- Email: [email protected]
Dopamine dysfunction in schizophrenia
e6
Abstracts
Woodberry, K.A., Giuliano, A.J., Seidman, L.J., 2008. Premorbid IQ in schizophrenia: a meta-analytic review. Am. J. Psychiatry 165 (5), 579–587. Wykes, T., Huddy, V., Cellard, C., McGurk, S.R., Czobor, P., 2011. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168 (5), 472–485. Kraepelin, E., 1919. Dementia Praecox and Paraphrenia. E & S Livingston, Edinburgh, Scotland. Seidman, L.J., Cassens, G., Kremen, W.S., Pepple, J.R., 1992. The neuropsychology of schizophrenia. In: White, R.W. (Ed.), Clinical Syndromes in Adult Neuropsychology: The Practitioner's Handbook. Elsevier, Amsterdam, pp. 381–450.
doi:10.1016/j.schres.2014.09.067
Biomarkers of vulnerability and progression in the psychosis prodrome Tyrone D. Cannon1 Department of Psychology, Yale University, United States; Department of Psychiatry, Yale University, United States 1 On behalf of the North American Prodrome Longitudinal Study (NAPLS) Consortium. E-mail: [email protected] Identification of the fundamental mechanisms underlying onset of psychosis is critical for the development of targeted pre-emptive interventions. This talk presented findings on clinical risk prediction algorithms as well as biomarkers assessed longitudinally in youth at clinical high-risk for psychosis as part of the second phase of the North American Prodrome Longitudinal Study (NAPLS2) (Addington et al., 2012). The study cohort consists of 765 clinical high-risk (CHR) participants and 260 healthy control subjects. The primary outcome was conversion to psychosis over 2 years from initial evaluation. Participants were evaluated with structural MRI, electrophysiology (mismatch negativity [MMN], auditory P300), and cortisol assays at baseline and at 12 months or at conversion to psychosis. Smaller subgroups were evaluated with functional MRI (resting state, verbal working memory, associative learning, emotion processing) and plasma analytes (indexing inflammatory and oxidative stress markers) at baseline. Multivariate models incorporating risk factors from clinical, demographic, neurocognitive, and psychosocial assessments achieved high levels of predictive accuracy when applied to individuals who meet criteria for a prodromal risk syndrome. A risk calculator was created that can be used to scale the risk for newly ascertained cases based on this set of predictors (Cannon, 2014). With respect to biomarkers, at risk individuals who converted to psychosis showed elevated levels of cortisol (Walker et al., 2013) and pro-inflammatory cytokines (Perkins et al., in press), as well as lower MMN and P300 amplitude (Mathalon et al., 2014) and disrupted resting state thalamo-cortical functional connectivity (Anticevic et al., 2014) at baseline, compared to those who do not. Further, converters showed a steeper rate of gray matter reduction, most prominent in prefrontal cortex that in turn was predicted by higher levels of cortisol and inflammatory markers as well as by lower MMN amplitude at baseline (Cannon et al., in press). Each biomarker was a significant predictor of psychosis on its own, and several improved predictions over and above the level achieved by the clinical, demographic, and cognitive algorithm (Cannon, 2014). Microglia, resident immune cells in the brain, have recently been discovered to influence synaptic plasticity in health (Schafer et al., 2013; Zhang et al., 2014) and impair plasticity in disease (Takano et al., 2014). Processes that modulate microglial activation may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of psychosis. Inflammatory markers are elevated in postmortem neural tissue from patients with schizophrenia (Catts et al., 2014; Fillman et al., 2013; Fung et al., 2014; Rao et al., 2013) and these same markers are associated with microglialmediated synaptic pruning and dendritic retraction in animal models (Milatovic et al., 2011; Schafer et al., 2013), thus, providing a potential mechanism for the reduced neuropil and disrupted functional connectivity seen in patients (Glausier and Lewis, 2013; Selemon and Goldman-Rakic, 1999; Selemon et al., 1998). Although prenatal neuroinflammatory processes could “program” for vulnerability (Meyer, 2013), subsequent exposure to stress, infection, autoimmune processes and/or synaptic pruning during adolescent brain development represents influences more proximal to psychosis onset (Frick et al., 2013; Glausier and Lewis, 2013; McGlashan and Hoffman, 2000; Meyer, 2013). Future work is encouraged to target these
mechanisms in longitudinal studies of CHR subjects; results will help to identify targets for preventative intervention.
