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REWARD PROCESSING, COGNITION AND PERCEPTION DURING ADOLESCENT BRAIN DEVELOPMENT AND VULNERABILITY FOR PSYCHOSIS
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
haloperidol in first-episode schizophrenia. One-year results of a randomized controlled trial within the German Research Network on Schizophrenia. J. Clin. Psychiatry. 68, 11, 1763-1774. [2] Gaebel et al. (2011). Relapse prevention in first-episode schizophrenia: Maintenance vs. intermittent drug treatment with prodrome-based early intervention. Results of a randomized controlled trial within the German Research Network on Schizophrenia. J. Clin. Psychiatry. 72, 205-18. [3] Gaebel & Riesbeck (2013). Are there clinically useful predictors and early warning signs for pending relapse? Schizophr Res [Epub ahead of print].
PATTERNS OF RESPONSE AND THE NEUROBIOLOGY OF RELAPSE IN SCHIZOPHRENIA Ofer Agid 1 , Cynthia Siu 2 , Gary Remington 3,4 University of Toronto; 2 Data Power (DP), Inc; 3 Department of Psychiatry, Univerity of Toronto; 4 Centre for Addiction and Mental Health, Toronto, ON, Canada
1
Background: Dopamine’s proposed role in psychosis provides a starting point for our understanding of the neurobiology of relapse in schizophrenia. While perturbations in dopamine have been proposed as the final common pathway in psychosis, it is evident that relapse, like response, cannot be conceptualized as a singular process. Similarly, the relationship between response and relapse appears to be multidimensional, with patterns of response defining relapse, and trajectories of response translating to different trajectories of relapse. Relapse can be defined as either primary (i.e. idiopathic) or secondary (e.g. substance abuse, medication non-adherence). Primary relapse occurs in the absence of clear precipitants and thus may better reflect the biology that underlies schizophrenia. Evidence suggests, however, that secondary relapse is more common and may be associated with a more attenuated response to antipsychotics than found in the treatment of the initial episode of psychosis. Methods: Antipsychotic-naïve individuals diagnosed with first-episode schizophrenia were treated following an algorithm that involved treatment with risperidone or olanzapine. Each trial consisted of 3 stages (low, full, or high-dose) lasting up to 4 weeks at each level and adjusted according to response and tolerability. Clinical response was defined as resulting in a Clinical Global Impression Inventory - Improvement (CGI-I) of “much” or “very much improved”, or a Brief Psychiatric Rating Scale (BPRS) Thought Disorder subscale of <6. Clinical data was collected on a monthly basis over a period of 6 months. In the case of relapse due to non-adherence, the same medication and dose where response was previously noted was offered again for the second episode. Results A total of 38 individuals (82% male; average age=22) reached that point following treatment with the first antipsychotic where they met criteria for response. Over a period of 2 years, each of these individuals relapsed due to non-adherence and went through a second trial with the same treatment. We observed that the BPRS (total/core psychosis scale) improvement was significantly greater for the first episode compared to the second episode at every time point over the first 6 months of treatment. The shape of trajectory was, however, similar for both first and second episodes. Discussion: Reinitiating antipsychotic treatment for a second episode of psychosis was found to be associated with an attenuated response to antipsychotic medication. This finding raises questions about the nature of changes that may be taking place in the dopamine system in patients who have relapsed after discontinuing their antipsychotic medication. Whether this observation reflects the progression of biological changes associated schizophrenia or the impact of previous treatment or its withdrawal is not yet understood. The doses of antipsychotic medication and the frequency of administration required to prevent relapse also remains to be elucidated. In a recent 6-month placebo-controlled trial, we found that administering antipsychotic medication on alternating days was not associated with an increased risk of relapse. These lines of evidence raise a number of important questions about the prevention and treatment of psychotic relapses. Our results challenge the assumption that sustained D2 antagonism is the singular requirement for preventing relapse and the expectation that reinstituting the previous level of D2 antagonism is likely to result in a return to a remitted state. Taken together, these findings indicate that response and relapse must be viewed as multidimensional and are likely mediated by distinct mechanisms.
