Alan Bates | University of British Columbia (original) (raw)
Papers by Alan Bates
The British Journal of Psychiatry
Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought d... more Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown. To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia. Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared. The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlate...
Schizophrenia Research, 2006
Schizophrenia Research, 2008
Controversy exists regarding whether young people at risk for schizophrenia are at increased risk... more Controversy exists regarding whether young people at risk for schizophrenia are at increased risk of adverse mental effects of cannabis use. We examined cannabis use and mental health functioning in three groups of young people aged 14-21; 36 non-psychotic siblings of adolescents with schizophrenia (genetic high risk group), 25 adolescents with attention deficit hyperactivity disorder (ADHD) and 72 healthy controls. The groups were sub-divided into 'users' and 'non-users' of cannabis based on how often they had used cannabis previously. Mental health functioning was quantified by creating a composite index derived from scores on the Schizotypal Personality Questionnaire (SPQ), Strengths and Difficulties Questionnaire (SDQ) and Global Assessment of Function (GAF). A significant positive association between cannabis use and mental health disturbance was confined to young people at genetic high risk for schizophrenia. To determine whether the relationship was specific to particular dimensions of mental health function, a second composite index was created based on scores from the SPQ Disorganisation and SDQ hyperactivity-inattention sub-scales. Again, there was a significant positive association between cannabis use and factor scores which was specific to the genetic high risk group. There was a trend for this association to be negative in the ADHD group (p=0.07). The findings support the view that young people at genetic high risk for schizophrenia are particularly vulnerable to mental health problems associated with cannabis use. Further research is needed to investigate the basis of relationships between cannabis and mental health in genetically vulnerable individuals.
To assess the interrater reliability, sensitivity and factor structure of a new sensitivity and f... more To assess the interrater reliability, sensitivity and factor structure of a new sensitivity and factor structure of a new assessment instrument, theThought and assessment instrument, theThought and Language Index (TLI), and to determine if Language Index (TLI), and to determine if minor aberrations detectable in the minor aberrations detectable in the speech of healthy individuals are related to speech of
Schizophrenia Research, 2009
Numerous studies have described attenuated event-related potential (ERP) component amplitudes in ... more Numerous studies have described attenuated event-related potential (ERP) component amplitudes in schizophrenia (e.g., P300, Mismatch Negativity (MMN), Error Negativity/Error-Related Negativity (Ne/ERN)). Functional magnetic resonance imaging (fMRI) studies have typically shown decreased recruitment of diverse brain areas during performance of tasks that elicit the above ERP components. Recent research suggests that phase-resetting of slow-oscillations (e.g., in the delta and theta bands) underlies the potentials observed in ERP averages. Several studies have reported that slow-oscillations are increased in amplitude in people with schizophrenia at rest. Few studies have examined event-related low-frequency oscillations in schizophrenia. We examined event-related evoked and induced delta and theta activity in 17 people with schizophrenia and 17 healthy controls in two go/no-go task variants. We analyzed stimulus-related and response-related oscillations associated with correct-hits, correct-rejects and false-alarms. Our results reveal a pattern of reduced delta and theta activity for task-relevant events in schizophrenia. The findings indicate that while low-frequency oscillations are increased in amplitude at rest, they are not coordinated effectively in schizophrenia during various information processing tasks including target-detection, response-inhibition and error-detection. This slow-oscillation coordination abnormality may help explain the decreased recruitment of brain areas seen in fMRI studies.
Schizophrenia Research, 2006
Schizophrenia Research, 2006
Schizophrenia Research, 2010
Psychophysiology, 2009
This study examines EEG low frequency characteristics which have been linked to specific cognitiv... more This study examines EEG low frequency characteristics which have been linked to specific cognitive functions such as stimulus encoding and attention during an auditory oddball task in schizophrenia patients and healthy controls. EEG data was recorded from 17 young schizophrenia patients in a stable phase of their illness and 17 healthy controls performing an auditory oddball task. Evoked and induced delta and theta activity, N100, P300 amplitude were computed. Between 200-500 ms after a stimulus was presented, patients displayed significantly reduced P300, less evoked and induced delta and theta activity than controls. We conclude that the well known finding of P300 reduction in schizophrenia can be linked to reductions in delta and theta activity, which are a manifestation of impaired stimulus evaluation, memory retrieval, and a lack of sustained attention.
