Publications by authors named "Colin Hawco"

41 Publications

Symptom dimensions of major depression in a large community-based cohort.

Psychol Med 2021 May 19:1-8. Epub 2021 May 19.

Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Our understanding of major depression is complicated by substantial heterogeneity in disease presentation, which can be disentangled by data-driven analyses of depressive symptom dimensions. We aimed to determine the clinical portrait of such symptom dimensions among individuals in the community.

Methods: This cross-sectional study consisted of 25 261 self-reported White UK Biobank participants with major depression. Nine questions from the UK Biobank Mental Health Questionnaire encompassing depressive symptoms were decomposed into underlying factors or 'symptom dimensions' via factor analysis, which were then tested for association with psychiatric diagnoses and polygenic risk scores for major depressive disorder (MDD), bipolar disorder and schizophrenia. Replication was performed among 655 self-reported non-White participants, across sexes, and among 7190 individuals with an ICD-10 code for MDD from linked inpatient or primary care records.

Results: Four broad symptom dimensions were identified, encompassing negative cognition, functional impairment, insomnia and atypical symptoms. These dimensions replicated across ancestries, sexes and individuals with inpatient or primary care MDD diagnoses, and were also consistent among 43 090 self-reported White participants with undiagnosed self-reported depression. Every dimension was associated with increased risk of nearly every psychiatric diagnosis and polygenic risk score. However, while certain psychiatric diagnoses were disproportionately associated with specific symptom dimensions, the three polygenic risk scores did not show the same specificity of associations.

Conclusions: An analysis of questionnaire data from a large community-based cohort reveals four replicable symptom dimensions of depression with distinct clinical, but not genetic, correlates.
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http://dx.doi.org/10.1017/S0033291721001707DOI Listing
May 2021

Social Cognitive Networks and Social Cognitive Performance Across Individuals With Schizophrenia Spectrum Disorders and Healthy Control Participants.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Dec 5. Epub 2020 Dec 5.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Schizophrenia spectrum disorders (SSDs) feature social cognitive deficits, although their neural basis remains unclear. Social cognitive performance may relate to neural circuit activation patterns more than to diagnosis, which would have important prognostic and therapeutic implications. The current study aimed to determine how functional connectivity within and between social cognitive networks relates to social cognitive performance across individuals with SSDs and healthy control participants.

Methods: Participants with SSDs (n = 164) and healthy control participants (n = 117) completed the Empathic Accuracy task during functional magnetic resonance imaging as well as lower-level (e.g., emotion recognition) and higher-level (e.g., theory of mind) social cognitive measures outside the scanner. Functional connectivity during the Empathic Accuracy task was analyzed using background connectivity and graph theory. Data-driven social cognitive networks were identified across participants. Regression analyses were used to examine network connectivity-performance relationships across individuals. Positive and negative within- and between-network connectivity strengths were also compared in poor versus good social cognitive performers and in SSD versus control groups.

Results: Three social cognitive networks were identified: motor resonance, affect sharing, and mentalizing. Regression and group-based analyses demonstrated reduced between-network negative connectivity, or segregation, and greater within- and between-network positive connectivity in worse social cognitive performers. There were no significant effects of diagnostic group on within- or between-network connectivity.

Conclusions: These findings suggest that the neural circuitry of social cognitive performance may exist dimensionally. Across participants, better social cognitive performance was associated with greater segregation between social cognitive networks, whereas poor versus good performers may compensate via hyperconnectivity within and between social cognitive networks.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.014DOI Listing
December 2020

Effects of Repetitive Transcranial Magnetic Stimulation on Working Memory Performance and Brain Structure in People With Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Trial.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 04 28;6(4):449-458. Epub 2020 Nov 28.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, California.

Background: There are currently no approved treatments for working memory deficits in schizophrenia spectrum disorders (SSDs). The objective of the present study was to assess whether repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) in people with SSDs 1) improves working memory deficits and 2) changes brain structure.

Methods: We conducted a double-blind, parallel, randomized, sham-controlled study at the Centre for Addiction and Mental Health in Toronto, Canada. We randomized 83 participants with SSDs to receive either active 20 Hz rTMS applied to the bilateral DLPFC or sham rTMS for 4 weeks. The participants also completed pre/posttreatment magnetic resonance imaging. Clinical and cognitive assessments were performed at baseline, treatment end, and 1 month later. The primary outcome was change in verbal n-back working memory performance accuracy (d-prime). The secondary outcome measures were change in DLPFC thickness and fractional anisotropy of white matter tracts connecting to the DLPFC. Prespecified exploratory outcome measures were changes in general cognition; positive, negative, and depressive symptoms.

Results: Compared with sham treatment, active rTMS did not lead to significant change in working memory performance; it was associated with an increase in right DLPFC thickness but not fractional anisotropy. Prespecified exploratory analysis showed a significant decrease in depressive symptoms in the active group; the decrease in depressive symptoms was correlated with an increase in right DLPFC thickness.

Conclusions: Although rTMS applied to the bilateral DLPFC was not efficacious in treating working memory deficits in SSDs, it did increase right DLPFC thickness and decrease depressive symptoms. These findings deserve further study given the lack of efficacy of antidepressant medications in SSDs.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.011DOI Listing
April 2021

Moving beyond the mean: Subgroups and dimensions of brain activity and cognitive performance across domains.

