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1.  Altered Cerebral Response During Cognitive Control: A Potential Indicator of Genetic Liability for Schizophrenia 
Neuropsychopharmacology  2013;38(5):846-853.
Aberrant activity in brain regions underlying various aspects of executive cognition has been reported in patients with schizophrenia and in their healthy relatives, suggesting an association with genetic liability. The aim of this study was to investigate brain responses to selective aspects of cognitive control in unaffected siblings who are at increased genetic risk of schizophrenia. Altogether, 65 non-affected siblings, 70 patients with schizophrenia spectrum disorders, and 235 normal controls participated in this study. Blood-oxygen-Ievel-dependent functional magnetic resonance imaging was conducted while participants performed a cognitive control task (‘flanker task') to identify brain activity and connectivity associated with response inhibition and conflict monitoring, and suppression. Behaviorally, similar to patients with schizophrenia, siblings were less accurate when inhibiting prepotent responses relative to normal controls. During response inhibition, again similar to patients with schizophrenia, siblings showed decreased activity in the anterior cingulate (ACC), along with increased functional coupling with the dorsolateral prefrontal cortex (PFC) when compared to normal controls. Our findings show altered ACC activity and PFC connectivity in unaffected siblings and patients with schizophrenia during response inhibition. These results suggest that such changes in the neural activity underlying aspects of cognitive control may represent a potential intermediate phenotype for the investigation of the genetic basis of schizophrenia.
doi:10.1038/npp.2012.250
PMCID: PMC3671987  PMID: 23299932
anterior cingulated; biological psychiatry; cognition; functional connectivity; functional magnetic resonance imaging; imaging; clinical or Preclinical; intermediate phenotype; prefrontal cortex; response inhibition; schizophrenia/Antipsychotics not open access; response inhibition; functional magnetic resonance imaging; anterior cingulate; heritability; intermediate phenotype
3.  DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding 
Schizophrenia Bulletin  2011;39(1):206-216.
The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.
doi:10.1093/schbul/sbr128
PMCID: PMC3523900  PMID: 21976709
DRD2; dopamine; default mode network; functional magnetic resonance imaging; single-photon emission computerized tomography
4.  Effect of Schizophrenia Risk-Associated Alleles in SREB2 (GPR85) on Functional MRI Phenotypes in Healthy Volunteers 
Neuropsychopharmacology  2012;38(2):341-349.
Genetic variants in GPR85 (SREB2: rs56080411 and rs56039557) have been associated with risk for schizophrenia. Here, we test the hypothesis that these variants impact on brain function in normal subjects, measured with functional magnetic resonance imaging (fMRI) paradigms that target regions with greatest SREB2 expression (hippocampal formation and amygdaloid complex). During a facial emotion recognition paradigm, a significant interaction of rs56080411 genotype by sex was found in the left amygdaloid complex (male risk allele carriers showed less activation than male homozygotes for the non-risk allele, while females showed the opposite pattern). During aversive encoding of an emotional memory paradigm, we found that risk allele carriers for rs56080411 had greater activation in the right inferior frontal gyrus. Trends in the same direction were present for rs56039557 in the right occipital cortex and right fusiform gyrus. During a working memory paradigm, a significant sex-by-genotype interaction was found with male risk allele carriers of rs56080411 having inefficient activation within the left dorsolateral prefrontal cortex (DLPFC), compared with same sex non-risk carriers, while females revealed an opposite pattern, despite similar levels of performance. These data suggest that risk-associated variants in SREB2 are associated with phenotypes similar to those found in patients with schizophrenia in the DLPFC and the amygdala of males, while the pattern is opposite in females. The findings in females and during the emotional memory paradigm are consistent with modulation by SREB2 of brain circuitries implicated in mood regulation and may be relevant to neuropsychiatric conditions other than schizophrenia.
doi:10.1038/npp.2012.184
PMCID: PMC3527120  PMID: 22968816
emotion; hippocampal formation; amygdala; dorsolateral prefrontal cortex; single-nucleotide polymorphisms; amygdala; biological psychiatry; dorsolateral prefrontal cortex; emotion; hippocampal formation; imaging; clinical or preclinical; mood/anxiety/stress disorders; schizophrenia/antipsychotics; single-nucleotide polymorphisms
5.  Neurophysiological correlates of age-related changes in working memory updating 
NeuroImage  2012;62(3):10.1016/j.neuroimage.2012.05.066.