S37
RISK OF SYMPTOM RECURRENCE WITH MEDICATION DISCONTINUATION IN FIRST-EPISODE PSYCHOSIS: A SYSTEMATIC REVIEW Robert Zipursky, Natasja M. Menezes, David L. Streiner Department of Psychiatry and Behavioural Neurosciences, McMaster University Background: The large majority of individuals with a first episode of schizophrenia will experience a remission of symptoms within their first year of treatment. It is not clear how long treatment with antipsychotic medications should be continued in this situation. The possibility that a percentage of patients may not require ongoing treatment and may be unnecessarily exposed to the long-term risks of antipsychotic medications has led to the development of a number of studies to address this question. Methods: We carried out a systematic review to determine the risk of experiencing a recurrence of psychotic symptoms in individuals who have discontinued antipsychotic medications after achieving symptomatic remission from a first episode of non-affective psychosis (FEP). Results: Six studies were identified that met our criteria and these reported a weighted mean one-year recurrence rate of 77% following discontinuation of antipsychotic medication. By two years, the risk of recurrence had increased to over 90%. By comparison, we estimated the one-year recurrence rate for patients who continued antipsychotic medication to be 3%. Discussion: These findings suggest that in the absence of uncertainty about the diagnosis or concerns about the contribution of medication side effects to problems with health or functioning, a trial off of antipsychotic medications is associated with a very high risk of symptom recurrence and should thus not be recommended.
Symposium REWARD PROCESSING, COGNITION AND PERCEPTION DURING ADOLESCENT BRAIN DEVELOPMENT AND VULNERABILITY FOR PSYCHOSIS Chairpersons: Richard S.E. Keefe and Bita Moghaddam Discussant: Philip McGuire Monday, 7 April 2014 4:15 PM – 6:15 PM Overall Abstract: Adolescence is a stage in which many neural processes are still maturing. Brain networks involved in context-based perception and reward processing are in frequent transition during this critical developmental stage. Although psychosis does not usually emerge until young adulthood, subtle neurobiological changes and the cognitive and behavioral manifestations of these changes may be present during adolescence. It is thus important to determine to what extent an abnormal maturation of reward networks contributes to these conditions. Social interaction, development of perceptual systems, and processing of rewarding information may have a strong impact on sculpting these circuits during adolescence. Cortical inhibitory processes that are essential for response selection and error detection may not be mature during adolescence. Alterations in the maturation of these processes may lead to vulnerability for psychosis. Bita Moghaddam will present single unit and local field potential data suggesting that during value processing and reinforcement expectation tasks, adolescent rats had local field potentials demonstrating that adolescent phasic neural activity is less inhibited and more variable during motivated/reward-driven behaviors. Specifically, diminished inhibitory response of orbitofrontal cortex neurons to salient events and the accompanying detrimental impact on coordinated large-scale activity may lead to reduced efficiency in the processing of cortical neural activity and related behaviors in adolescents. Alison Adcock will present fMRI data from young healthy subjects and ultra high risk participants suggesting a directional prefrontal influence on dopaminergic regions during reward anticipation. These data suggest a model in which the dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior. Hypoactivation in the high-risk group during reward anticipation may be explained by failures in prefrontal regulation of mesolimbic systems. Markus Leweke will present data suggesting that the failures of these neural systems may be evident in basic measures of perceptual integration assessed with binocular depth inversion methodology. These perceptual-cognitive measures may be impaired very early in the disease process in individuals who will later
S38
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
develop psychosis compared to healthy subjects and individuals with other psychiatric diagnoses. Phil McGuire will serve as discussant. These lines of research indicate the maturation of reward processing during adolescence may be essential for adult performance.