References Addington, J., Cadenhead, K., Cornblatt, B., Mathalon, D., McGlashan, T., Perkins, D., Seidman, L., Tsuang, M., Walker, E., Woods, S., Addington, J., Cannon, T.D., 2012. North American Prodrome Longitudinal Study 2 (NAPLS-2): overview and recruitment. Schizophr. Res. 142 (1–3), 77–82. Anticevic, A., Haut, K., Cole, M.W., Repovs, G., Yang, G., McEwen, S., Cannon, T.D., 2014. Thalamic dysconnectivity predicts risk for conversion to schizophrenia. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., 2014. The development and implementation of a psychosis risk prediction algorithm. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T.G.M., McEwen, S., Addington, J., Bearden, C.E., Cadenhead, K., Cornblatt, B., Mathalon, D.H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L.J., Tsuang, M., Walker, E., Woods, S.W., Heinssen, R., 2014. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry (in press). Catts, V.S., Wong, J., Fillman, S.G., Fung, S.J., Weickert, C.S., 2014. Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust. N. Z. J. Psychiatry 48 (8), 722–734. Fillman, S.G., Cloonan, N., Catts, V.S., Miller, L.C., Wong, J., McCrossin, T., Cairns, M., Weickert, C.S., 2013. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18 (2), 206–214. Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013, 608654. Fung, S.J., Joshi, D., Fillman, S.G., Weickert, C.S., 2014. High white matter neuron density with elevated cortical cytokine expression in schizophrenia. Biol. Psychiatry 75 (4), e5–e7. Glausier, J.R., Lewis, D.A., 2013. Dendritic spine pathology in schizophrenia. Neuroscience 251, 90–107. Mathalon, D.H., Perkins, D., Walker, E., Addington, J., Bearden, C., Cadenhead, K., Cornblatt, B., McGlashan, T., Seidman, L., Tsuang, M., Woods, S., Cannon, T.D., 2014. Impaired synaptic plasticity, synaptic over-pruning, inflammation, and stress: a pathogenic model of the transition to psychosis in clinical high risk youth. Biol. Psychiatry 75 (9 Supplement). McGlashan, T.H., Hoffman, R.E., 2000. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry 57 (7), 637–648. Meyer, U., 2013. Developmental neuroinflammation and schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 42, 20–34. Milatovic, D., Gupta, R.C., Yu, Y., Zaja-Milatovic, S., Aschner, M., 2011. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury. Toxicol. Appl. Pharmacol. 256 (3), 219–226. Perkins, D.O., Jeffries, C.D., Addington, J., Bearden, C.E., Cadenhead, K.S., Cannon, T.D., Cornblatt, B.A., Mathalon, D.H., McGlashan, T.H., Seidman, L.J., Tsuang, M.T., Walker, E.F., Woods, S.W., Heinssen, R., 2014. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: preliminary results from the NAPLS project. Schizophr. Bull. (in press). Rao, J.S., Kim, H.W., Harry, G.J., Rapoport, S.I., Reese, E.A., 2013. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 147 (1), 24–31. Schafer, D.P., Lehrman, E.K., Stevens, B., 2013. The “quad-partite” synapse: microgliasynapse interactions in the developing and mature CNS. Glia 61 (1), 24–36. Selemon, L.D., Goldman-Rakic, P.S., 1999. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45 (1), 17–25. Selemon, L.D., Rajkowska, G., Goldman-Rakic, P.S., 1998. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a threedimensional, stereologic counting method. J. Comp. Neurol. 392 (3), 402–412. Takano, M., Kawabata, S., Komaki, Y., Shibata, S., Hikishima, K., Toyama, Y., Okano, H., Nakamura, M., 2014. Inflammatory cascades mediate synapse elimination in spinal cord compression. J. Neuroinflammation 11, 40. Walker, E.F., Trotman, H.D., Pearce, B.D., Addington, J., Cadenhead, K.S., Cornblatt, B. A., Heinssen, R., Mathalon, D.H., Perkins, D.O., Seidman, L.J., Tsuang, M.T., Cannon, T.D., McGlashan, T.H., Woods, S.W., 2013. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol. Psychiatry 74 (6), 410–417. Zhang, J., Malik, A., Choi, H.B., Ko, R.W., Dissing-Olesen, L., MacVicar, B.A., 2014. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82 (1), 195–207.