Psychological Medicine, 2013
2013). Inefcient cerebral recruitment as a vulnerability marker for schizophrenia.
Personality and Individual Differences, 2006
Accumulating evidence suggests that psychopathy is associated with behavioral and event-related p... more Accumulating evidence suggests that psychopathy is associated with behavioral and event-related potential (ERP) abnormalities during semantic language tasks. PsychopathsÕ ERP abnormalities are most prominent in the 300-500 ms post-stimulus time window. It is unclear whether these ERP differences are related to neurocognitive processes associated with the P300 (i.e., poor attention/orienting/working memory) or N400 (i.e., aberrant semantic processes). To address this issue, the present study employed a canonical semantic sentence processing paradigm known to selectively elicit the N400. Fifty incarcerated participants were divided into psychopathic (n = 25) or nonpsychopathic (n = 25) groups based on scores from the Hare Psychopathy Checklist-Revised. The N400 and P600 components elicited by terminal words of sentences either congruent or incongruent with the previous sentence context were examined. No differences were observed between groups in the behavioral or ERP data. These data do not support the hypothesis that the semantic processes, and underlying neural systems, associated with the generation of the N400 during sentence processing tasks are abnormal in psychopathy. (K.A. Kiehl). www.elsevier.com/locate/paid Personality and Individual Differences 40 (2006) 293-304
Journal of Psychophysiology, 2005
Abstract. The discovery of mirror neurons in monkeys has reshaped thinking about how the brain pr... more Abstract. The discovery of mirror neurons in monkeys has reshaped thinking about how the brain processes observed actions. There is growing evidence that these neurons, which show similar firing patterns for action execution and observation, also exist in humans. Many parts of ...
Journal of Psychiatric Research, 2004
The aim of this study was to determine if error negativity/error-related negativity (N e /ERN), e... more The aim of this study was to determine if error negativity/error-related negativity (N e /ERN), error positivity (P e ), correct response negativity (CRN) or correct response positivity (P c ) amplitude are influenced by state changes in schizophrenia. Eventrelated potentials (ERPs) were recorded from nine schizophrenic patients while they performed a simple go/no-go task during the early stages of an acute episode and again following 6 weeks of treatment with antipsychotics. ERPs were also recorded from nine healthy participants while they performed the same task. Response-locked potentials were computed for errors of commission and for correct responses. Scores for reality distortion syndrome, psychomotor poverty syndrome and disorganization syndrome were determined for the schizophrenic participants before and after treatment using the Signs and Symptoms of Psychotic Illness (SSPI) Scale. N e /ERN amplitude was significantly reduced, compared with that in healthy participants, in the schizophrenic patients when acutely ill, and increased significantly following treatment. N e /ERN amplitude remained significantly larger in the healthy group than in the patients with schizophrenia after treatment. This study suggests that N e /ERN and CRN amplitude are modulated by clinical state in schizophrenia and provides further support to findings that decreased N e /ERN amplitude is a potentially useful trait marker for schizophrenia, while P c and P e amplitude are not abnormal. #
Journal of Child Psychology and Psychiatry, 2010
• Deficits in cognitive control, including error monitoring, may be one factor underlying hyperac... more • Deficits in cognitive control, including error monitoring, may be one factor underlying hyperactive and impulsive behaviour in ADHD as young people with ADHD are less able to utilise performance feedback to regulate ongoing behaviour. • Understanding the neural basis of error monitoring deficits can give important clues to the underlying physiology of ADHD. • Abnormalities in electrophysiological indices of error processing, particularly increased variability in the phasic neural response to errors (inter trial coherence; ITC), provide novel insights into the neural correlates of these behavioural features. • The work extends previous findings in children with ADHD to those in adolescence.
