Important Findings Published in Biological Psychiatry
By Caleb M. Adler, MD.
January 15, 2012
Commentary by Aysenil Belger, Gunes H. Yucel, and Franc C.L. Donkers
Atkinson RJ, Michie PT, Schall U (2012). Duration mismatch negativity and p3a in first-episode psychosis and individuals at ultra-high risk of psychosis. Biol Psychiatry 71:98-104
Patients with schizophrenia have been observed to display reduced mismatch negativity (MMN), an early negative ERP component seen in response to discriminable changes in repetitive auditory stimuli. MMN have been separated into components, some of which may be more prominent in varying disease states and chronicity. In this paper, the authors measured MMN and P3a, an ERP component reflecting attentional reorientation, in subjects at "ultra-high" risk of psychosis (UHR), subjects having their first psychotic episode (FEP), and healthy controls. Ultra-high risk subjects are "clinically high risk" (CHR) individuals, defined by at least some prodromal symptoms. The authors found that MMN and P3a were reduced in both UHR and FEP subjects, at least at the trend level. They noted that these findings suggest that MMN and P3a are reduced very early in the course of illness and might represent potential prodromal markers. In the commentary, the potential relationship between MMN and the pathophysiology of schizophrenia is reviewed. The commentary authors note the importance of studying early disease markers but point out that in the absence of longitudinal follow-up, one cannot conclude that findings in CHR individuals are not markers of subsyndromic pathology rather than predictors of future pathology.
Commentary by Michael F. Green and Junghee Lee
Taylor SF, Kang J, Brege IS, et al (2012). Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia. Biol Psychiatry 71:136-145
In this paper, the authors describe their meta-analysis of functional imaging studies of emotion in patients with schizophrenia. The authors subdivide the available data in several ways to separately address specific aspects of emotional experience. They report that emotional perception is associated with decreased activity in schizophrenic patients throughout much of the expanded limbic network, including amygdala/hippocampus, portions of the prefrontal cortex, and subcortical structures. Schizophrenic patients showed increased activity in other regions, suggested to be compensatory in nature. The authors further describe differences in findings during implicit emotion tasks, in which subjects typically viewed emotion-inducing stimuli (e.g. faces) and explicit tasks, during which subjects were called upon to take a more active role-- noting in particular that areas of increased activation with schizophrenia were seen only during the latter. In the commentary, Drs. Green and Lee suggest some interpretations of these findings in light of previous work, as well as offering some cautionary notes.
February 1, 2012
Commentary by Wolfram Schultz
Sugam JA, Day JJ, Wightman RM, et al (2012). Phasic nucleus accumbens dopamine encodes risk-based decision-making behavior. Biol Psychiatry 71:199-205
The authors examined dopamine release in the nucleus accumbens (NAc) of a small group of rodents trained on a risk-based decision-making task. Rats showed individual-specific preferences for risk-taking or risk-avoidant behavior that was reflected in dopamine release during choice and forced-choice trials. These findings suggest a role for dopamine projections to the NAc in risk-related decision making. The commentary expands on the manuscript by reviewing the cognitive nature of risk and current findings linking risk-related decision making to dopaminergic activity. Potential follow-up studies are discussed as well.
Commentary by Scott J. Russo
Wei Q, Fentress HM, Hoversten MT, et al (2012). Early-life forebrain glucocorticoid receptor overexpression increases anxiety behavior and cocaine sensitization. Biol Psychiatry 71:224-231
In this elegant experiment, Wei and colleagues address the importance of timing to the relationship between forebrain glucocorticoid receptor (GR) over-expression and emotional reactivity. The investigators show that in a mouse line with inducible GR over-expression, transient over-expression during early life led to increased behavioral effects. In contrast, post-weaning over-expression was not associated with similar outcomes. Early over-expression was also associated with long-term changes in transcription patterns. In the commentary, the role of glucocorticoids in stress response is reviewed. Dr. Russo observes that this manuscript extends current understanding of potential mechanisms underlying the effects of glucocorticoids on stress response, and suggests both further research avenues and potential therapeutic applications.
February 15, 2012
Commentary by Joan Kaufman
Dannlowski U, Stuhrmann A, Beutelmann V, et al (2012). Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry 71:286-293
The investigators obtained structural and functional magnetic resonance images from a large group of healthy adults. All subjects were screened for childhood trauma. The investigators report that exposure to traumatic events in childhood, reflected in scores on the Childhood Trauma Questionnaire (CTQ) was associated with amygdala activation in response to threatening faces, presented as part of a face-matching paradigm. High CTQ scores were further associated with reduced gray matter volume in prefrontal, medial temporal and subcortical structures including the insula, orbitofrontal cortex, anterior cingulate, hippocampus, and caudate. The authors note that these findings are consistent with studies of patients with depression and PTSD, suggesting that these functional and structural changes may be mediators between adverse childhood events and the appearance of later psychopathology.
Nikulina V, Widom CS, Brzustowicz LM (2012). Child abuse and neglect, MAOA, and mental health outcomes: a prospective examination. Biol Psychiatry 71:350-357
The investigators recruited a large number of adults with substantiated history of child abuse and neglect, as well as a matched comparison group. All participants were genotyped for monoamine oxidase A (MAOA) alleles. The MAOA encodes for an enzyme involved in the elimination of monoamine neurotransmitters, and has been identified as a moderator between childhood stress and longer term outcomes. The investigators found that a low-activity genotype decreased dysthymia in abused and maltreated women; and was associated with decreased risk of dysthymia, depression and alcohol abuse in white participants who had been sexually abused. In contrast, the high-activity genotype was protective in non-white (predominantly African-American) individuals. In the commentary, Dr. Kaufman comprehensively reviews genetic influences, and particularly the possible role of the MAOA gene in moderating between childhood abuse and the appearance of psychopathology.