doi:10.1016/j.schres.2014.09.068
Dopamine dysfunction in schizophrenia Anissa Abi-Dargham Department of Psychiatry, Columbia University, New York State Psychiatric Institute, NY, USA E-mail: [email protected]
Abstracts
Brain imaging studies with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have yielded over the past decade robust evidence for alterations in dopamine (DA) transmission in schizophrenia. Imaging studies showed that DA release, as measured with amphetamine-induced displacement of [123I]IBZM or [11C]raclopride from DA D2/3 receptors, is elevated in untreated patients with schizophrenia compared to healthy volunteers (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996). We observed a significant relationship between the magnitude of dopamine release and the transient induction or worsening of positive symptoms. This exaggerated response of the DA system to amphetamine was observed in both first episode/drug naive patients and previously treated patients (Laruelle et al., 1999), but was larger in patients experiencing an episode of illness exacerbation than in patients in remission at the time of the scan (Laruelle et al., 1999). Furthermore we observed that amphetaminestimulated DA release and baseline DA activity measured with an acute DA depletion paradigm are related in patients but not in controls (Abi-Dargham et al., 2009), and similarly elevated (Abi-Dargham et al., 2000). Elevated DA predicted the response of positive symptoms to antipsychotics. More recently, with advances in clinical and imaging analysis tools, we showed that the largest DA excess was observed in the associative striatum and not in limbic striatum as was long hypothesized (2010). This area of the striatum receives convergent input from both cognitive and limbic cortical areas, making it a unique site of integration across functional domains (Haber et al., 2006). This finding received support from studies by Howes and colleagues showing increases in [18F]DOPA uptake in associative striatum in patients prodromal for schizophrenia (Howes et al., 2009) predicting conversion (Howes et al., 2011b) and progressing further on follow-up after two years to involve the sensorimotor striatal subregion (Howes et al., 2011a). Furthermore, studies in patients with schizophrenia comorbid for addiction show low presynaptic dopamine release yet a transient increase in psychosis related to the narrow and blunted range of amphetamine induced dopamine release, suggesting a supersensitivity of the D2 receptor, especially in the rostral caudate (Thompson et al., 2013). In summary, the evidence points to both pre and postsynaptic striatal DA dysfunction, most prominent in the rostral caudate, manifesting already in the prodromal phase, predicting symptoms, and predicting response to treatment. Studies of extrastrial DA release are needed to get a more global phenotype, especially in light of the findings from the D2 overexpressing mouse model showing that an isolated increased D2 stimulation in the striatum can lead to cortical deficits, and in light of the prominence of the concept of cortical hypodopaminergia in schizophrenia research (Akil et al., 1999; GoldmanRakic, 1999; Weinberger et al., 1992).
References Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R., Seibyl, J., Bowers, M., van Dyck, C., Charney, D., Innis, R., Laruelle, M., 1998. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767. Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., Kegeles, L.S., Weiss, R., Cooper, T.B., Mann, J.J., Van Heertum, R.L., Gorman, J.M., Laruelle, M., 2000. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 97 (14), 8104–8109. Abi-Dargham, A., van de Giessen, E., Slifstein, M., Kegeles, L.S., Laruelle, M., 2009. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol. Psychiatry 65 (12), 1091–1093. Akil, M., Pierri, J.N., Whitehead, R.E., Edgar, C.L., Mohila, C., Sampson, A.R., Lewis, D.A., 1999. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am. J. Psychiatry 156 (10), 1580–1589. Breier, A., Su, T.P., Saunders, R., Carson, R.E., Kolachana, B.S., deBartolomeis, A., Weinberger, D.R., Weisenfeld, N., Malhotra, A.K., Eckelman, W.C., Pickar, D., 1997. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc. Natl. Acad. Sci. U. S. A. 94 (6), 2569–2574. Goldman-Rakic, P.S., 1999. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol. Psychiatry 46 (5), 650–661. Haber, S.N., Kim, K.S., Mailly, P., Calzavara, R., 2006. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J. Neurosci. 26 (32), 8368–8376. Howes, O., Bose, S., Turkheimer, F., Valli, I., Egerton, A., Stahl, D., Valmaggia, L., Allen, P., Murray, R., McGuire, P., 2011a. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol. Psychiatry 16 (9), 885–886. Howes, O.D., Bose, S.K., Turkheimer, F., Valli, I., Egerton, A., Valmaggia, L.R., Murray, R.M., McGuire, P., 2011b. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am. J. Psychiatry 168 (12), 1311–1317.