Journal of Abnormal Psychology, 2006
Psychopathy is associated with abnormalities in attention and orienting. However, few studies hav... more Psychopathy is associated with abnormalities in attention and orienting. However, few studies have examined the neural systems underlying these processes. To address this issue, the authors recorded event-related potentials (ERPs) while 80 incarcerated men, classified as psychopathic or nonpsychopathic via the Hare Psychopathy Checklist-Revised (R. D. , completed an auditory oddball task. Consistent with hypotheses, processing of targets elicited larger frontocentral negativities (N550) in psychopaths than in nonpsychopaths. Psychopaths also showed an enlarged N2 and reduced P3 during target detection. Similar ERP modulations have been reported in patients with amygdala and temporal lobe damage. The data are interpreted as supporting the hypothesis that psychopathy may be related to dysfunction of the paralimbic system-a system that includes parts of the temporal and frontal lobes.
International Journal of Psychophysiology, 2012
A reduction in the error-related negativity (ERN), a response-locked event-related potential (ERP... more A reduction in the error-related negativity (ERN), a response-locked event-related potential (ERP) observed when participants commit errors during processing of stimuli, is a well-replicated cerebral abnormality in schizophrenia. However, the extent to which this abnormality reflects susceptibility to schizophrenia rather than overt change in behavioural state is unclear. As the unaffected siblings of individuals with schizophrenia are at an increased genetic risk, this study examines whether they display abnormality of the ERN similar to that observed in individuals with schizophrenia. ERPs were recorded from 29 individuals with schizophrenia, 36 unaffected siblings and 35 healthy control participants while they performed a simple Go/No-Go task. Group differences in the ERN and also in the error positivity (Pe), a response-locked positive component that follows the ERN, were investigated. Reductions of ERN amplitudes were found in both individuals with schizophrenia and siblings. No significant abnormalities were observed in Pe. The finding of reduced ERN amplitudes in siblings without prodromal symptoms supports the hypothesis that the abnormality is not a consequence of behavioural disturbance, and that it is a trait marker for susceptibility to schizophrenia, rather than being a result of illness or medication.
Clinical Neurophysiology, 2002
Objectives: To examine error-related negativity (ERN) and correct response negativity (CRN) in sc... more Objectives: To examine error-related negativity (ERN) and correct response negativity (CRN) in schizophrenia in light of two previous conflicting reports, and to determine their relation to disorganization, psychomotor poverty and reality distortion.
Clinical Neurophysiology, 2010
To confirm previously reported abnormalities in time domain EEG components during a go/no-go task... more To confirm previously reported abnormalities in time domain EEG components during a go/no-go task in schizophrenia, and to test the hypothesis that patients exhibit abnormalities in frequency domain components reflecting indices of behavioural impairment. EEG data were recorded from 17 male schizophrenia patients in a stable phase of illness and 17 healthy controls. As compared with controls, patients displayed smaller N200 amplitudes and less evoked theta for correct hit trials; and smaller N200 and P300 amplitudes and less evoked delta and theta for correct reject trials. Effect sizes were largest for evoked delta. Source localisation revealed reduced activation in schizophrenia patients during the N200 and P300 time windows in anterior and posterior cingulate, medial frontal gyrus and precuneus. Evoked delta and theta oscillations were significantly correlated with the variability of reaction times and the performance level statistic d-prime. The results demonstrate impairment of frontal and parietal brain areas involved in response control in schizophrenia. They also suggest that the timing of oscillations in patients is less precise leading to smaller evoked amplitudes and more variable reaction times. These findings add to the evidence that abnormal EEG oscillations contribute to impaired behavioural control in schizophrenia.
Brain, 2003
be a disturbed affective or motivational response to the commission of errors in schizophrenia. A... more be a disturbed affective or motivational response to the commission of errors in schizophrenia. Abbreviations: ACC = anterior cingulate cortex; CR = correct rejects; EoC = errors of commission; ERN = error-related negativity; ERP = event-related potential; fMRI = functional MRI; Ne = error negativity; Pe = error positivity; ROI = region of interest; RT = reaction time ã Guarantors of Brain 2003
The British Journal of Psychiatry
Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought d... more Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown. To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia. Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared. The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlate...