ABNORMALITIES IN REWARD PROCESSING IN OFFSPRING OF SCHIZOPHRENIA PATIENTS: FRONTAL-STRIATAL ABNORMALITIES AS A HIGH-RISK PHENOTYPE René S. Kahn 1 , M. Vink 2 , M. Hillegers 2 , M. Vleeschouwer 2 1 UMC Utrecht; 2 Department of Psychiatry, Brain Center Rudolf Magnus, UMC Utrecht Background: During adolescence the brain changes to prepare for the challenges of adulthood. These changes occur at different rates throughout the brain: subcortical regions such as the striatum mature early, whereas the frontal lobe is one of the last regions to fully develop. During adolescence, these regions begin to form fronto-striatal circuits, which subserve important cognitive functions such as inhibitory control and reward processing. Interestingly, adolescence is also the time of onset of most psychiatric illnesses, of which schizophrenia is the most devastating. We have shown that this disorder is characterized by dysfunctions in the fronto-striatal network: these dysfunctions are related to both the cognitive impairments such as inhibitory control and reward processing and the clinical symptoms of schizophrenia, such as psychosis and anhedonia. We hypothesized that schizophrenia is a developmental disorder, in which the fronto-striatal network fails to develop properly during adolescence. We examined the frontostriatal network with functional MRI (inhibitory control and reward processing) in 20 adolescent offspring of schizophrenia patients and 40 age and sex-matched healthy control subjects. We also included 40 childeren of bi[polar patients to examine the specificity of the findings in schizophrenia. Methods: Structural measures: High-resolution T1-weighted scans (on a 3T Philips Achieva scanner) of the striatum and frontal lobe, including volume, diffusion tensor (DTI) and magnetic transfer (MTR) scans. DTI and MTR scans were analyzed using fiber-tracking, based on diffusion tensor fields Functional measures: Inhibition task: This task is geared towards the cognitive aspects of the fronto-striatal network, triggering activation in the rIFG, SMA, and striatum, and deactivation in the motor cortex. Reward task: This task is geared towards the motivational aspects of the fronto-striatal network, triggering activation in the OFC, SMA, ventral striatum, and insula. Functional connectivity: The level of functional coupling between regions in the fronto-striatal network will be investigated using resting-state fMRI as well as the activations during the two tasks. Preliminary results in 14 offspring of schizophrenia patients (mean age 13.3±3 years) and 25 healthy controls (mean age 12.8±2 years). None of the participants received (medical) treatment, nor had a clinical diagnosis. Inhibitory control: Offspring of patients showed hyperactivation of the striatum and frontal cortex during proactive inhibition indicating abnormal functioning in the fronto-striatal network. Activation during reactive inhibition did not differ from healthy controls. Reward processing: Offspring of patients showed hyperactivation in the ventral striatum during reward anticipation. In contrast, activation of the ventral striatum and orbitofrontal cortex was diminished while receiving the reward. Conclusion: Taken together, these preliminary data suggest a fundamentally different developmental trajectory in high-risk offspring of schizophrenia patients than what is seen in healthy developing adolescents, suggesing a dysfunctional frontal-striatal network is present in (unsymptomatic and unmedicated) offspring of schizophrenia patients. Thus, this phenotype is related to the (genetic) risk of developing the illness.
NEURONAL PROCESSING DIFFERENCES IN THE PREFRONTAL CORTEX OF ADOLESCENTS AND ADULTS DURING MOTIVATED BEHAVIOR Bita Moghaddam, David Sturman University of Pittsburgh Introduction: Adolescence coincides with increased sensation-seeking and impulsive behavior, and is often the time of symptomatic onset for psychopathologies, such as mood disorders and schizophrenia. Little is known
about the neuronal basis of the vast behavioral changes that occurs during adolescence. Methods: We recorded single unit and local field potential (LFP) activity from the orbitofrontal cortex of adolescent and adult rats during an instrumental associative learning task. The orbitofrontal cortex is involved in value processing and reinforcement expectation. Results: While both groups performed the task comparably well, there were striking age-related differences in the neural encoding of salient events. At a large-scale level, adolescent LFPs had smaller increases in alpha, beta, and gamma power during reinforcement retrieval and adolescent neurons exhibited greater firing-rate variability throughout the task. Consistent with the mechanism that the coordination of spike timing and the entrainment of LFP oscillations is regulated by inhibitory activity, a smaller proportion of single units were inhibited in adolescents compared to adults during reinforcement retrieval. Discussion: Diminished inhibitory response of orbitofrontal cortex neurons to salient events and the accompanying detrimental impact on coordinated large-scale activity may lead to reduced efficiency in the processing of cortical neural activity and related behaviors in adolescents. Understanding the neural basis of adolescent motivated behavior may give us insight into normal development and ultimately lead to clues to therapeutic strategies for schizophrenia.