Neuroimage 2021 05 4;231:117823. Epub 2021 Feb 4.

Centre for Addiction and Mental Health, Campbell Family Mental Health Institute, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address:

Human neuroimaging during cognitive tasks has provided unique and important insights into the neurobiology of cognition. However, the vast majority of research relies on group aggregate or average statistical maps of activity, which do not fully capture the rich intersubject variability in brain function. In order to fully understand the neurobiology of cognitive processes, it is necessary to explore the range of variability in activation patterns across individuals. To better characterize individual variability, hierarchical clustering was performed separately on six fMRI tasks in 822 participants from the Human Connectome Project. Across all tasks, clusters ranged from a predominantly 'deactivating' pattern towards a more 'activating' pattern of brain activity, with significant differences in out-of-scanner cognitive test scores between clusters. Cluster stability was assessed via a resampling approach; a cluster probability matrix was generated, as the probability of any pair of participants clustering together when both were present in a random subsample. Rather than forming distinct clusters, participants fell along a spectrum or into pseudo-clusters without clear boundaries. A principal components analysis of the cluster probability matrix revealed three components explaining over 90% of the variance in clustering. Plotting participants in this lower-dimensional 'similarity space' revealed manifolds of variations along an S 'snake' shaped spectrum or a folded circle or 'tortilla' shape. The 'snake' shape was present in tasks where individual variability related to activity along covarying networks, while the 'tortilla' shape represented multiple networks which varied independently.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117823DOI Listing
May 2021

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms.

Transl Psychiatry 2020 11 24;10(1):410. Epub 2020 Nov 24.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.

Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts toward depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a nonclinical sample of 478 young adults (225 men; age 19.79 +/- 1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression toward a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p < 0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p < 0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.
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http://dx.doi.org/10.1038/s41398-020-01093-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686479PMC
November 2020

Integration of brain and behavior measures for identification of data-driven groups cutting across children with ASD, ADHD, or OCD.

Neuropsychopharmacology 2021 02 9;46(3):643-653. Epub 2020 Nov 9.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network was used including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Future work is needed to build on this early attempt through replication of the current findings in independent samples and testing longitudinally for prognostic value.
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http://dx.doi.org/10.1038/s41386-020-00902-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027842PMC
February 2021

Variability in the analysis of a single neuroimaging dataset by many teams.

Nature 2020 06 20;582(7810):84-88. Epub 2020 May 20.

Department of Psychology, Rutgers University-Newark, Newark, NJ, USA.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.
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http://dx.doi.org/10.1038/s41586-020-2314-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771346PMC
June 2020

Greater Individual Variability in Functional Brain Activity during Working Memory Performance in young people with Autism and Executive Function Impairment.

Neuroimage Clin 2020 23;27:102260. Epub 2020 Apr 23.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada; Margaret and Wallace McCain Centre for Child, Youth & Family Mental Health, Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address:

Background: Individuals with autism spectrum disorder (ASD) often present with executive functioning (EF) deficits, including spatial working memory (SWM) impairment, which impedes real-world functioning. The present study examined task-related brain activity, connectivity and individual variability in fMRI-measured neural response during an SWM task in older youth and young adults with autism and clinically significant EF impairment.

Methods: Neuroimaging was analyzed in 29 individuals with ASD without intellectual disability who had clinically significant EF impairment on the Behavior Rating Inventory of Executive Function, and 20 typically developing controls (participant age range=16-34). An SWM N-Back task was performed during fMRI. SWM activity (2-Back vs. 0-Back) and task-related dorsolateral prefrontal cortex (DLPFC) connectivity was examined within and between groups. Variability of neural response during SWM was also examined.

Results: During SWM performance both groups activated the expected networks, and no group differences in network activation or task-related DLPFC-connectivity were found. However, greater individual variability in the pattern of SWM activity was found in the ASD versus the typically developing control group.

Conclusions: While there were no group differences in SWM task-evoked activity or connectivity, fronto-parietal network engagement was found to be more variable/idiosyncratic in ASD. Our results suggest that the fronto-parietal network may be shifted or sub-optimally engaged during SWM performance in participants with ASD with clinically significant EF impairment, with implications for developing targeted interventions for this subgroup.
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http://dx.doi.org/10.1016/j.nicl.2020.102260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218076PMC
March 2021

Effort-based decision-making is affected by overweight/obesity in major depressive disorder.

J Affect Disord 2019 09 4;256:221-227. Epub 2019 Jun 4.

Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, M5T 2S8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, M5T 2S8, Canada; Research Group in Molecular and Behavioral Neurosciences of Mood Disorders, Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, SP, 04038-000, Brazil; Brain and Cognition Discovery Foundation, Mississauga, ON L5C 4E, Canada.

Background: Anhedonia and abnormalities in reward behavior are core features of major depressive disorder (MDD). Convergent evidence indicates that overweight/obesity (OW), a highly prevalent condition in MDD, is independently associated with reward disturbances. We therefore aimed to investigate the moderating effect of OW on the willingness to expend efforts for reward in individuals with MDD and healthy controls (HC).