Schizophrenia Research, 2006
Schizophrenia Research, 2008
Controversy exists regarding whether young people at risk for schizophrenia are at increased risk... more Controversy exists regarding whether young people at risk for schizophrenia are at increased risk of adverse mental effects of cannabis use. We examined cannabis use and mental health functioning in three groups of young people aged 14-21; 36 non-psychotic siblings of adolescents with schizophrenia (genetic high risk group), 25 adolescents with attention deficit hyperactivity disorder (ADHD) and 72 healthy controls. The groups were sub-divided into 'users' and 'non-users' of cannabis based on how often they had used cannabis previously. Mental health functioning was quantified by creating a composite index derived from scores on the Schizotypal Personality Questionnaire (SPQ), Strengths and Difficulties Questionnaire (SDQ) and Global Assessment of Function (GAF). A significant positive association between cannabis use and mental health disturbance was confined to young people at genetic high risk for schizophrenia. To determine whether the relationship was specific to particular dimensions of mental health function, a second composite index was created based on scores from the SPQ Disorganisation and SDQ hyperactivity-inattention sub-scales. Again, there was a significant positive association between cannabis use and factor scores which was specific to the genetic high risk group. There was a trend for this association to be negative in the ADHD group (p=0.07). The findings support the view that young people at genetic high risk for schizophrenia are particularly vulnerable to mental health problems associated with cannabis use. Further research is needed to investigate the basis of relationships between cannabis and mental health in genetically vulnerable individuals.
To assess the interrater reliability, sensitivity and factor structure of a new sensitivity and f... more To assess the interrater reliability, sensitivity and factor structure of a new sensitivity and factor structure of a new assessment instrument, theThought and assessment instrument, theThought and Language Index (TLI), and to determine if Language Index (TLI), and to determine if minor aberrations detectable in the minor aberrations detectable in the speech of healthy individuals are related to speech of
Schizophrenia Research, 2009
Numerous studies have described attenuated event-related potential (ERP) component amplitudes in ... more Numerous studies have described attenuated event-related potential (ERP) component amplitudes in schizophrenia (e.g., P300, Mismatch Negativity (MMN), Error Negativity/Error-Related Negativity (Ne/ERN)). Functional magnetic resonance imaging (fMRI) studies have typically shown decreased recruitment of diverse brain areas during performance of tasks that elicit the above ERP components. Recent research suggests that phase-resetting of slow-oscillations (e.g., in the delta and theta bands) underlies the potentials observed in ERP averages. Several studies have reported that slow-oscillations are increased in amplitude in people with schizophrenia at rest. Few studies have examined event-related low-frequency oscillations in schizophrenia. We examined event-related evoked and induced delta and theta activity in 17 people with schizophrenia and 17 healthy controls in two go/no-go task variants. We analyzed stimulus-related and response-related oscillations associated with correct-hits, correct-rejects and false-alarms. Our results reveal a pattern of reduced delta and theta activity for task-relevant events in schizophrenia. The findings indicate that while low-frequency oscillations are increased in amplitude at rest, they are not coordinated effectively in schizophrenia during various information processing tasks including target-detection, response-inhibition and error-detection. This slow-oscillation coordination abnormality may help explain the decreased recruitment of brain areas seen in fMRI studies.
Schizophrenia Research, 2006
Schizophrenia Research, 2006
Schizophrenia Research, 2010
Psychophysiology, 2009
This study examines EEG low frequency characteristics which have been linked to specific cognitiv... more This study examines EEG low frequency characteristics which have been linked to specific cognitive functions such as stimulus encoding and attention during an auditory oddball task in schizophrenia patients and healthy controls. EEG data was recorded from 17 young schizophrenia patients in a stable phase of their illness and 17 healthy controls performing an auditory oddball task. Evoked and induced delta and theta activity, N100, P300 amplitude were computed. Between 200-500 ms after a stimulus was presented, patients displayed significantly reduced P300, less evoked and induced delta and theta activity than controls. We conclude that the well known finding of P300 reduction in schizophrenia can be linked to reductions in delta and theta activity, which are a manifestation of impaired stimulus evaluation, memory retrieval, and a lack of sustained attention.