DORSOLATERAL PREFRONTAL CORTEX DRIVES MESOLIMBIC DOPAMINERGIC REGIONS DURING MOTIVATED BEHAVIOR: INSIGHTS FROM DYNAMIC CAUSAL MODELING AND FMRI IN AT-RISK ADOLESCENTS R. Alison Adcock 1,2 , Jeffrey MacInnes 1 , Vishnu Murty 1 , Ian Ballard 1 , Siow Ann Chong 3 , Mythily Subramaniam 3 , Richard Keefe 3,4 , Katherine MacDuffie 1 , Joann Poh 5 , Kavitha Dorairaj 5 , Jamie Thong 3 , Yioe Bong 3 1 Center for Cognitive Neuroscience, Duke University, Durham, NC; 2 Center for Cognitive Neuroscience; 3 Translational and Clinical Research, Institute of Mental Health, Singapore; 4 Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC; 5 Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore; 6 Department of Psychiatry and Behavioral Sciences, Duke University, Durham Introduction: Motivation translates goals into action. Motivation to obtain reward is thought to depend on the midbrain [particularly the ventral tegmental area (VTA)], the nucleus accumbens (NAcc), and the dorsolateral prefrontal cortex (dlPFC), but how do the interactions among these regions relate to reward-motivated behavior? To study the influence of motivation on these reward-responsive regions and their interactions, we used functional magnetic resonance imaging (fMRI) data from healthy participants and adolescents or young adults at ultra-high risk for developing psychotic disorders (CAARMS+) as they anticipated and prepared for opportunities to obtain reward, thus allowing characterization of how information about reward changes physiology underlying motivational drive in these two populations. We modeled mesolimbic sensitivity to anticipation of reward and punishment, and used Dynamic Causal Modeling to assess the impact of external reward cues on causal relationships within this network. Results: In healthy participants, DLPFC was the exclusive entry point of information about reward in this network: anticipated reward availability caused VTA and NAcc activation indirectly, via effects on the dlPFC. In group contrasts between at-risk participants and matched controls, there were no main effects of group during reward or loss anticipation, but both the NAcc and the VTA showed greater activation for anticipated gains than losses in controls but not the CAARMS+ participants (p=0.02 for VTA, p=0.001 for NAcc.) Furthermore, both VTA (−0.234, p=0.04) and NAcc activation (−0.414, p=0.04) were inversely correlated with clinical severity as indexed by PANSS positive symptom scales. Our findings of a directional prefrontal influence on dopaminergic regions during reward anticipation suggest a model in which the dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior; ongoing analyses will test the hypothesis that the clinically-correlated hypoactivation in the CAAMRS+ group is explained by failures in prefontal regulation of mesolimbic systems during motivtated behavior.
haloperidol in first-episode schizophrenia. One-year results of a randomized controlled trial within the German Research Network on Schizophrenia. J. Clin. Psychiatry. 68, 11, 1763-1774. [2] Gaebel et al. (2011). Relapse prevention in first-episode schizophrenia: Maintenance vs. intermittent drug treatment with prodrome-based early intervention. Results of a randomized controlled trial within the German Research Network on Schizophrenia. J. Clin. Psychiatry. 72, 205-18. [3] Gaebel & Riesbeck (2013). Are there clinically useful predictors and early warning signs for pending relapse? Schizophr Res [Epub ahead of print].
PATTERNS OF RESPONSE AND THE NEUROBIOLOGY OF RELAPSE IN SCHIZOPHRENIA Ofer Agid 1 , Cynthia Siu 2 , Gary Remington 3,4 University of Toronto; 2 Data Power (DP), Inc; 3 Department of Psychiatry, Univerity of Toronto; 4 Centre for Addiction and Mental Health, Toronto, ON, Canada
1
Background: Dopamine’s proposed role in psychosis provides a starting point for our understanding of the neurobiology of relapse in schizophrenia. While perturbations in dopamine have been proposed as the final common pathway in psychosis, it is evident that relapse, like response, cannot be conceptualized as a singular process. Similarly, the relationship between response and relapse appears to be multidimensional, with patterns of response defining relapse, and trajectories of response translating to different trajectories of relapse. Relapse can be defined as either primary (i.e. idiopathic) or secondary (e.g. substance abuse, medication non-adherence). Primary relapse occurs in the absence of clear precipitants and thus may better reflect the biology that underlies schizophrenia. Evidence suggests, however, that secondary relapse is more common and may be associated with a more attenuated response to antipsychotics than found in the treatment of the initial episode of psychosis. Methods: Antipsychotic-naïve individuals diagnosed with first-episode schizophrenia were treated following an algorithm that involved treatment with risperidone or olanzapine. Each trial consisted of 3 stages (low, full, or high-dose) lasting up to 4 weeks at each level and adjusted according to response and tolerability. Clinical response was defined as resulting in a Clinical Global Impression Inventory - Improvement (CGI-I) of “much” or “very much improved”, or a Brief Psychiatric Rating Scale (BPRS) Thought Disorder subscale of <6. Clinical data was collected on a monthly basis over a period of 6 months. In the case of relapse due to non-adherence, the same medication and dose where response was previously noted was offered again for the second episode. Results A total of 38 individuals (82% male; average age=22) reached that point following treatment with the first antipsychotic where they met criteria for response. Over a period of 2 years, each of these individuals relapsed due to non-adherence and went through a second trial with the same treatment. We observed that the BPRS (total/core psychosis scale) improvement was significantly greater for the first episode compared to the second episode at every time point over the