Normal aging is associated with a gradual decline in executive functions such as set-shifting, inhibition, and updating, along with a progressive decline of neurotransmitter systems including the dopamine system. Modulation from the dopamine system is thought to be critical for the gating of information during working memory. Given the known relationships between executive aging, cognition, and dopamine, this study aims to explore the neurobiology underlying age-related changes in working memory updating using fMRI with healthy subjects from across the adult age spectrum. Our results indicate that older age is associated with poorer performance, reduced meso-cortico-striatal activation, and reduced functional coupling between the caudate and the VLPFC during the updating task. Additionally, caudate activation is associated with improved accuracy and VLPFC activation with faster reaction times in the full sample. Thus, older subjects’ under-recruitment of and reduced functional coupling between these regions may specifically underlie age-related changes in working memory updating. These results are consistent with computational models of executive cognition and dopamine-mediated age-related cognitive decline.
doi:10.1016/j.neuroimage.2012.05.066
PMCID: PMC3856325  PMID: 22659476
working memory; aging; fMRI; functional connectivity; caudate; prefrontal cortex
6.  Normal aging modulates prefrontoparietal networks underlying multiple memory processes 
The European journal of neuroscience  2012;36(11):3559-3567.
Functional decline of brain regions underlying memory processing represents a hallmark of cognitive aging. Although a rich literature documents age-related differences in several memory domains, the effect of aging on networks that underlie multiple memory processes has been relatively unexplored. Here we used functional magnetic resonance imaging during working memory and incidental episodic encoding memory to investigate patterns of age-related differences in activity and functional covariance patterns common across multiple memory domains. Relative to younger subjects, older subjects showed increased activation in left dorso-lateral prefrontal cortex along with decreased deactivation in the posterior cingulate. Older subjects showed greater functional covariance during both memory tasks in a set of regions that included a positive prefronto-parietal-occipital networkas well as a negative network that spanned the default mode regions. These findings suggest that the memory process-invariant recruitment of brain regions within prefronto-parietal-occipital network increases with aging.Our results are in line with the dedifferentiation hypothesis of neurocognitive aging, thereby suggesting a decreased specialization of the brain networks supporting different memory networks.
doi:10.1111/j.1460-9568.2012.08254.x
PMCID: PMC3511913  PMID: 22909094
working memory; episodic memory; aging; functional magnetic resonance imaging
7.  Investigation of Anatomical Thalamo-Cortical Connectivity and fMRI Activation in Schizophrenia 
Neuropsychopharmacology  2011;37(2):499-507.
The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age- and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.
doi:10.1038/npp.2011.215
PMCID: PMC3242311  PMID: 21956440
diffusion tensor imaging (DTI), probabilistic tractography; medio-dorsal nucleus; prefrontal cortex; working memory; reproducibility; schizophrenia/antipsychotics; imaging; clinical or preclinical; learning & memory; neuroanatomy; DTI; probabilistic tractography; medio-dorsal nucleus; prefrontal cortex; working memory
8.  Magnetic resonance perfusion imaging of resting-state cerebral blood flow in preclinical Huntington's disease 
Magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). The aim of this study was to investigate the sensitivity of resting-state perfusion MRI in preHD and to identify neural changes, which could serve as biomarkers for future clinical trials. Differences in regional cerebral blood flow (rCBF) in 18 preHD and 18 controls were assessed with a novel MRI method based on perfusion images obtained with continuous arterial spin labeling. High-resolution structural data were collected to test for changes of brain volume. Compared with controls, preHD individuals showed decreased rCBF in medial and lateral prefrontal regions and increased rCBF in the precuneus. PreHD near to symptom onset additionally showed decreased rCBF in the putamen and increased rCBF in the hippocampus. Network analyses revealed an abnormal lateral prefrontal pattern in preHD far and near to motor onset. These data suggest early changes of frontostriatal baseline perfusion in preHD independent of substantial reductions of gray matter volume. This study also shows the feasibility of detecting neural changes in preHD with a robust MRI technique that would be suitable for longitudinal multisite application.
doi:10.1038/jcbfm.2011.60
PMCID: PMC3185882  PMID: 21559028
arterial spin labeling; cerebral blood flow; Huntington's disease; prefrontal cortex; magnetic resonance imaging; striatum
9.  Dysconnectivity of multiple resting-state networks in patients with schizophrenia who have persistent auditory verbal hallucinations 
Background
Functional neuroimaging studies on schizophrenia have suggested abnormal task-related functional connectivity in patients with schizophrenia who have auditory verbal hallucinations (AVHs). However, little is known about intrinsic functional connectivity in these patients.