Psychological Medicine, 2013
2013). Inefcient cerebral recruitment as a vulnerability marker for schizophrenia.
Personality and Individual Differences, 2006
Accumulating evidence suggests that psychopathy is associated with behavioral and event-related p... more Accumulating evidence suggests that psychopathy is associated with behavioral and event-related potential (ERP) abnormalities during semantic language tasks. PsychopathsÕ ERP abnormalities are most prominent in the 300-500 ms post-stimulus time window. It is unclear whether these ERP differences are related to neurocognitive processes associated with the P300 (i.e., poor attention/orienting/working memory) or N400 (i.e., aberrant semantic processes). To address this issue, the present study employed a canonical semantic sentence processing paradigm known to selectively elicit the N400. Fifty incarcerated participants were divided into psychopathic (n = 25) or nonpsychopathic (n = 25) groups based on scores from the Hare Psychopathy Checklist-Revised. The N400 and P600 components elicited by terminal words of sentences either congruent or incongruent with the previous sentence context were examined. No differences were observed between groups in the behavioral or ERP data. These data do not support the hypothesis that the semantic processes, and underlying neural systems, associated with the generation of the N400 during sentence processing tasks are abnormal in psychopathy. (K.A. Kiehl). www.elsevier.com/locate/paid Personality and Individual Differences 40 (2006) 293-304
Journal of Psychophysiology, 2005
Abstract. The discovery of mirror neurons in monkeys has reshaped thinking about how the brain pr... more Abstract. The discovery of mirror neurons in monkeys has reshaped thinking about how the brain processes observed actions. There is growing evidence that these neurons, which show similar firing patterns for action execution and observation, also exist in humans. Many parts of ...
Journal of Psychiatric Research, 2004
The aim of this study was to determine if error negativity/error-related negativity (N e /ERN), e... more The aim of this study was to determine if error negativity/error-related negativity (N e /ERN), error positivity (P e ), correct response negativity (CRN) or correct response positivity (P c ) amplitude are influenced by state changes in schizophrenia. Eventrelated potentials (ERPs) were recorded from nine schizophrenic patients while they performed a simple go/no-go task during the early stages of an acute episode and again following 6 weeks of treatment with antipsychotics. ERPs were also recorded from nine healthy participants while they performed the same task. Response-locked potentials were computed for errors of commission and for correct responses. Scores for reality distortion syndrome, psychomotor poverty syndrome and disorganization syndrome were determined for the schizophrenic participants before and after treatment using the Signs and Symptoms of Psychotic Illness (SSPI) Scale. N e /ERN amplitude was significantly reduced, compared with that in healthy participants, in the schizophrenic patients when acutely ill, and increased significantly following treatment. N e /ERN amplitude remained significantly larger in the healthy group than in the patients with schizophrenia after treatment. This study suggests that N e /ERN and CRN amplitude are modulated by clinical state in schizophrenia and provides further support to findings that decreased N e /ERN amplitude is a potentially useful trait marker for schizophrenia, while P c and P e amplitude are not abnormal. #
Journal of Child Psychology and Psychiatry, 2010
• Deficits in cognitive control, including error monitoring, may be one factor underlying hyperac... more • Deficits in cognitive control, including error monitoring, may be one factor underlying hyperactive and impulsive behaviour in ADHD as young people with ADHD are less able to utilise performance feedback to regulate ongoing behaviour. • Understanding the neural basis of error monitoring deficits can give important clues to the underlying physiology of ADHD. • Abnormalities in electrophysiological indices of error processing, particularly increased variability in the phasic neural response to errors (inter trial coherence; ITC), provide novel insights into the neural correlates of these behavioural features. • The work extends previous findings in children with ADHD to those in adolescence.