Methods: Forty-one adults (HC n = 20, MDD n = 21) completed the Effort Expenditure for Rewards Task (EEfRT), clinical and cognitive measures. Anthropometric parameters were assessed in all participants, and an additional evaluation of laboratorial parameters were conducted solely on those with MDD. Individuals with MDD were all on vortioxetine monotherapy (10-20 mg/day).

Results: Interactions between reward magnitude, group and OW were observed (χ = 9.192, p = 0.010); the OW-MDD group chose the hard task significantly less than normal weight (NW)-HC (p = 0.033) and OW-HC (p = 0.034), whereas there were no differences between NW-MDD and HCs. Within individuals with MDD, the proportion of hard task choices was more strongly correlated with body mass index (BMI) (r = -0.456, p = 0.043) and insulin resistance (HOMA2-IR) (r = -0.467, p = 0.038), than with depressive symptoms (r = 0.290, p = 0.214).

Conclusions: OW significantly moderated the association between MDD and willingness to make efforts for rewards. These findings offer novel evidence on the potential role of metabolic factors on the basis of anhedonia, and for the heuristic models proposing a pathophysiological connection between mood and metabolic disorders.
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http://dx.doi.org/10.1016/j.jad.2019.06.002DOI Listing
September 2019

Separable and Replicable Neural Strategies During Social Brain Function in People With and Without Severe Mental Illness.

Am J Psychiatry 2019 07 4;176(7):521-530. Epub 2019 Jan 4.

Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto (Hawco, Calarco, Mulsant, Viviano, Dickie, Foussias, Voineskos); the Department of Psychiatry, University of Toronto, Toronto (Hawco, Foussias, Mulsant, Voineskos); Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Md. (Buchanan, Gold); Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, N.Y. (Argyelan, DeRosse, Malhotra); Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. (Argyelan, DeRosse, Malhotra); the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California, Los Angeles (Iacoboni).

Objective: Case-control study design and disease heterogeneity may impede biomarker discovery in brain disorders, including serious mental illnesses. To identify biologically and/or behaviorally driven as opposed to diagnostically driven subgroups of individuals, the authors used hierarchical clustering to identify individuals with similar patterns of brain activity during a facial imitate/observe functional MRI task.

Methods: Participants in the Social Processes Initiative in Neurobiology of the Schizophrenia(s) study (N=179; 109 with a schizophrenia spectrum disorder and 70 healthy control participants) underwent MRI scanning at three sites. Hierarchical clustering was used to identify new data-driven groups of participants; differences on social and neurocognitive tests completed outside the scanner were compared among the new groups.

Results: Three clusters with distinct patterns of neural activity were found. Cluster membership was not related to diagnosis or scan site. The largest cluster consisted of "typical activators," with activity in the canonical "simulation" circuit. The other clusters represented a "hyperactivating" group and a "deactivating" group. Between-participants Euclidean distances were smaller within clusters than within site or diagnostics groups. The deactivating group had the highest social cognitive and neurocognitive test scores. The hierarchical clustering analysis was repeated on a replication sample (N=108; 32 schizophrenia spectrum disorder, 37 euthymic bipolar disorder, and 39 healthy control participants), which exhibited the same three cluster patterns.

Conclusions: The study findings demonstrate replicable differing patterns of neural activity among individuals during a socio-emotional task, independent of DSM diagnosis or scan site. The findings may provide objective neuroimaging endpoints (biomarkers) for subgroups of individuals in target engagement research aimed at enhancing cognitive performance independent of diagnostic category.
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http://dx.doi.org/10.1176/appi.ajp.2018.17091020DOI Listing
July 2019

Spread of activity following TMS is related to intrinsic resting connectivity to the salience network: A concurrent TMS-fMRI study.

Cortex 2018 11 30;108:160-172. Epub 2018 Jul 30.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Transcranial magnetic stimulation (TMS) modulates activity at local and regions distal to the site of simulation. TMS has also been found to modulate brain networks, and it has been hypothesized that functional connectivity may predict the neuronal changes at local and distal sites in response to a TMS pulse. However, a direct relationship between resting connectivity and change in TMS-induced brain activation has yet to be demonstrated. Concurrent TMS-fMRI is a technique to directly measure this spread activity following TMS in real time. In twenty-two participants, resting-state fMRI scans were acquired, followed by four ten minute sessions of concurrent TMS-fMRI over the left dorsolateral prefrontal cortex (DLPFC). Seed-based functional connectivity to the individualized TMS target was examined using the baseline resting fMRI scan data, and the change of activity resulting from TMS was determined using a general linear model (High vs Low intensity TMS). While at the group level the spatial pattern of resting connectivity related to the pattern of TMS-induced cortical changes, there was substantial variability across individuals. This variability was further probed by examining individual's connectivity from the TMS target to six resting state networks. Only connectivity between the salience network (SN) and the TMS target site correlated with the RSC-TMS score. This suggests that resting state connectivity is correlated with TMS-induced changes in activity following DLPFC stimulation, particularly when the DLPFC target interacts with the SN. These results highlight the importance of examining such relationships at the individual level and may help to guide individual treatment in clinical populations.
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http://dx.doi.org/10.1016/j.cortex.2018.07.010DOI Listing
November 2018

A longitudinal human phantom reliability study of multi-center T1-weighted, DTI, and resting state fMRI data.