Methods
Between January 2009 and February 2010, we studied patients with schizophrenia who had persistent and treatment-refractory AVHs in comparison with healthy controls. Using functional magnetic resonance imaging, we studied the functional connectivity of multiple resting state networks (RSNs) and their relation to symptom severity. We analyzed the data using a spatial group independent component analysis, and we used random-effects t tests to compare spatial components between groups.
Results
There were 10 patients and 14 controls enrolled in this study. In total, 16 RSNs were identified, from which we selected 4 networks of interest for further analyses. Within a speech-related network, patients showed increased connectivity in bilateral temporal regions and decreased connectivity in the cingulate cortex. Within 2 additional RSNs associated with attention and executive control, respectively, patients exhibited abnormal connectivity in the precuneus and right lateral prefrontal areas. We found correlations between measures of AVH severity and functional connectivity of the left anterior cingulate, left superior temporal gyrus and right lateral prefrontal cortex.
Limitations
The relatively small sample size, the patients’ use of antipsychotic medication and the lack of a clinical control group have to be considered as potential limitations.
Conclusion
Our findings indicate that disrupted intrinsic connectivity of a speech-related network could underlie persistent AVHs in patients with schizophrenia. In addition, the occurrence of hallucinatory symptoms seems to modulate RSNs associated with attention and executive control.
doi:10.1503/jpn.110008
PMCID: PMC3201990  PMID: 21791169
10.  Aberrant connectivity of resting-state networks in borderline personality disorder 
Background
Several functional neuroimaging studies have reported regionally abnormal activation of the frontal cortex in individuals with borderline personality disorder (BPD) during cognitive and affective task performance. However, little is known about neural function in individuals with BPD during the resting state. Using functional magnetic resonance imaging (fMRI), this study investigated the functional connectivity of prefrontal and limbic networks in patients with BPD.
Methods
Between January 2009 and March 2010, we investigated patients with BPD according to DSM-IV criteria and healthy controls by means of resting-state fMRI. The data were analyzed using a spatial group independent component analysis, and random effects t tests were used to compare spatial components between groups (p < 0.005, uncorrected).
Results
There were 17 women with BPD and 17 female healthy controls enrolled in this study. Within a network comprising cortical midline regions (“default mode network”), patients with BPD showed an increase in functional connectivity in the left frontopolar cortex (FPC) and the left insula, whereas decreased connectivity was found in the left cuneus. Within a network comprising predominantly right lateral prefrontal and bilateral parietal regions, patients with BPD showed decreased connectivity of the left inferior parietal lobule and the right middle temporal cortex compared with healthy controls. Two networks comprising lateral prefrontal and cingulate regions did not exhibit significant between-group differences. We found correlations between functional connectivity of the FPC and measures of impulsivity as well as between connectivity of the insula/cuneus and dissociation tension.
Limitations
Co-occurrent axis I disorders and medication use in this sample of patients with BPD have to be considered as potential limitations.
Conclusion
These data suggest that abnormal functional connectivity of temporally coherent resting-state networks may underlie certain symptom clusters in patients with BPD.
doi:10.1503/jpn.100150
PMCID: PMC3201994  PMID: 21406160
11.  Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition 
Neuropsychopharmacology  2010;35(10):2101-2109.
Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks—a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.
doi:10.1038/npp.2010.83
PMCID: PMC3013347  PMID: 20555311
modafinil; fMRI; emotion; amygdala; cognitive processing; healthy volunteers; imaging; clinical or preclinical; cognition; psychopharmacology; learning and memory; modafinil; fMRI; emotion; amygdale; cognitive processing
12.  Neurobiology of Cognitive Aging: Insights from Imaging Genetics 
Biological psychology  2008;79(1):9-22.