e7
Howes, O.D., Montgomery, A.J., Asselin, M.C., Murray, R.M., Valli, I., Tabraham, P., Bramon-Bosch, E., Valmaggia, L., Johns, L., Broome, M., McGuire, P.K., Grasby, P.M., 2009. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66 (1), 13–20. Kegeles, L.S., Abi-Dargham, A., Frankle, W.G., Gil, R., Cooper, T.B., Slifstein, M., Hwang, D.R., Huang, Y., Haber, S.N., Laruelle, M., 2010. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch. Gen. Psychiatry 67 (3), 231–239. Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L., Innis, R., 1999. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol. Psychiatry 46 (1), 56–72. Laruelle, M., Abi-Dargham, A., van Dyck, C.H., Gil, R., De Souza, C.D., Erdos, J., Mc Cance, E., Rosenblatt, W., Fingado, C., Zoghbi, S.S., Baldwin, R.M., Seibyl, J.P., Krystal, J.H., Charney, D.S., Innis, R.B., 1996. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc. Natl. Acad. Sci. U. S. A. 93, 9235–9240. Thompson, J.L., Urban, N., Slifstein, M., Xu, X., Kegeles, L.S., Girgis, R.R., Beckerman, Y., Harkavy-Friedman, J.M., Gil, R., Abi-Dargham, A., 2013. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol. Psychiatry 18, 909–915. Weinberger, D.R., Berman, K.F., Daniel, D.G., 1992. Mesoprefrontal cortical dopaminergic activity and prefrontal hypofunction in schizophrenia. Clin. Neuropharmacol. 15 (Suppl. 1 Pt A), 568A–569A.
doi:10.1016/j.schres.2014.09.069
A neural circuitry basis for impaired cortical network oscillations and cognitive dysfunction in schizophrenia David A. Lewis Department of Psychiatry, University of Pittsburgh, United States E-mail: [email protected] Major challenges in schizophrenia research today include 1) the need for a diagnostic approach based on an understanding of the underlying disease process(es) as opposed to the current reliance on the presence of a cluster of certain clinical signs and symptoms; and 2) therapeutic interventions that target disease mechanisms as opposed to current symptomatic treatments. The premise of this presentation is that understanding disease processes at the level of the affected neural circuits has the potential to provide an empirical substrate for diagnostic categories and a rational basis for developing novel therapeutics, as well as an effective explanation to patients for the nature of their problems and the therapeutic solution. Hence, the goal of the presentation is to illustrate one strategy for dissecting the disease process of a domain of dysfunction in schizophrenia, specifically, to identify a neural circuitry substrate for certain cognitive deficits in schizophrenia. The presentation focuses on cognitive deficits as a core and clinically critical feature of schizophrenia. This view is supported by the findings that cognitive impairments are highly prevalent in affected individuals, detectable in milder form in unaffected relatives, present and progressive before the onset of psychosis, persistent across the course of illness, a strong predictor of long-term functional outcome, and likely a product of impaired cortical network oscillations. Specifically, working memory deficits have been associated with impaired neural network oscillations at gamma band frequency (40–80 Hz) in the prefrontal cortex. The generation of cortical gamma oscillations appears to occur principally in layer 3 and depend upon reciprocal connections between excitatory pyramidal neurons and inhibitory interneurons, specifically the parvalbumin-containing, basket cell class of GABA neurons. Multiple markers of the function of parvalbumin neurons, including mRNA and protein levels of the GAD1 gene that is responsible for most cortical GABA synthesis, have been consistently shown to be lower in the prefrontal cortex of subjects with schizophrenia. These findings are not attributable to other medications or other factors that frequently accompany a diagnosis of schizophrenia. Such findings have been interpreted as evidence that parvalbumin neurons may be the principal site of cortical pathology in the illness. However, layer 3 pyramidal cells that innervate parvalbumin basket cells have a lower density of dendritic spines, the principal site of excitatory inputs to pyramidal neurons, as well as patterns of gene expression that could provide a molecular basis for an intrinsic deficit in the capacity of the specific class of neurons to form and maintain spines. In addition, layer 3 pyramidal cells have lower levels of the alpha-1 subunit of the GABA-A receptor, which is located
Abstracts
Woodberry, K.A., Giuliano, A.J., Seidman, L.J., 2008. Premorbid IQ in schizophrenia: a meta-analytic review. Am. J. Psychiatry 165 (5), 579–587. Wykes, T., Huddy, V., Cellard, C., McGurk, S.R., Czobor, P., 2011. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am. J. Psychiatry 168 (5), 472–485. Kraepelin, E., 1919. Dementia Praecox and Paraphrenia. E & S Livingston, Edinburgh, Scotland. Seidman, L.J., Cassens, G., Kremen, W.S., Pepple, J.R., 1992. The neuropsychology of schizophrenia. In: White, R.W. (Ed.), Clinical Syndromes in Adult Neuropsychology: The Practitioner's Handbook. Elsevier, Amsterdam, pp. 381–450.