Psychiatry Res Neuroimaging 2018 12 9;282:134-142. Epub 2018 Jun 9.

Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, 250 College St., Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address:

Multi-center MRI studies can enhance power, generalizability, and discovery for clinical neuroimaging research in brain disorders. Here, we sought to establish the utility of a clustering algorithm as an alternative to more traditional intra-class correlation coefficient approaches in a longitudinal multi-center human phantom study. We completed annual reliability scans on 'travelling human phantoms'. Acquisitions across sites were harmonized prospectively. Twenty-seven MRI sessions were available across four participants, scanned on five scanners, across three years. For each scan, three metrics were extracted: cortical thickness (CT), white matter fractional anisotropy (FA), and resting state functional connectivity (FC). For each metric, hierarchical clustering (Ward's method) was performed. The cluster solutions were compared to participant and scanner using the adjusted Rand index (ARI). For all metrics, data clustered by participant rather than by scanner (ARI > 0.8 comparing clusters to participants, ARI < 0.2 comparing clusters to scanners). These results demonstrate that hierarchical clustering can reliably identify structural and functional scans from different participants imaged on different scanners across time. With increasing interest in data-driven approaches in psychiatric and neurologic brain imaging studies, our findings provide a framework for multi-center analytic approaches aiming to identify subgroups of participants based on brain structure or function.
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http://dx.doi.org/10.1016/j.pscychresns.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482446PMC
December 2018

Resting-State Connectivity Biomarkers of Cognitive Performance and Social Function in Individuals With Schizophrenia Spectrum Disorder and Healthy Control Subjects.

Biol Psychiatry 2018 11 13;84(9):665-674. Epub 2018 Apr 13.

Kimel Family Translational Imaging-Genetics Research Lab, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario; Department of Psychiatry, University of Toronto, Toronto, Ontario. Electronic address:

Background: Deficits in neurocognition and social cognition are drivers of reduced functioning in schizophrenia spectrum disorders, with potentially shared neurobiological underpinnings. Many studies have sought to identify brain-based biomarkers of these clinical variables using a priori dichotomies (e.g., good vs. poor cognition, deficit vs. nondeficit syndrome).

Methods: We evaluated a fully data-driven approach to do the same by building and validating a brain connectivity-based biomarker of social cognitive and neurocognitive performance in a sample using resting-state and task-based functional magnetic resonance imaging (n = 74 healthy control participants, n = 114 persons with schizophrenia spectrum disorder, 188 total). We used canonical correlation analysis followed by clustering to identify a functional connectivity signature of normal and poor social cognitive and neurocognitive performance.

Results: Persons with poor social cognitive and neurocognitive performance were differentiated from those with normal performance by greater resting-state connectivity in the mirror neuron and mentalizing systems. We validated our findings by showing that poor performers also scored lower on functional outcome measures not included in the original analysis and by demonstrating neuroanatomical differences between the normal and poorly performing groups. We used a support vector machine classifier to demonstrate that functional connectivity alone is enough to distinguish normal and poorly performing participants, and we replicated our findings in an independent sample (n = 75).

Conclusions: A brief functional magnetic resonance imaging scan may ultimately be useful in future studies aimed at characterizing long-term illness trajectories and treatments that target specific brain circuitry in those with impaired cognition and function.
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http://dx.doi.org/10.1016/j.biopsych.2018.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177285PMC
November 2018

Heightened Responses of the Parahippocampal and Retrosplenial Cortices during Contextualized Recognition of Congruent Objects.

Front Behav Neurosci 2017 14;11:232. Epub 2017 Dec 14.

Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Context sometimes helps make objects more recognizable. Previous studies using functional magnetic resonance imaging (fMRI) have examined regional neural activity when objects have strong or weak associations with their contexts. Such studies have demonstrated that activity in the parahippocampal cortex (PHC) generally corresponds with strong associations between objects and their spatial contexts while retrosplenial cortex (RSC) activity is linked with episodic memory. However these studies investigated objects viewed in associated contexts, but the direct influence of scene on the perception of visual objects has not been widely investigated. We hypothesized that the PHC and RSC may only be engaged for congruent contexts in which the object could typically be found but not for neutral contexts. While in an fMRI scanner, 15 participants rated the recognizability of 152 photographic images of objects, presented within congruent and incongruent contexts. Regions of interest were created to examine PHC and RSC activity using a hypothesis-driven approach. Exploratory analyses were also performed to identify other regional activity. In line with previous studies, PHC and RSC activity emerged when objects were viewed in congruent contexts. Activity in the RSC, inferior parietal lobe (IPL) and fusiform gyrus also emerged. These findings indicate that different brain regions are employed when objects are meaningfully contextualized.
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http://dx.doi.org/10.3389/fnbeh.2017.00232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735118PMC
December 2017

Differing Time of Onset of Concurrent TMS-fMRI during Associative Memory Encoding: A Measure of Dynamic Connectivity.