Over the last several years, neuroscientists have been increasingly using neuroimaging techniques to unravel the neurobiology underlying cognitive aging, and in more recent years to explore the role of genes on the variability of the aging process. One of the primary goals of this research is to identify proteins involved in cognitive aging with the hope that this would facilitate the development of novel treatments to combat cognitive impairment. Further, it is likely with early identification of susceptible individuals, early intervention through life-style changes and other methods could increase an individual’s resilience to the effects of aging.
doi:10.1016/j.biopsycho.2008.03.015
PMCID: PMC3127547  PMID: 18511173
13.  Anterior Cingulate Desynchronization and Functional Connectivity with the Amygdala During a Working Memory Task Predict Rapid Antidepressant Response to Ketamine 
Neuropsychopharmacology  2010;35(7):1415-1422.
Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl--aspartate receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally arousing tasks. This study tested the hypothesis that during the N-back task, a widely used working memory paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement after ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance 1 to 3 days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r=−0.73, p=0.0021, FDR <0.05).These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.
doi:10.1038/npp.2010.24
PMCID: PMC2869391  PMID: 20393460
major depressive disorder (MDD); magnetoencephalography (MEG); N-back; biomarker; beta desynchronization; Biological Psychiatry; Mood/Anxiety/Stress Disorders; Imaging; Clinical or Preclinical; Glutamate; magnetoencephalography; N-back; beta desynchronization; biomarker
14.  Catechol-O-Methyltransferase Valine158Methionine Polymorphism Modulates Brain Networks Underlying Working Memory Across Adulthood 
Biological psychiatry  2009;66(6):540-548.
Background
Cognitive abilities decline with age with large individual variability. Genetic variations have been suggested to be an important source for some of this heterogeneity. Among these variations, those related to the dopaminergic system, particularly the valine158methionine polymorphism in catechol-O-methyltransferase (COMTval158met), have been implicated in modulating age-related changes in executive function.
Methods
We studied 75 subjects (age 21–90 years) using functional neuroimaging while they performed a low-level working memory (WM) task to explore the effects of aging, of the COMTval158met polymorphism, and their interactions on the physiological patterns of interconnected cortical activity engaged by WM.
Results
Our results show that val homozygotes and older subjects showed increased activity in dorsolateral prefrontal cortex (DLPFC) and decreased activity in ventrolateral prefrontal cortex (VLPFC) relative to met homozygotes and younger subjects, respectively. Interestingly, there were also independent effects of the COMTval158met polymorphism and age on the strength of connectivity between brain regions within the left prefrontal-parietal network; val homozygotes and older subjects showed greater connectivity between the DLPFC and other brain regions within the network and met homozygotes showed greater connectivity between the VLPFC and other brain regions within the network. Furthermore, the greater functional connectivity strength of DLPFC in val homozygotes relative to met homozygotes was much more pronounced in older adults
Conclusions
Our findings suggest that the COMTval158met polymorphism modulates both the activity and functional connectivity of brain regions within WM networks and most importantly that this effect is exaggerated with increasing age, contributing to the variability in age-related decline in executive cognition.
doi:10.1016/j.biopsych.2009.04.014
PMCID: PMC3085346  PMID: 19539269
Aging; COMT; functional magnetic resonance imaging; independent component analysis; working memory
15.  Treatment with Olanzapine is Associated with Modulation of the Default Mode Network in Patients with Schizophrenia 
Neuropsychopharmacology  2009;35(4):904-912.
Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN.
doi:10.1038/npp.2009.192
PMCID: PMC3055362  PMID: 19956088
default mode network; schizophrenia; antipsychotics; working memory; ventromedial prefrontal cortex; fMRI; Biological Psychiatry; Imaging; Clinical or Preclinical; Schizophrenia/Antipsychotics; Cognition; default mode network; ventromedial prefrontal cortex; fMRI; olanzapine
16.  Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition 
Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks—a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.
doi:10.1038/npp.2010.83
PMCID: PMC3013347  PMID: 20555311
modafinil; fMRI; emotion; amygdala; cognitive processing; healthy volunteers
17.  Preferential Amygdala Reactivity to the Negative Assessment of Neutral Faces 
Biological psychiatry  2009;66(9):847-853.