doi:10.1016/j.schres.2014.09.067
Biomarkers of vulnerability and progression in the psychosis prodrome Tyrone D. Cannon1 Department of Psychology, Yale University, United States; Department of Psychiatry, Yale University, United States 1 On behalf of the North American Prodrome Longitudinal Study (NAPLS) Consortium. E-mail: [email protected] Identification of the fundamental mechanisms underlying onset of psychosis is critical for the development of targeted pre-emptive interventions. This talk presented findings on clinical risk prediction algorithms as well as biomarkers assessed longitudinally in youth at clinical high-risk for psychosis as part of the second phase of the North American Prodrome Longitudinal Study (NAPLS2) (Addington et al., 2012). The study cohort consists of 765 clinical high-risk (CHR) participants and 260 healthy control subjects. The primary outcome was conversion to psychosis over 2 years from initial evaluation. Participants were evaluated with structural MRI, electrophysiology (mismatch negativity [MMN], auditory P300), and cortisol assays at baseline and at 12 months or at conversion to psychosis. Smaller subgroups were evaluated with functional MRI (resting state, verbal working memory, associative learning, emotion processing) and plasma analytes (indexing inflammatory and oxidative stress markers) at baseline. Multivariate models incorporating risk factors from clinical, demographic, neurocognitive, and psychosocial assessments achieved high levels of predictive accuracy when applied to individuals who meet criteria for a prodromal risk syndrome. A risk calculator was created that can be used to scale the risk for newly ascertained cases based on this set of predictors (Cannon, 2014). With respect to biomarkers, at risk individuals who converted to psychosis showed elevated levels of cortisol (Walker et al., 2013) and pro-inflammatory cytokines (Perkins et al., in press), as well as lower MMN and P300 amplitude (Mathalon et al., 2014) and disrupted resting state thalamo-cortical functional connectivity (Anticevic et al., 2014) at baseline, compared to those who do not. Further, converters showed a steeper rate of gray matter reduction, most prominent in prefrontal cortex that in turn was predicted by higher levels of cortisol and inflammatory markers as well as by lower MMN amplitude at baseline (Cannon et al., in press). Each biomarker was a significant predictor of psychosis on its own, and several improved predictions over and above the level achieved by the clinical, demographic, and cognitive algorithm (Cannon, 2014). Microglia, resident immune cells in the brain, have recently been discovered to influence synaptic plasticity in health (Schafer et al., 2013; Zhang et al., 2014) and impair plasticity in disease (Takano et al., 2014). Processes that modulate microglial activation may represent convergent mechanisms that influence brain dysconnectivity and risk for onset of psychosis. Inflammatory markers are elevated in postmortem neural tissue from patients with schizophrenia (Catts et al., 2014; Fillman et al., 2013; Fung et al., 2014; Rao et al., 2013) and these same markers are associated with microglialmediated synaptic pruning and dendritic retraction in animal models (Milatovic et al., 2011; Schafer et al., 2013), thus, providing a potential mechanism for the reduced neuropil and disrupted functional connectivity seen in patients (Glausier and Lewis, 2013; Selemon and Goldman-Rakic, 1999; Selemon et al., 1998). Although prenatal neuroinflammatory processes could “program” for vulnerability (Meyer, 2013), subsequent exposure to stress, infection, autoimmune processes and/or synaptic pruning during adolescent brain development represents influences more proximal to psychosis onset (Frick et al., 2013; Glausier and Lewis, 2013; McGlashan and Hoffman, 2000; Meyer, 2013). Future work is encouraged to target these
mechanisms in longitudinal studies of CHR subjects; results will help to identify targets for preventative intervention.
