if DD patients respond to various antidepressant medications, there has been little systematic study on antidepressant-refractory DD. Only a few trials have evaluated the effects of treatment on psychosocial functioning of dysthymic patients. In this 3-month, open-label study, 60 outpatients with DSM-IV criteria for dysthymic disorder who failed to respond to 3-month treatment with paroxetine 20 mg/day were randomly assigned to treatment with paroxetine 40 mg/day or paroxetine 20 mg/day plus amisulpride 50 mg/day. The effects of the two treatments were assessed for both mood symptoms (21-item Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression, severity and improvement) and psychosocial outcomes (DSM-IV Global Assessment of Functioning, Social Adaptation Self-evaluation Scale). Analysis of variance on all rating scales showed that both treatments were effective over this observation period. Response and remission rates did not differ in the treatment groups. A significantly greater psychosocial improvement was observed in the group receiving combined treatment compared with patients receiving paroxetine alone. Both treatments appeared to be effective in our sample of dysthymic subjects. Combined treatment with paroxetine and amisulpride resulted in a better outcome in terms of social functioning.
Psychiatry Research, 2006
The present study aims at exploring the relationship between content-related aspects of delusions... more The present study aims at exploring the relationship between content-related aspects of delusions and hallucinations in schizophrenia and the basic domains of cognition, controlling for the other clinical and demographic variables that could produce bias in the interpretation of the results. Seventy stable schizophrenic patients were evaluated through psychiatric assessment and a neuropsychological battery including tests on attention, memory, perceptual-motor speed and executive functions. We found that the severity of negative symptoms was strongly correlated with poor performance in almost all domains of cognitive functions, while only the attentional deficit was correlated with positive symptoms. The relationships between different cognitive domains and specific types of delusions and hallucinations showed that thought insertion, guilt, grandiose, religious and somatic delusions were associated with impairment in different cognitive functions (verbal and visual memory, attention and executive functions). Voices arguing and tactile hallucinations were correlated to delay-recall memory function. Our results suggest that no specific cognitive pattern is associated with typical-content delusions and hallucinations. On the basis of our findings, cognitive impairments associated with delusions and hallucinations, as measured by our battery, seem not to play a central role in the genesis and the maintenance of these symptoms, suggesting a more complex model of pathogenesis. D