Front Hum Neurosci 2017 14;11:404. Epub 2017 Aug 14.

Douglas Mental Health University Institute, McGill University, MontrealQC, Canada.

There has been a distinct shift in neuroimaging from localization of function into a more network based approach focused on connectivity. While fMRI has proven very fruitful for this, the hemodynamic signal is inherently slow which limits the temporal resolution of fMRI-only connectivity measures. The brain, however, works on a time scale of milliseconds. This study utilized concurrent transcranial magnetic stimulation (TMS)-fMRI in a novel way to obtain measures of dynamic connectivity by measuring changes in fMRI signal amplitude in regions distal to the site of stimulation following differing TMS onset times. Seventeen healthy subjects completed an associative memory encoding task known to involve the DLPFC, viewing pairs of objects which could be semantically related or unrelated. Three pulses of 10 Hz repetitive TMS were applied over the left DLPFC starting either at 200, 600, or 1000 ms after stimulus onset. Associations for related pairs were better remembered than unrelated pairs in a post-scan cued recall test. Differences in neural activity were assessed across different TMS onsets, separately for related and unrelated pairs. Time specific TMS effects were observed in several regions, including those associated with higher-level processing (lateral frontal, anterior cingulate), visual areas (occipital), and regions involved in semantic processing (e.g., left mid-temporal and medial frontal). Activity in the frontal cortex was decreased at 200 ms post-stimulus for unrelated pairs, and 1000 ms post-stimulus for related pairs. This suggests differences in the timing across conditions in which the DLFPC interacts with other PFC regions, consistent with the notion that the DLPFC is facilitating extended semantic processing for related items. This study demonstrates that time-varying TMS onset inside the MRI can be used to reliably measure fast dynamic connectivity with a temporal resolution in the hundreds of milliseconds.
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http://dx.doi.org/10.3389/fnhum.2017.00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557775PMC
August 2017

Neural Activity while Imitating Emotional Faces is Related to Both Lower and Higher-Level Social Cognitive Performance.

Sci Rep 2017 04 28;7(1):1244. Epub 2017 Apr 28.

Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, 250 College St., Toronto, M5T 1R8, ON, Canada.

Imitation and observation of actions and facial emotional expressions activates the human fronto-parietal mirror network. There is skepticism regarding the role of this low-level network in more complex high-level social behaviour. We sought to test whether neural activation during an observation/imitation task was related to both lower and higher level social cognition. We employed an established observe/imitate task of emotional faces during functional MRI in 28 healthy adults, with final analyses based on 20 individuals following extensive quality control. Partial least squares (PLS) identified patterns of relationships between spatial activation and a battery of objective out-of-scanner assessments that index lower and higher-level social cognitive performance, including the Penn emotion recognition task, reading the mind in the eyes, the awareness of social inference test (TASIT) parts 1, 2, and 3, and the relationships across domains (RAD) test. Strikingly, activity in limbic, right inferior frontal, and inferior parietal areas during imitation of emotional faces correlated with performance on emotion evaluation (TASIT1), social inference - minimal (TASIT2), social inference - enriched (TASIT3), and the RAD tests. These results show a role for this network in both lower-level and higher-level social cognitive processes which are collectively critical for social functioning in everyday life.
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http://dx.doi.org/10.1038/s41598-017-01316-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430668PMC
April 2017

Cortical Thinning in Network-Associated Regions in Cognitively Normal and Below-Normal Range Schizophrenia.

Schizophr Res Treatment 2017 28;2017:9760905. Epub 2017 Feb 28.

McMaster University, Hamilton, ON, Canada.

This study assessed whether cortical thickness across the brain and regionally in terms of the default mode, salience, and central executive networks differentiates schizophrenia patients and healthy controls with normal range or below-normal range cognitive performance. Cognitive normality was defined using the MATRICS Consensus Cognitive Battery (MCCB) composite score ( = 50 ± 10) and structural magnetic resonance imaging was used to generate cortical thickness data. Whole brain analysis revealed that cognitively normal range controls ( = 39) had greater cortical thickness than both cognitively normal ( = 17) and below-normal range ( = 49) patients. Cognitively normal controls also demonstrated greater thickness than patients in regions associated with the default mode and salience, but not central executive networks. No differences on any thickness measure were found between cognitively normal range and below-normal range controls ( = 24) or between cognitively normal and below-normal range patients. In addition, structural covariance between network regions was high and similar across subgroups. Positive and negative symptom severity did not correlate with thickness values. Cortical thinning across the brain and regionally in relation to the default and salience networks may index shared aspects of the psychotic psychopathology that defines schizophrenia with no relation to cognitive impairment.
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http://dx.doi.org/10.1155/2017/9760905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350425PMC
February 2017

Prefrontal activity and impaired memory encoding strategies in schizophrenia.

J Psychiatr Res 2017 08 8;91:64-73. Epub 2017 Mar 8.