first 6 months of treatment. The shape of trajectory was, however, similar for both first and second episodes. Discussion: Reinitiating antipsychotic treatment for a second episode of psychosis was found to be associated with an attenuated response to antipsychotic medication. This finding raises questions about the nature of changes that may be taking place in the dopamine system in patients who have relapsed after discontinuing their antipsychotic medication. Whether this observation reflects the progression of biological changes associated schizophrenia or the impact of previous treatment or its withdrawal is not yet understood. The doses of antipsychotic medication and the frequency of administration required to prevent relapse also remains to be elucidated. In a recent 6-month placebo-controlled trial, we found that administering antipsychotic medication on alternating days was not associated with an increased risk of relapse. These lines of evidence raise a number of important questions about the prevention and treatment of psychotic relapses. Our results challenge the assumption that sustained D2 antagonism is the singular requirement for preventing relapse and the expectation that reinstituting the previous level of D2 antagonism is likely to result in a return to a remitted state. Taken together, these findings indicate that response and relapse must be viewed as multidimensional and are likely mediated by distinct mechanisms.
S37
RISK OF SYMPTOM RECURRENCE WITH MEDICATION DISCONTINUATION IN FIRST-EPISODE PSYCHOSIS: A SYSTEMATIC REVIEW Robert Zipursky, Natasja M. Menezes, David L. Streiner Department of Psychiatry and Behavioural Neurosciences, McMaster University Background: The large majority of individuals with a first episode of schizophrenia will experience a remission of symptoms within their first year of treatment. It is not clear how long treatment with antipsychotic medications should be continued in this situation. The possibility that a percentage of patients may not require ongoing treatment and may be unnecessarily exposed to the long-term risks of antipsychotic medications has led to the development of a number of studies to address this question. Methods: We carried out a systematic review to determine the risk of experiencing a recurrence of psychotic symptoms in individuals who have discontinued antipsychotic medications after achieving symptomatic remission from a first episode of non-affective psychosis (FEP). Results: Six studies were identified that met our criteria and these reported a weighted mean one-year recurrence rate of 77% following discontinuation of antipsychotic medication. By two years, the risk of recurrence had increased to over 90%. By comparison, we estimated the one-year recurrence rate for patients who continued antipsychotic medication to be 3%. Discussion: These findings suggest that in the absence of uncertainty about the diagnosis or concerns about the contribution of medication side effects to problems with health or functioning, a trial off of antipsychotic medications is associated with a very high risk of symptom recurrence and should thus not be recommended.
Symposium REWARD PROCESSING, COGNITION AND PERCEPTION DURING ADOLESCENT BRAIN DEVELOPMENT AND VULNERABILITY FOR PSYCHOSIS Chairpersons: Richard S.E. Keefe and Bita Moghaddam Discussant: Philip McGuire Monday, 7 April 2014 4:15 PM – 6:15 PM Overall Abstract: Adolescence is a stage in which many neural processes are still maturing. Brain networks involved in context-based perception and reward processing are in frequent transition during this critical developmental stage. Although psychosis does not usually emerge until young adulthood, subtle neurobiological changes and the cognitive and behavioral manifestations of these changes may be present during adolescence. It is thus important to determine to what extent an abnormal maturation of reward networks contributes to these conditions. Social interaction, development of perceptual systems, and processing of rewarding information may have a strong impact on sculpting these circuits during adolescence. Cortical inhibitory processes that are essential for response selection and error detection may not be mature during adolescence. Alterations in the maturation of these processes may lead to vulnerability for psychosis. Bita Moghaddam will present single unit and local field potential data suggesting that during value processing and reinforcement expectation tasks, adolescent rats had local field potentials demonstrating that adolescent phasic neural activity is less inhibited and more variable during motivated/reward-driven behaviors. Specifically, diminished inhibitory response of orbitofrontal cortex neurons to salient events and the accompanying detrimental impact on coordinated large-scale activity may lead to reduced efficiency in the processing of cortical neural activity and related behaviors in adolescents. Alison Adcock will present fMRI data from young healthy subjects and ultra high risk participants suggesting a directional prefrontal influence on dopaminergic regions during reward anticipation. These data suggest a model in which the dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior. Hypoactivation in the high-risk group during reward anticipation may be explained by failures in prefrontal regulation of mesolimbic systems. Markus Leweke will present data suggesting that the failures of these neural systems may be evident in basic measures of perceptual integration assessed with binocular depth inversion methodology. These perceptual-cognitive measures may be impaired very early in the disease process in individuals who will later
S38
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
develop psychosis compared to healthy subjects and individuals with other psychiatric diagnoses. Phil McGuire will serve as discussant. These lines of research indicate the maturation of reward processing during adolescence may be essential for adult performance.