References Addington, J., Cadenhead, K., Cornblatt, B., Mathalon, D., McGlashan, T., Perkins, D., Seidman, L., Tsuang, M., Walker, E., Woods, S., Addington, J., Cannon, T.D., 2012. North American Prodrome Longitudinal Study 2 (NAPLS-2): overview and recruitment. Schizophr. Res. 142 (1–3), 77–82. Anticevic, A., Haut, K., Cole, M.W., Repovs, G., Yang, G., McEwen, S., Cannon, T.D., 2014. Thalamic dysconnectivity predicts risk for conversion to schizophrenia. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., 2014. The development and implementation of a psychosis risk prediction algorithm. Biol. Psychiatry 75 (9 Supplement). Cannon, T.D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T.G.M., McEwen, S., Addington, J., Bearden, C.E., Cadenhead, K., Cornblatt, B., Mathalon, D.H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L.J., Tsuang, M., Walker, E., Woods, S.W., Heinssen, R., 2014. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry (in press). Catts, V.S., Wong, J., Fillman, S.G., Fung, S.J., Weickert, C.S., 2014. Increased expression of astrocyte markers in schizophrenia: association with neuroinflammation. Aust. N. Z. J. Psychiatry 48 (8), 722–734. Fillman, S.G., Cloonan, N., Catts, V.S., Miller, L.C., Wong, J., McCrossin, T., Cairns, M., Weickert, C.S., 2013. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18 (2), 206–214. Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial dysregulation in psychiatric disease. Clin. Dev. Immunol. 2013, 608654. Fung, S.J., Joshi, D., Fillman, S.G., Weickert, C.S., 2014. High white matter neuron density with elevated cortical cytokine expression in schizophrenia. Biol. Psychiatry 75 (4), e5–e7. Glausier, J.R., Lewis, D.A., 2013. Dendritic spine pathology in schizophrenia. Neuroscience 251, 90–107. Mathalon, D.H., Perkins, D., Walker, E., Addington, J., Bearden, C., Cadenhead, K., Cornblatt, B., McGlashan, T., Seidman, L., Tsuang, M., Woods, S., Cannon, T.D., 2014. Impaired synaptic plasticity, synaptic over-pruning, inflammation, and stress: a pathogenic model of the transition to psychosis in clinical high risk youth. Biol. Psychiatry 75 (9 Supplement). McGlashan, T.H., Hoffman, R.E., 2000. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry 57 (7), 637–648. Meyer, U., 2013. Developmental neuroinflammation and schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 42, 20–34. Milatovic, D., Gupta, R.C., Yu, Y., Zaja-Milatovic, S., Aschner, M., 2011. Protective effects of antioxidants and anti-inflammatory agents against manganese-induced oxidative damage and neuronal injury. Toxicol. Appl. Pharmacol. 256 (3), 219–226. Perkins, D.O., Jeffries, C.D., Addington, J., Bearden, C.E., Cadenhead, K.S., Cannon, T.D., Cornblatt, B.A., Mathalon, D.H., McGlashan, T.H., Seidman, L.J., Tsuang, M.T., Walker, E.F., Woods, S.W., Heinssen, R., 2014. Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: preliminary results from the NAPLS project. Schizophr. Bull. (in press). Rao, J.S., Kim, H.W., Harry, G.J., Rapoport, S.I., Reese, E.A., 2013. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 147 (1), 24–31. Schafer, D.P., Lehrman, E.K., Stevens, B., 2013. The “quad-partite” synapse: microgliasynapse interactions in the developing and mature CNS. Glia 61 (1), 24–36. Selemon, L.D., Goldman-Rakic, P.S., 1999. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45 (1), 17–25. Selemon, L.D., Rajkowska, G., Goldman-Rakic, P.S., 1998. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a threedimensional, stereologic counting method. J. Comp. Neurol. 392 (3), 402–412. Takano, M., Kawabata, S., Komaki, Y., Shibata, S., Hikishima, K., Toyama, Y., Okano, H., Nakamura, M., 2014. Inflammatory cascades mediate synapse elimination in spinal cord compression. J. Neuroinflammation 11, 40. Walker, E.F., Trotman, H.D., Pearce, B.D., Addington, J., Cadenhead, K.S., Cornblatt, B. A., Heinssen, R., Mathalon, D.H., Perkins, D.O., Seidman, L.J., Tsuang, M.T., Cannon, T.D., McGlashan, T.H., Woods, S.W., 2013. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol. Psychiatry 74 (6), 410–417. Zhang, J., Malik, A., Choi, H.B., Ko, R.W., Dissing-Olesen, L., MacVicar, B.A., 2014. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82 (1), 195–207.