Douglas Mental Health University Institute, Montréal, Canada; Department of Psychiatry, McGill University, Montréal, Canada. Electronic address:

Schizophrenia patients have significant memory difficulties that have far-reaching implications in their daily life. These impairments are partly attributed to an inability to self-initiate effective memory encoding strategies, but its core neurobiological correlates remain unknown. The current study addresses this critical gap in our knowledge of episodic memory impairments in schizophrenia. Schizophrenia patients (n = 35) and healthy controls (n = 23) underwent a Semantic Encoding Memory Task (SEMT) during an fMRI scan. Brain activity was examined for conditions where participants were a) prompted to use semantic encoding strategies, or b) not prompted but required to self-initiate such strategies. When prompted to use semantic encoding strategies, schizophrenia patients exhibited similar recognition performance and brain activity as healthy controls. However, when required to self-initiate these strategies, patients had significant reduced recognition performance and brain activity in the left dorsolateral prefrontal cortex, as well as in the left temporal gyrus, left superior parietal lobule, and cerebellum. When patients were divided based on performance on the SEMT, the subgroup with more severe deficits in self-initiation also showed greater reduction in left dorsolateral prefrontal activity. These results suggest that impaired self-initiation of elaborative encoding strategies is a driving feature of memory deficits in schizophrenia. We also identified the neural correlates of impaired self-initiation of semantic encoding strategies, in which a failure to activate the left dorsolateral prefrontal cortex plays a key role. These findings provide important new targets in the development of novel treatments aiming to improve memory and ultimately patients' outcome.
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http://dx.doi.org/10.1016/j.jpsychires.2017.02.024DOI Listing
August 2017

Age and gender interactions in white matter of schizophrenia and obsessive compulsive disorder compared to non-psychiatric controls: commonalities across disorders.

Brain Imaging Behav 2017 Dec;11(6):1836-1848

Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Unit 4-1, Office 125, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada.

Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) are psychiatric disorders with abnormalities in white matter structure. These disorders share high comorbidity and family history of OCD is a risk factor for SCZ which suggests some shared neurobiology. White matter was examined using diffusion tensor imaging in relativity large samples of SCZ (N = 48), OCD (N = 38) and non-psychiatric controls (N = 45). Fractional anisotropy (FA) was calculated and tract based spatial statistics were used to compare groups. In a whole brain analysis, SCZ and OCD both showed small FA reductions relative to controls in the corpus callosum. Both SCZ and OCD showed accelerated reductions in FA with age; specifically in the left superior longitudinal fasciculus in OCD, while the SCZ group demonstrated a more widespread pattern of FA reduction. Patient groups did not differ from each other in total FA or age effects in any regions. A general linear model using 13 a-priori regions of interest showed marginal group, group*gender, and group*age interactions. When OCD and SCZ groups were analyzed together, these marginal effects became significant (p < 0.05), suggesting commonalities exist between these patient groups. Overall, our results demonstrate a similar pattern of accelerated white matter decline with age and greater white matter deficit in females in OCD and SCZ, with overlap in the spatial pattern of deficits. There was no evidence for statistical differences in overall white matter between OCD and SCZ. Taken together, the results support the notion of shared neurobiology in SCZ and OCD.
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http://dx.doi.org/10.1007/s11682-016-9657-8DOI Listing
December 2017

Recollection rejection of new items in individuals with first-episode psychosis.

J Abnorm Psychol 2016 Jan;125(1):104-113

Douglas Mental Health University Institute.

Many objects seen for the first time look familiar because they resemble known objects. To overcome this feeling of familiarity and detect novelty, memories of known objects must be recollected and compared to new objects. This experiment examines whether recollection performed when perceiving new items (i.e., recollection rejection) is abnormal in people who experienced a first episode of psychosis (FEP). Recollection of old items is impaired in this clinical population but it has not yet been demonstrated that this impairment influences the processing of new items. Eighteen FEP participants and 19 healthy controls completed an episodic memory task consisting of a study phase and a recognition phase. All the new objects looked familiar because they resembled the studied objects. Brain activity underlying false recognition and correct rejection of new objects was measured with functional resonance magnetic imaging and compared across groups. Behavioral responses to new items were not significantly different between the 2 groups. However, the between-groups analysis revealed significant differences in brain activity in the left middle frontal gyrus, the left inferior parietal lobule, the right superior parietal lobule, and the right temporal fusiform gyrus during the correct rejection of new items. This activity seems related to recollection rejection and suggests that FEP patients do not normally recollect information of past events when they process new items.
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http://dx.doi.org/10.1037/abn0000102DOI Listing
January 2016

Relational Memory as a Possible Neurocognitive Marker of Schizophrenia.

JAMA Psychiatry 2015 Sep;72(9):946-7

Department of Psychology, McGill University, Montreal, Quebec, Canada3Douglas Mental Health University Institute, Montreal, Quebec, Canada.

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http://dx.doi.org/10.1001/jamapsychiatry.2015.0488DOI Listing
September 2015

Cognitive insight in first-episode schizophrenia: further evidence for a role of the ventrolateral prefrontal cortex.

Schizophr Res 2015 Aug 23;166(1-3):65-8. Epub 2015 May 23.

Prevention and Early Intervention Program for Psychoses, Douglas Mental Health University Institute, Verdun, Canada; Department of Psychiatry, McGill University, Montreal, Canada; Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. Electronic address:

In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES.
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http://dx.doi.org/10.1016/j.schres.2015.05.009DOI Listing
August 2015

Source retrieval is not properly differentiated from object retrieval in early schizophrenia: an fMRI study using virtual reality.