ABNORMALITIES IN REWARD PROCESSING IN OFFSPRING OF SCHIZOPHRENIA PATIENTS: FRONTAL-STRIATAL ABNORMALITIES AS A HIGH-RISK PHENOTYPE René S. Kahn 1 , M. Vink 2 , M. Hillegers 2 , M. Vleeschouwer 2 1 UMC Utrecht; 2 Department of Psychiatry, Brain Center Rudolf Magnus, UMC Utrecht Background: During adolescence the brain changes to prepare for the challenges of adulthood. These changes occur at different rates throughout the brain: subcortical regions such as the striatum mature early, whereas the frontal lobe is one of the last regions to fully develop. During adolescence, these regions begin to form fronto-striatal circuits, which subserve important cognitive functions such as inhibitory control and reward processing. Interestingly, adolescence is also the time of onset of most psychiatric illnesses, of which schizophrenia is the most devastating. We have shown that this disorder is characterized by dysfunctions in the fronto-striatal network: these dysfunctions are related to both the cognitive impairments such as inhibitory control and reward processing and the clinical symptoms of schizophrenia, such as psychosis and anhedonia. We hypothesized that schizophrenia is a developmental disorder, in which the fronto-striatal network fails to develop properly during adolescence. We examined the frontostriatal network with functional MRI (inhibitory control and reward processing) in 20 adolescent offspring of schizophrenia patients and 40 age and sex-matched healthy control subjects. We also included 40 childeren of bi[polar patients to examine the specificity of the findings in schizophrenia. Methods: Structural measures: High-resolution T1-weighted scans (on a 3T Philips Achieva scanner) of the striatum and frontal lobe, including volume, diffusion tensor (DTI) and magnetic transfer (MTR) scans. DTI and MTR scans were analyzed using fiber-tracking, based on diffusion tensor fields Functional measures: Inhibition task: This task is geared towards the cognitive aspects of the fronto-striatal network, triggering activation in the rIFG, SMA, and striatum, and deactivation in the motor cortex. Reward task: This task is geared towards the motivational aspects of the fronto-striatal network, triggering activation in the OFC, SMA, ventral striatum, and insula. Functional connectivity: The level of functional coupling between regions in the fronto-striatal network will be investigated using resting-state fMRI as well as the activations during the two tasks. Preliminary results in 14 offspring of schizophrenia patients (mean age 13.3±3 years) and 25 healthy controls (mean age 12.8±2 years). None of the participants received (medical) treatment, nor had a clinical diagnosis. Inhibitory control: Offspring of patients showed hyperactivation of the striatum and frontal cortex during proactive inhibition indicating abnormal functioning in the fronto-striatal network. Activation during reactive inhibition did not differ from healthy controls. Reward processing: Offspring of patients showed hyperactivation in the ventral striatum during reward anticipation. In contrast, activation of the ventral striatum and orbitofrontal cortex was diminished while receiving the reward. Conclusion: Taken together, these preliminary data suggest a fundamentally different developmental trajectory in high-risk offspring of schizophrenia patients than what is seen in healthy developing adolescents, suggesing a dysfunctional frontal-striatal network is present in (unsymptomatic and unmedicated) offspring of schizophrenia patients. Thus, this phenotype is related to the (genetic) risk of developing the illness.