Commentary by Elisabeth B. Binder and Florian Holsboer
Lovallo WR, Farag NH, Sorocco KH, et al (2012). Lifetime adversity leads to blunted stress axis reactivity: studies from the Oklahoma Family Health Patterns Project. Biol Psychiatry 71:344-349
The investigators tested 354 healthy young adults using a version of the Trier Social Stress Test (TSST) in which subjects were asked to engage in public speaking and mental arithmetic in front of a panel. Subjects were stratified by the number of sign infant adverse life events they had previously experienced, ranging from zero to four. The investigators report that previous adverse events were associated with lower heart rates and cortisol response to the stress task across gender. They note that their findings support previous suggestions that early life events may have a significant impact on reactivity to stress. In the commentary, these findings are discussed and potential explanations explored.
Commentary by Jacek Dębiec
Schwabe L, Nader K, Wolf OT, et al (2012). Neural signature of reconsolidation impairments by propranolol in humans. Biol Psychiatry 71:380-386
The investigators sought to test whether the β-adrenergic receptor antagonist, propranolol would interfere with the reconsolidation of recalled negative emotional pictures by altering medial temporal activity. Healthy individuals were exposed to neutral and emotional pictures and subsequently participated in an fMRI scan during which they were asked to recall the pictures-some after receiving propranolol. Subjects later participated in another fMRI scan during which they performed a recognition task around the same pictures. The investigators report that propranolol reduced subsequent memory for emotional pictures. Further, propranolol administration was associated with increased medial temporal activity during recall of recognized pictures. The commentary discusses the role of norepinephrine in memory consolidation and reconsolidation in light of previous preclinical and clinical studies. The findings of Schwabe and colleagues are further reviewed with particular emphasis on some seemingly paradoxical results and possible explanations for these data.
March 1, 2012
Commentary by Jennifer G. Mulle and Stephen T. Warren
Fernandez TV, Sanders SJ, Yurkiewicz IR, et al (2012). Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71:392-402
The authors studied copy number variants (CNV) in patients with Tourette Syndome (TS) as well as healthy controls. Individuals with TS did not differ from controls in number of de novo or transmitted rare CNVs. Nonetheless, the TS patients did show non-significantly larger rare CMVs, as has been found in other psychiatric disorders. Further evaluation of rare CMVs suggested the involvement of genes implicated in several psychiatric disorders, including genes involved in histaminergic neurotransmission. The commentary notes the importance of these findings to hypotheses of shared risk between developmental disorders.
March 15, 2012
Commentary by Michael D. Ehlers
Cavus I, Reinhart RM, Roach BJ, et al (2012). Impaired visual cortical plasticity in schizophrenia. Biol Psychiatry 71:512-520
The investigators build on previous studies of cortical plasticity that have identified abnormalities in patients with schizophrenia, using visual evoked potentials to measure long-term potentiation (LTP), a form of neuroplasticity. Visual evoked potentials (VEP) were elicited from healthy controls and patients with schizophrenia using a series of stimuli designed to evoke VEP potentiation as part of an odd-ball paradigm. Two negative-voltage components were identified in a principal components analysis, and compared between groups. The investigators found significant differences between schizophrenic patients and healthy controls indicative of impaired visual cortical plasticity in the former group.
Clapp WC, Hamm JP, Kirk IJ, et al (2012). Translating long-term potentiation from animals to humans: a novel method for noninvasive assessment of cortical plasticity. Biol Psychiatry 71:496-502
The authors synopsized and discussed their previous research demonstrating that repetitive sensory stimuli may induce long term potentiation that may be measured with EEG and fMRI. They further present evidence that LTP in humans is homologous with synaptic LTP observed in preclinical experiments, and discuss potential clinical applications of these findings.
Cooke SF, Bear MF (2012). Stimulus-selective response plasticity in the visual cortex: an assay for the assessment of pathophysiology and treatment of cognitive impairment associated with psychiatric disorders. Biol Psychiatry 71:487-495
The authors describe stimulus-specific response potentiation (SRP), an example of experience-dependent plasticity observed in the visual cortex of rodents in response to repeated visual stimuli. They present evidence that SRP represents a form of long-term potentiation involving thalamo-cortical synaptic transmission. They further describe potential clinical utility of SRP, particularly in patients with schizophrenia.
Mears RP, Spencer KM (2012). Electrophysiological assessment of auditory stimulus-specific plasticity in schizophrenia. Biol Psychiatry 71:503-511
The authors used event-related potentials (ERP) to measure neuroplasticity in schizophrenic patients and healthy controls in response to an auditory odd-ball task. They reports significant differences in response that suggest abnormal auditory neuroplasticity in the former group. They further suggest that these methods may be clinically useful for developing novel therapeutics for schizophrenia. The commentary reviews the legacy of long-term potentiation research in psychiatry, and places the findings of the four studies reviewed into that larger context. Dr. Ehlers notes that the four articles suggest methodologies to facilitate non-invasive assessment of LTP, and suggest the presence of LTP abnormalities in patients with schizophrenia. The commentary goes on to discuss the potential role for these techniques in clinical psychiatry as bio-markers and in advancing our understanding of the underlying neuropathology of psychiatric illnesses thought to involve abnormalities in neural circuitry.
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