Neuroimage Clin 2015 13;7:336-46. Epub 2014 Aug 13.

Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada ; Prevention and Early Intervention Program for Psychoses, Douglas Mental Health University Institute, Verdun, Canada ; Department of Psychiatry, McGill University, Montreal, Canada.

Source memory, the ability to identify the context in which a memory occurred, is impaired in schizophrenia and has been related to clinical symptoms such as hallucinations. The neurobiological underpinnings of this deficit are not well understood. Twenty-five patients with recent onset schizophrenia (within the first 4.5 years of treatment) and twenty-four healthy controls completed a source memory task. Participants navigated through a 3D virtual city, and had 20 encounters of an object with a person at a place. Functional magnetic resonance imaging was performed during a subsequent forced-choice recognition test. Two objects were presented and participants were asked to either identify which object was seen (new vs. old object recognition), or identify which of the two old objects was associated with either the person or the place being presented (source memory recognition). Source memory was examined by contrasting person or place with object. Both patients and controls demonstrated significant neural activity to source memory relative to object memory, though activity in controls was much more widespread. Group differences were observed in several regions, including the medial parietal and cingulate cortex, lateral frontal lobes and right superior temporal gyrus. Patients with schizophrenia did not differentiate between source and object memory in these regions. Positive correlations with hallucination proneness were observed in the left frontal and right middle temporal cortices and cerebellum. Patients with schizophrenia have a deficit in the neural circuits which facilitate source memory, which may underlie both the deficits in this domain and be related to auditory hallucinations.
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http://dx.doi.org/10.1016/j.nicl.2014.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297883PMC
September 2015

Overlapping patterns of neural activity for different forms of novelty in fMRI.

Front Hum Neurosci 2014 8;8:699. Epub 2014 Sep 8.

Douglas Mental Health University Institute, McGill University Montreal, QC, Canada.

When stimuli are presented multiple times, the neural response to repeated stimuli is reduced relative to novel stimuli (repetition suppression). Responses to different types of novelty were examined. Stimulus novelty was examined by contrasting first vs. second presentation of triads of objects during memory encoding. Semantic novelty was contrasted by comparing unrelated (semantically novel) triads of objects to triads in which all three objects were related (e.g., all objects were tools). In recognition, associative novelty was examined by contrasting rearranged triads (previously seen objects in a new association) with intact triads. Activity was observed in posterior regions (occipital and fusiform), with the largest extent of activity for stimulus novelty and smallest for associational novelty. Frontal activity was also observed in stimulus and semantic novelty. Additional analysis indicated that the hemodynamic response in voxels identified in the stimulus and semantic novelty contrasts was modulated by reaction time on a trial-by-trial basis. That is, the duration of the hemodynamic response was driven by reaction time. This was not the case for associative novelty. The high level of overlap across different forms of novelty suggests a similar mechanism for reduced neural activity, which may be related to reduced visual processing time. This is consistent with a facilitation model of repetition suppression, which posits a reduced peak and duration of neuronal firing for repeated stimuli.
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http://dx.doi.org/10.3389/fnhum.2014.00699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157542PMC
September 2014

Functional magnetic resonance imaging study of external source memory and its relation to cognitive insight in non-clinical subjects.

Psychiatry Clin Neurosci 2014 Sep 13;68(9):683-91. Epub 2014 Apr 13.

Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.

Aim: Previous research has linked cognitive insight (a measure of self-reflectiveness and self-certainty) in psychosis with neurocognitive and neuroanatomical disturbances in the fronto-hippocampal neural network. The authors' goal was to use functional magnetic resonance imaging (fMRI) to investigate the neural correlates of cognitive insight during an external source memory paradigm in non-clinical subjects.

Methods: At encoding, 24 non-clinical subjects travelled through a virtual city where they came across 20 separate people, each paired with a unique object in a distinct location. fMRI data were then acquired while participants viewed images of the city, and completed source recognition memory judgments of where and with whom objects were seen, which is known to involve prefrontal cortex. Cognitive insight was assessed with the Beck Cognitive Insight Scale.

Results: External source memory was associated with neural activity in a widespread network consisting of frontal cortex, including ventrolateral prefrontal cortex (VLPFC), temporal and occipital cortices. Activation in VLPFC correlated with higher self-reflectiveness and activation in midbrain correlated with lower self-certainty during source memory attributions. Neither self-reflectiveness nor self-certainty significantly correlated with source memory accuracy.

Conclusion: By means of virtual reality and in the context of an external source memory paradigm, the study identified a preliminary functional neural basis for cognitive insight in the VLPFC in healthy people that accords with our fronto-hippocampal theoretical model as well as recent neuroimaging data in people with psychosis. The results may facilitate the understanding of the role of neural mechanisms in psychotic disorders associated with cognitive insight distortions.
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http://dx.doi.org/10.1111/pcn.12177DOI Listing
September 2014

The dorsolateral prefrontal cortex plays a role in self-initiated elaborative cognitive processing during episodic memory encoding: rTMS evidence.

PLoS One 2013 5;8(9):e73789. Epub 2013 Sep 5.