Background
Prior studies suggest that the amygdala shapes complex behavioral responses to socially ambiguous cues. We explored human amygdala function during explicit behavioral decision making about discrete emotional facial expressions that can represent socially unambiguous and ambiguous cues.
Methods
During functional magnetic resonance imaging, 43 healthy adults were required to make complex social decisions (i.e., approach or avoid) about either relatively unambiguous (i.e., angry, fearful, happy) or ambiguous (i.e., neutral) facial expressions. Amygdala activation during this task was compared with that elicited by simple, perceptual decisions (sex discrimination) about the identical facial stimuli.
Results
Angry and fearful expressions were more frequently judged as avoidable and happy expressions most often as approachable. Neutral expressions were equally judged as avoidable and approachable. Reaction times to neutral expressions were longer than those to angry, fearful, and happy expressions during social judgment only. Imaging data on stimuli judged to be avoided revealed a significant task by emotion interaction in the amygdala. Here, only neutral facial expressions elicited greater activity during social judgment than during sex discrimination. Furthermore, during social judgment only, neutral faces judged to be avoided were associated with greater amygdala activity relative to neutral faces that were judged as approachable. Moreover, functional coupling between the amygdala and both dorsolateral prefrontal (social judgment > sex discrimination) and cingulate (sex discrimination > social judgment) cortices was differentially modulated by task during processing of neutral faces.
Conclusions
Our results suggest that increased amygdala reactivity and differential functional coupling with prefrontal circuitries may shape complex decisions and behavioral responses to socially ambiguous cues.
doi:10.1016/j.biopsych.2009.06.017
PMCID: PMC3013358  PMID: 19709644
Amygdala; cingulate; facial expressions; fMRI; prefrontal cortex; social decision making
18.  Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine 
Pregenual anterior cingulate (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally-salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally-arousing tasks. The present study tested the hypothesis that during the N-back task, a widely-used working memory paradigm, low pre-treatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement following ketamine.
Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance one to three days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala.
Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within four hours of ketamine administration (r = 0.82, p = 0.0002, FDR < 0.05). Pre-treatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r = −0.73, p = 0.0021, FDR <0.05).
These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.
doi:10.1038/npp.2010.24
PMCID: PMC2869391  PMID: 20393460
major depressive disorder (MDD); magnetoencephalography (MEG); N-back; biomarker; beta desynchronization
19.  Genetic variation in FGF20 modulates hippocampal biology 
We explored the effect of Single Nucleotide Polymorphisms (SNPs) in the Fibroblast Growth Factor 20 gene (FGF20) associated with risk for Parkinson’s disease (PD) on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237, 116 men, 18–87 years). We analyzed high resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in post-mortem human brain tissue to determine the molecular correlates of these SNPs (N = 108, 72 men, 18–74 years). We found that the T allele carriers of rs12720208 in the 3’ UTR had relatively larger hippocampal volume (p = 0.0059), diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal ageing (p = 0.026). In post-mortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGF receptor 1 (FGFR1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with ageing, confirm a role of FGF20 in human brain structure and function during development and aging.
doi:10.1523/JNEUROSCI.5773-09.2010
PMCID: PMC2909689  PMID: 20427658
FGF20; Genetic; Voxel-Based Morphometry; Neuroimaging; MRI; Hippocampus
20.  Association of the Ser704Cys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding 
The European journal of neuroscience  2008;28(10):2129-2136.
A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser704Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser704Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser/Ser subjects exhibited greater engagement of the HF together with greater HF–dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser704Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.
doi:10.1111/j.1460-9568.2008.06482.x
PMCID: PMC2865560  PMID: 19046394
DISC1; fMRI; gray matter; hippocampus; memory encoding; phenotypic variance
21.  Age-related alterations in default mode network: impact on working memory performance 
Neurobiology of aging  2008;31(5):839-852.
The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.
doi:10.1016/j.neurobiolaging.2008.05.022
PMCID: PMC2842461  PMID: 18674847
functional magnetic resonance imaging; aging; default mode; connectivity; working memory
22.  Age-related Alterations in Simple Declarative Memory and the Effect of Negative Stimulus Valence 
Journal of cognitive neuroscience  2009;21(10):1920-1933.