doi:10.1016/j.schres.2014.09.068
Dopamine dysfunction in schizophrenia Anissa Abi-Dargham Department of Psychiatry, Columbia University, New York State Psychiatric Institute, NY, USA E-mail: [email protected]
Abstracts
Brain imaging studies with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have yielded over the past decade robust evidence for alterations in dopamine (DA) transmission in schizophrenia. Imaging studies showed that DA release, as measured with amphetamine-induced displacement of [123I]IBZM or [11C]raclopride from DA D2/3 receptors, is elevated in untreated patients with schizophrenia compared to healthy volunteers (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996). We observed a significant relationship between the magnitude of dopamine release and the transient induction or worsening of positive symptoms. This exaggerated response of the DA system to amphetamine was observed in both first episode/drug naive patients and previously treated patients (Laruelle et al., 1999), but was larger in patients experiencing an episode of illness exacerbation than in patients in remission at the time of the scan (Laruelle et al., 1999). Furthermore we observed that amphetaminestimulated DA release and baseline DA activity measured with an acute DA depletion paradigm are related in patients but not in controls (Abi-Dargham et al., 2009), and similarly elevated (Abi-Dargham et al., 2000). Elevated DA predicted the response of positive symptoms to antipsychotics. More recently, with advances in clinical and imaging analysis tools, we showed that the largest DA excess was observed in the associative striatum and not in limbic striatum as was long hypothesized (2010). This area of the striatum receives convergent input from both cognitive and limbic cortical areas, making it a unique site of integration across functional domains (Haber et al., 2006). This finding received support from studies by Howes and colleagues showing increases in [18F]DOPA uptake in associative striatum in patients prodromal for schizophrenia (Howes et al., 2009) predicting conversion (Howes et al., 2011b) and progressing further on follow-up after two years to involve the sensorimotor striatal subregion (Howes et al., 2011a). Furthermore, studies in patients with schizophrenia comorbid for addiction show low presynaptic dopamine release yet a transient increase in psychosis related to the narrow and blunted range of amphetamine induced dopamine release, suggesting a supersensitivity of the D2 receptor, especially in the rostral caudate (Thompson et al., 2013). In summary, the evidence points to both pre and postsynaptic striatal DA dysfunction, most prominent in the rostral caudate, manifesting already in the prodromal phase, predicting symptoms, and predicting response to treatment. Studies of extrastrial DA release are needed to get a more global phenotype, especially in light of the findings from the D2 overexpressing mouse model showing that an isolated increased D2 stimulation in the striatum can lead to cortical deficits, and in light of the prominence of the concept of cortical hypodopaminergia in schizophrenia research (Akil et al., 1999; GoldmanRakic, 1999; Weinberger et al., 1992).
References Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R., Seibyl, J., Bowers, M., van Dyck, C., Charney, D., Innis, R., Laruelle, M., 1998. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatry 155, 761–767. Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., Kegeles, L.S., Weiss, R., Cooper, T.B., Mann, J.J., Van Heertum, R.L., Gorman, J.M., Laruelle, M., 2000. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 97 (14), 8104–8109. Abi-Dargham, A., van de Giessen, E., Slifstein, M., Kegeles, L.S., Laruelle, M., 2009. Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol. Psychiatry 65 (12), 1091–1093. Akil, M., Pierri, J.N., Whitehead, R.E., Edgar, C.L., Mohila, C., Sampson, A.R., Lewis, D.A., 1999. Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am. J. Psychiatry 156 (10), 1580–1589. Breier, A., Su, T.P., Saunders, R., Carson, R.E., Kolachana, B.S., deBartolomeis, A., Weinberger, D.R., Weisenfeld, N., Malhotra, A.K., Eckelman, W.C., Pickar, D., 1997. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc. Natl. Acad. Sci. U. S. A. 94 (6), 2569–2574. Goldman-Rakic, P.S., 1999. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol. Psychiatry 46 (5), 650–661. Haber, S.N., Kim, K.S., Mailly, P., Calzavara, R., 2006. Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. J. Neurosci. 26 (32), 8368–8376. Howes, O., Bose, S., Turkheimer, F., Valli, I., Egerton, A., Stahl, D., Valmaggia, L., Allen, P., Murray, R., McGuire, P., 2011a. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol. Psychiatry 16 (9), 885–886. Howes, O.D., Bose, S.K., Turkheimer, F., Valli, I., Egerton, A., Valmaggia, L.R., Murray, R.M., McGuire, P., 2011b. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am. J. Psychiatry 168 (12), 1311–1317.