Journal of Abnormal Psychology, 2006
Psychopathy is associated with abnormalities in attention and orienting. However, few studies hav... more Psychopathy is associated with abnormalities in attention and orienting. However, few studies have examined the neural systems underlying these processes. To address this issue, the authors recorded event-related potentials (ERPs) while 80 incarcerated men, classified as psychopathic or nonpsychopathic via the Hare Psychopathy Checklist-Revised (R. D. , completed an auditory oddball task. Consistent with hypotheses, processing of targets elicited larger frontocentral negativities (N550) in psychopaths than in nonpsychopaths. Psychopaths also showed an enlarged N2 and reduced P3 during target detection. Similar ERP modulations have been reported in patients with amygdala and temporal lobe damage. The data are interpreted as supporting the hypothesis that psychopathy may be related to dysfunction of the paralimbic system-a system that includes parts of the temporal and frontal lobes.
International Journal of Psychophysiology, 2012
A reduction in the error-related negativity (ERN), a response-locked event-related potential (ERP... more A reduction in the error-related negativity (ERN), a response-locked event-related potential (ERP) observed when participants commit errors during processing of stimuli, is a well-replicated cerebral abnormality in schizophrenia. However, the extent to which this abnormality reflects susceptibility to schizophrenia rather than overt change in behavioural state is unclear. As the unaffected siblings of individuals with schizophrenia are at an increased genetic risk, this study examines whether they display abnormality of the ERN similar to that observed in individuals with schizophrenia. ERPs were recorded from 29 individuals with schizophrenia, 36 unaffected siblings and 35 healthy control participants while they performed a simple Go/No-Go task. Group differences in the ERN and also in the error positivity (Pe), a response-locked positive component that follows the ERN, were investigated. Reductions of ERN amplitudes were found in both individuals with schizophrenia and siblings. No significant abnormalities were observed in Pe. The finding of reduced ERN amplitudes in siblings without prodromal symptoms supports the hypothesis that the abnormality is not a consequence of behavioural disturbance, and that it is a trait marker for susceptibility to schizophrenia, rather than being a result of illness or medication.
Clinical Neurophysiology, 2002
Objectives: To examine error-related negativity (ERN) and correct response negativity (CRN) in sc... more Objectives: To examine error-related negativity (ERN) and correct response negativity (CRN) in schizophrenia in light of two previous conflicting reports, and to determine their relation to disorganization, psychomotor poverty and reality distortion.
Clinical Neurophysiology, 2010
To confirm previously reported abnormalities in time domain EEG components during a go/no-go task... more To confirm previously reported abnormalities in time domain EEG components during a go/no-go task in schizophrenia, and to test the hypothesis that patients exhibit abnormalities in frequency domain components reflecting indices of behavioural impairment. EEG data were recorded from 17 male schizophrenia patients in a stable phase of illness and 17 healthy controls. As compared with controls, patients displayed smaller N200 amplitudes and less evoked theta for correct hit trials; and smaller N200 and P300 amplitudes and less evoked delta and theta for correct reject trials. Effect sizes were largest for evoked delta. Source localisation revealed reduced activation in schizophrenia patients during the N200 and P300 time windows in anterior and posterior cingulate, medial frontal gyrus and precuneus. Evoked delta and theta oscillations were significantly correlated with the variability of reaction times and the performance level statistic d-prime. The results demonstrate impairment of frontal and parietal brain areas involved in response control in schizophrenia. They also suggest that the timing of oscillations in patients is less precise leading to smaller evoked amplitudes and more variable reaction times. These findings add to the evidence that abnormal EEG oscillations contribute to impaired behavioural control in schizophrenia.
Brain, 2003
be a disturbed affective or motivational response to the commission of errors in schizophrenia. A... more be a disturbed affective or motivational response to the commission of errors in schizophrenia. Abbreviations: ACC = anterior cingulate cortex; CR = correct rejects; EoC = errors of commission; ERN = error-related negativity; ERP = event-related potential; fMRI = functional MRI; Ne = error negativity; Pe = error positivity; ROI = region of interest; RT = reaction time ã Guarantors of Brain 2003