Healthy aging has been shown to modulate the neural circuitry underlying simple declarative memory; however, the functional impact of negative stimulus valence on these changes has not been fully investigated. Using BOLD fMRI, we explored the effects of aging on behavioral performance, neural activity, and functional coupling during the encoding and retrieval of novel aversive and neutral scenes. Behaviorally, there was a main effect of valence with better recognition performance for aversive greater than neutral stimuli in both age groups. There was also a main effect of age with better recognition performance in younger participants compared to older participants. At the imaging level, there was a main effect of valence with increased activity in the medial-temporal lobe (amygdala and hippocampus) during both encoding and retrieval of aversive relative to neutral stimuli. There was also a main effect of age with older participants showing decreased engagement of medial-temporal lobe structures and increased engagement of prefrontal structures during both encoding and retrieval sessions. Interestingly, older participants presented with relatively decreased amygdalar–hippocampal coupling and increased amygdalar– prefrontal coupling when compared to younger participants. Furthermore, older participants showed increased activation in prefrontal cortices and decreased activation in the amygdala when contrasting the retrieval of aversive and neutral scenes. These results suggest that although normal aging is associated with a decline in declarative memory with alterations in the neural activity and connectivity of brain regions underlying simple declarative memory, memory for aversive stimuli is relatively better preserved than for neutral stimuli, possibly through greater compensatory prefrontal cortical activity.
doi:10.1162/jocn.2009.21130
PMCID: PMC2757312  PMID: 18823239
23.  Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance 
PLoS ONE  2010;5(2):e9348.
Background
Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.
Methods
Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory.
Results
Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.
Conclusions
Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.
doi:10.1371/journal.pone.0009348
PMCID: PMC2825256  PMID: 20179754
24.  Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia 
Psychiatry research  2009;173(1):31-38.
Earlier imaging studies in schizophrenia have reported abnormal amygdala and prefrontal cortex activity during emotion processing. We investigated with functional magnetic resonance imaging (fMRI) during emotion processing changes in activity of the amygdala and of prefrontal cortex in patients with schizophrenia during 8 weeks of olanzapine treatment. Twelve previously drug-free/naive patients with schizophrenia were treated with olanzapine for 8 weeks and underwent two fMRI scans after 4 and 8 weeks of treatment during implicit and explicit emotional processing. Twelve healthy subjects were also scanned twice to control for potential repetition effects. Results showed a diagnosis by time interaction in left amygdala and a diagnosis by time by task interaction in right ventrolateral prefrontal cortex. In particular, activity in left amygdala was greater in patients than in controls at the first scan during both explicit and implicit processing, while it was lower in patients at the second relative to the first scan. Furthermore, during implicit processing, right ventrolateral prefrontal cortex activity was lower in patients than controls at the first scan, while it was greater in patients at the second relative to the first scan. These results suggest that longitudinal treatment with olanzapine may be associated with specific changes in activity of the amygdala and prefrontal cortex during emotional processing in schizophrenia.
doi:10.1016/j.pscychresns.2008.09.001
PMCID: PMC2736305  PMID: 19428222
Amygdala; Antipsychotic drugs; Emotions; Functional magnetic resonance imaging; Schizophrenia
25.  A novel, primate-specific, brain isoform of KCNH2 impacts cortical physiology, cognition, neuronal repolarization and risk for schizophrenia 
Nature medicine  2009;15(5):509-518.
Organized neuronal firing is critical for cortical processing and is disrupted in schizophrenia. Using 5’ RACE in human brain, we identified a primate-specific isoform (3.1) of the K+-channel KCNH2 that modulates neuronal firing. KCNH2-3.1 mRNA levels are comparable to KCNH2-1A in brain, but 1000-fold lower in heart. In schizophrenic hippocampus, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A. A meta-analysis of 5 clinical samples (367 families, 1158 unrelated cases, 1704 controls) shows association of SNPs in KCNH2 with schizophrenia. Risk-associated alleles predict lower IQ scores and speed of cognitive processing, altered memory-linked fMRI signals, and increased KCNH2-3.1 expression in post-mortem hippocampus. KCNH2-3.1 lacks a domain critical for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, non-adapting firing pattern. These results identify a novel KCNH2 channel involved in cortical physiology, cognition, and psychosis, providing a potential new psychotherapeutic drug target.
doi:10.1038/nm.1962
PMCID: PMC2756110  PMID: 19412172

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