NEURONAL PROCESSING DIFFERENCES IN THE PREFRONTAL CORTEX OF ADOLESCENTS AND ADULTS DURING MOTIVATED BEHAVIOR Bita Moghaddam, David Sturman University of Pittsburgh Introduction: Adolescence coincides with increased sensation-seeking and impulsive behavior, and is often the time of symptomatic onset for psychopathologies, such as mood disorders and schizophrenia. Little is known
about the neuronal basis of the vast behavioral changes that occurs during adolescence. Methods: We recorded single unit and local field potential (LFP) activity from the orbitofrontal cortex of adolescent and adult rats during an instrumental associative learning task. The orbitofrontal cortex is involved in value processing and reinforcement expectation. Results: While both groups performed the task comparably well, there were striking age-related differences in the neural encoding of salient events. At a large-scale level, adolescent LFPs had smaller increases in alpha, beta, and gamma power during reinforcement retrieval and adolescent neurons exhibited greater firing-rate variability throughout the task. Consistent with the mechanism that the coordination of spike timing and the entrainment of LFP oscillations is regulated by inhibitory activity, a smaller proportion of single units were inhibited in adolescents compared to adults during reinforcement retrieval. Discussion: Diminished inhibitory response of orbitofrontal cortex neurons to salient events and the accompanying detrimental impact on coordinated large-scale activity may lead to reduced efficiency in the processing of cortical neural activity and related behaviors in adolescents. Understanding the neural basis of adolescent motivated behavior may give us insight into normal development and ultimately lead to clues to therapeutic strategies for schizophrenia.
DORSOLATERAL PREFRONTAL CORTEX DRIVES MESOLIMBIC DOPAMINERGIC REGIONS DURING MOTIVATED BEHAVIOR: INSIGHTS FROM DYNAMIC CAUSAL MODELING AND FMRI IN AT-RISK ADOLESCENTS R. Alison Adcock 1,2 , Jeffrey MacInnes 1 , Vishnu Murty 1 , Ian Ballard 1 , Siow Ann Chong 3 , Mythily Subramaniam 3 , Richard Keefe 3,4 , Katherine MacDuffie 1 , Joann Poh 5 , Kavitha Dorairaj 5 , Jamie Thong 3 , Yioe Bong 3 1 Center for Cognitive Neuroscience, Duke University, Durham, NC; 2 Center for Cognitive Neuroscience; 3 Translational and Clinical Research, Institute of Mental Health, Singapore; 4 Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC; 5 Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore; 6 Department of Psychiatry and Behavioral Sciences, Duke University, Durham Introduction: Motivation translates goals into action. Motivation to obtain reward is thought to depend on the midbrain [particularly the ventral tegmental area (VTA)], the nucleus accumbens (NAcc), and the dorsolateral prefrontal cortex (dlPFC), but how do the interactions among these regions relate to reward-motivated behavior? To study the influence of motivation on these reward-responsive regions and their interactions, we used functional magnetic resonance imaging (fMRI) data from healthy participants and adolescents or young adults at ultra-high risk for developing psychotic disorders (CAARMS+) as they anticipated and prepared for opportunities to obtain reward, thus allowing characterization of how information about reward changes physiology underlying motivational drive in these two populations. We modeled mesolimbic sensitivity to anticipation of reward and punishment, and used Dynamic Causal Modeling to assess the impact of external reward cues on causal relationships within this network. Results: In healthy participants, DLPFC was the exclusive entry point of information about reward in this network: anticipated reward availability caused VTA and NAcc activation indirectly, via effects on the dlPFC. In group contrasts between at-risk participants and matched controls, there were no main effects of group during reward or loss anticipation, but both the NAcc and the VTA showed greater activation for anticipated gains than losses in controls but not the CAARMS+ participants (p=0.02 for VTA, p=0.001 for NAcc.) Furthermore, both VTA (−0.234, p=0.04) and NAcc activation (−0.414, p=0.04) were inversely correlated with clinical severity as indexed by PANSS positive symptom scales. Our findings of a directional prefrontal influence on dopaminergic regions during reward anticipation suggest a model in which the dlPFC integrates and transmits representations of reward to the mesolimbic and mesocortical dopamine systems, thereby initiating motivated behavior; ongoing analyses will test the hypothesis that the clinically-correlated hypoactivation in the CAAMRS+ group is explained by failures in prefontal regulation of mesolimbic systems during motivtated behavior.