e7
Howes, O.D., Montgomery, A.J., Asselin, M.C., Murray, R.M., Valli, I., Tabraham, P., Bramon-Bosch, E., Valmaggia, L., Johns, L., Broome, M., McGuire, P.K., Grasby, P.M., 2009. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch. Gen. Psychiatry 66 (1), 13–20. Kegeles, L.S., Abi-Dargham, A., Frankle, W.G., Gil, R., Cooper, T.B., Slifstein, M., Hwang, D.R., Huang, Y., Haber, S.N., Laruelle, M., 2010. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch. Gen. Psychiatry 67 (3), 231–239. Laruelle, M., Abi-Dargham, A., Gil, R., Kegeles, L., Innis, R., 1999. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol. Psychiatry 46 (1), 56–72. Laruelle, M., Abi-Dargham, A., van Dyck, C.H., Gil, R., De Souza, C.D., Erdos, J., Mc Cance, E., Rosenblatt, W., Fingado, C., Zoghbi, S.S., Baldwin, R.M., Seibyl, J.P., Krystal, J.H., Charney, D.S., Innis, R.B., 1996. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug free schizophrenic subjects. Proc. Natl. Acad. Sci. U. S. A. 93, 9235–9240. Thompson, J.L., Urban, N., Slifstein, M., Xu, X., Kegeles, L.S., Girgis, R.R., Beckerman, Y., Harkavy-Friedman, J.M., Gil, R., Abi-Dargham, A., 2013. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol. Psychiatry 18, 909–915. Weinberger, D.R., Berman, K.F., Daniel, D.G., 1992. Mesoprefrontal cortical dopaminergic activity and prefrontal hypofunction in schizophrenia. Clin. Neuropharmacol. 15 (Suppl. 1 Pt A), 568A–569A.
doi:10.1016/j.schres.2014.09.069
A neural circuitry basis for impaired cortical network oscillations and cognitive dysfunction in schizophrenia David A. Lewis Department of Psychiatry, University of Pittsburgh, United States E-mail: [email protected] Major challenges in schizophrenia research today include 1) the need for a diagnostic approach based on an understanding of the underlying disease process(es) as opposed to the current reliance on the presence of a cluster of certain clinical signs and symptoms; and 2) therapeutic interventions that target disease mechanisms as opposed to current symptomatic treatments. The premise of this presentation is that understanding disease processes at the level of the affected neural circuits has the potential to provide an empirical substrate for diagnostic categories and a rational basis for developing novel therapeutics, as well as an effective explanation to patients for the nature of their problems and the therapeutic solution. Hence, the goal of the presentation is to illustrate one strategy for dissecting the disease process of a domain of dysfunction in schizophrenia, specifically, to identify a neural circuitry substrate for certain cognitive deficits in schizophrenia. The presentation focuses on cognitive deficits as a core and clinically critical feature of schizophrenia. This view is supported by the findings that cognitive impairments are highly prevalent in affected individuals, detectable in milder form in unaffected relatives, present and progressive before the onset of psychosis, persistent across the course of illness, a strong predictor of long-term functional outcome, and likely a product of impaired cortical network oscillations. Specifically, working memory deficits have been associated with impaired neural network oscillations at gamma band frequency (40–80 Hz) in the prefrontal cortex. The generation of cortical gamma oscillations appears to occur principally in layer 3 and depend upon reciprocal connections between excitatory pyramidal neurons and inhibitory interneurons, specifically the parvalbumin-containing, basket cell class of GABA neurons. Multiple markers of the function of parvalbumin neurons, including mRNA and protein levels of the GAD1 gene that is responsible for most cortical GABA synthesis, have been consistently shown to be lower in the prefrontal cortex of subjects with schizophrenia. These findings are not attributable to other medications or other factors that frequently accompany a diagnosis of schizophrenia. Such findings have been interpreted as evidence that parvalbumin neurons may be the principal site of cortical pathology in the illness. However, layer 3 pyramidal cells that innervate parvalbumin basket cells have a lower density of dendritic spines, the principal site of excitatory inputs to pyramidal neurons, as well as patterns of gene expression that could provide a molecular basis for an intrinsic deficit in the capacity of the specific class of neurons to form and maintain spines. In addition, layer 3 pyramidal cells have lower levels of the alpha-1 subunit of the GABA-A receptor, which is located