Department of Neurology and Neurosurgery, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.

During episodic memory encoding, elaborative cognitive processing can improve later recall or recognition. While multiple studies examined the neural correlates of encoding strategies, few studies have explicitly focused on the self-initiation of elaborative encoding. Repetitive transcranial magnetic stimulation (rTMS), a method which can transiently disrupt neural activity, was administered during an associative encoding task. rTMS was either applied to the left dorsolateral prefrontal cortex (DLPFC) or to the vertex (a control region not involved in memory encoding) during presentation of pairs of words. Pairs could be semantically related or not related. Two encoding instructions were given, either cueing participants to analyze semantic relationships (cued condition), or to memorize the pair without any specific strategy cues (the self-initiated condition). Participants filled out a questionnaire regarding their use of memory strategies and performed a cued-recall task. We hypothesized that if the DLPFC plays a role in the self-initiation of elaborative encoding we would observe a reduction in memory performance in the self-initiated condition, particularly for related. We found a significant correlation between the effects of rTMS and strategy use, only in the self-initiated condition with related pairs. High strategy users showed reduced performance following DLPFC stimulation, while low strategy users tended to show increased recall following DLPFC stimulation during encoding. These results suggest the left DLPFC may be involved in the self-initiation of memory strategy use, and individuals may utilize different neural networks depending on their use of encoding strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764025PMC
July 2014

Auditory-motor adaptation to frequency-altered auditory feedback occurs when participants ignore feedback.

BMC Neurosci 2013 Mar 9;14:25. Epub 2013 Mar 9.

Psychology Department & Laurier Centre for Cognitive Neuroscience, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada.

Background: Auditory feedback is important for accurate control of voice fundamental frequency (F(0)). The purpose of this study was to address whether task instructions could influence the compensatory responding and sensorimotor adaptation that has been previously found when participants are presented with a series of frequency-altered feedback (FAF) trials. Trained singers and musically untrained participants (nonsingers) were informed that their auditory feedback would be manipulated in pitch while they sang the target vowel [/α /]. Participants were instructed to either 'compensate' for, or 'ignore' the changes in auditory feedback. Whole utterance auditory feedback manipulations were either gradually presented ('ramp') in -2 cent increments down to -100 cents (1 semitone) or were suddenly ('constant') shifted down by 1 semitone.

Results: Results indicated that singers and nonsingers could not suppress their compensatory responses to FAF, nor could they reduce the sensorimotor adaptation observed during both the ramp and constant FAF trials.

Conclusions: Compared to previous research, these data suggest that musical training is effective in suppressing compensatory responses only when FAF occurs after vocal onset (500-2500 ms). Moreover, our data suggest that compensation and adaptation are automatic and are influenced little by conscious control.
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http://dx.doi.org/10.1186/1471-2202-14-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602002PMC
March 2013

Neural activity related to self-initiating elaborative semantic encoding in associative memory.

Neuroimage 2013 Feb 9;67:273-82. Epub 2012 Nov 9.

Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, Qubeec, Canada H4H 1R3.

During episodic memory encoding, elaborative encoding strategies have been related to greater performance on later memory tests. However, many clinical populations display a deficit in self-initiating encoding strategies. We designed an fMRI study to examine the neural correlates of self-initiating elaborative encoding. Twenty-three healthy participants were presented triads of objects in which either neither, one or both objects in the bottom of the triad were related to the top object, and given two encoding instructions that required them to indicate the number of semantic ("related?") or physical ("smaller?") relationships in the triad. Reaction time decreased with more semantic relationships for both encoding instructions, indicating that semantic analysis was performed during the non-semantic encoding task. Recognition memory was better for the semantic encoding condition ("related?"), but there was no modulation of the number of semantic links on memory performance for either encoding condition. We performed a conjunction analysis on the fMRI data to find areas with greater activity for the non-semantic>semantic encoding tasks that were modulated by increasing semantic relationships during non-semantic encoding. Activity was found in the left dorsolateral prefrontal cortex (DLPFC) and bilaterally in the supramarginal gyrus. We suggest that the DLPFC is the most likely candidate region for the self-initiation of elaborative encoding while the supramarginal activity is likely related to attentional effects.
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http://dx.doi.org/10.1016/j.neuroimage.2012.11.004DOI Listing
February 2013

Multiple instances of vocal sensorimotor adaptation to frequency-altered feedback within a single experimental session.

J Acoust Soc Am 2010 Jan;127(1):EL13-8

Department of Psychology, Wilfrid Laurier University, Waterloo, Ontario N2L 2C5, Canada.

Vocal sensory-motor adaptation is typically studied by introducing a prolonged change in auditory feedback. While it may be preferable to perform multiple blocks of adaptation within a single experiment, it is possible that a carry-over effect from previous blocks of adaptation may affect the results of subsequent blocks. Speakers were asked to vocalize an /a/ sound and match a target note during ten adaptation blocks. Each block represented a unique combination of target note and shift direction. The adaptation response was found to be similar for all blocks, indicating that there were no carry-over effects from previous blocks of adaptation.
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http://dx.doi.org/10.1121/1.3272633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803716PMC
January 2010