Long-term potentiation (LTP) is a synaptic mechanism underlying learning and memory that has been studied extensively in laboratory animals. The study of LTP recently has been extended into humans using repetitive sensory stimulation to induce cortical LTP. In this review paper we will discuss past results from our group demonstrating that repetitive sensory stimulation (visual or auditory) induces LTP within the sensory cortex (visual/auditory, respectively) and can be measured non-invasively using EEG or fMRI. We will discuss a number of studies that indicate that this form of LTP shares several characteristics with the synaptic LTP described in animals: it is frequency dependent, long-lasting (>1 hour), input specific, depotentiates with low-frequency stimulation, and is blocked by NMDA receptor blockers in rats. In this paper we also present new data regarding the behavioral significance of human sensory LTP.
These advances will permit enquiry into the functional significance of LTP that has been hindered by the absence of a human model. The ability to elicit LTP using a natural sensory stimulus non-invasively will provide a model system allowing the detailed examination of synaptic plasticity in normal subjects and may have future clinical applications in the diagnosis and assessment of neuropsychiatric and neurocognitive disorders.
Long-term potentiation (LTP); Human; Electroencephalography (EEG); Sensory stimulation; Visual evoked potential (VEP); Cortical plasticity
Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation (LTP) is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ.
Electroencephalographic (EEG) data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual LTP paradigm. VEPs were elicited by standard visual stimuli (~0.83 Hz, 2 minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS; ~8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. VEPs were subjected to principal components analysis (PCA). Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 ms (C1) and at 146 ms (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups.
HFS produced sustained potentiation of visual C1 and N1b in HCs, but not in SZs. The HCs and SZs had comparable HFS-driven EEG visual steady state responses (VSSR). However, greater VSSR to the HFS predicted greater N1b potentiation in HCs but not in SZs. SZ patients with greater N1b potentiation decreased their reaction times to target stimuli.
Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in NMDA receptor function.
Long-term potentiation; schizophrenia; visual cortex; evoked potential; plasticity
The neuropathology of schizophrenia remains elusive. One indication of this elusiveness is that the literature, in contrast to that on the neuropathology of almost any other disease, deals predominantly with measures of normal structures rather than with the demonstration and characterization of pathological structures. An important exception to this trend has been the continued search, over four decades, for reactive glia. In this article, we review histological and radiological evidence for and against astrocytosis and microgliosis specifically associated with schizophrenia. The studies are generally limited by small samples, flawed designs, and potentially biased methods of counting cells. Interpretation of these studies is further complicated by the frequent presence of glial reactions in older individuals without psychiatric disease. Nonetheless, some of the positive findings in the literature cannot easily be dismissed. A sufficiently large autopsy study, weighted towards younger subjects, could provide a definitive answer, which if positive could be a major step towards finding an underlying pathological process.
human; positron emission tomography; microglia; astrocytes; peripheral benzodiazepine receptor; glial fibrillary acidic protein
Limited success has been achieved through previous ADHD linkage scans which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci.
A set of 1,094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative SNP panel. Two quantitative traits measuring the children’s symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score.
A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p<0.04. Setting-specific suggestive linkage signals were also found: LOD=2.2 at 9p23 for home trait and LOD=2.6 at 11q21 for school trait.
These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia.
The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures.
We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 ± 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 ± 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations.
Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8).
These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.
Bipolar disorder; cortical pattern matching; lithium; magnetic resonance imaging; mood disorders; neuroprotection
Depression is associated with elevated levels of the inflammation marker C -reactive protein (CRP), yet the direction of this association remains unclear. This study tested bi-directional longitudinal associations between CRP and depression in a sample of adolescent and young adults. The study compared the effects of current depression to the cumulative episodes of depression over time.
Nine waves of data from the prospective population-based Great Smoky Mountains Study (N = 1,420) were used, covering children in the community aged 9–16, 19, and 21 years old. Structured interviews were used to assess depressive symptoms, depression diagnosis, and cumulative depressive episodes. Bloodspots were collected at each observation and assayed for CRP levels.
CRP levels were not associated with later depression status. In contrast, all depression-related variables displayed evidence of association with later CRP levels. The associations with depressive symptoms and diagnostic status were attenuated after controlling for covariates particularly body mass index, smoking, and medication use. The effect of cumulative depressive episodes, however, continued to be significant after accounting for a range of covariates. Body mass index, smoking behavior and recent infections may mediate a portion of the effect of cumulative episodes on later CRP, but cumulative depressive episodes continued to predict CRP levels independently.
The occurrence of multiple depressive episodes exerted the greatest effect on later CRP levels. This suggests that risk for the diseases of middle age - cardiovascular and metabolic disease – may begin in childhood and depend, in part, upon long-term emotional functioning.
Inflammation; CRP; Depression; Epidemiology; Childhood; Adolescence
Psychostimulants improve a variety of cognitive/behavioral processes in patients with attention deficit hyperactivity disorder (ADHD). Limited observations suggest a potentially different dose-sensitivity of prefrontal cortex (PFC)-dependent function (narrow inverted-U-shaped dose-response curves) vs. classroom/overt behavior (broad inverted-U) in children with ADHD. Recent work in rodents observed that methylphenidate (MPH; Ritalin®) elicits a narrow inverted-U shaped improvement in performance in PFC-dependent tests of working memory. The current studies first tested the hypothesis that PFC-dependent tasks, in general, display narrow dose sensitivity to the beneficial actions of MPH.
The effects of varying doses of MPH were examined on performance of rats in two tests of PFC-dependent cognition, sustained attention and attentional set shifting. Additionally, the effect of pretreatment with the α1-antagonist, prazosin (0.5 mg/kg), on MPH-induced improvement in sustained attention was examined.
MPH produced a broad inverted-U-shaped facilitation of sustained attention and attentional set shifting. Prior research indicates α1-receptors impair, while α2-receptors improve, working memory. In contrast, attentional set shifting is improved with α1-receptor activation, while α2-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set shifting tasks, additional studies examined whether α1-receptors promote sustained attention, similar to attentional set shifting. In these studies MPH-induced improvement in sustained attention was abolished by α1-receptor blockade.
PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α1- vs. α2-receptors in these processes. These observations have significant preclinical and clinical implications.
ADHD; Prefrontal Cortex; Cognition; Methylphenidate; Norepinephrine; Dopamine
In specific vole and primate species the neuropeptide Oxytocin (OT) plays a central role in the regulation of pair-bonding behavior. Here we investigate to what extent genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans.
We first genotyped twelve Single Nucleotide Polymorphisms (SNPs) in the Twin and Offspring Study in Sweden (TOSS, N=2309) and the Swedish Twin Study of CHild and Adolescent Development (TCHAD, N=1240) comprising measures of self-reported pair-bonding behavior. In the TOSS-sample we further investigated one the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in TCHAD and in the Child and Adolescent Twin Study of Sweden (CATSS, N=1771) the association between the same SNP and childhood behaviors was investigated.
One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD-sample. This association was replicated in the CATSS-sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected.
These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well described influence of OT on affiliative behavior in voles could also be of importance for humans.
Monogamy; Neuropeptide; Polymorphism; Autism; Affiliative behavior; Social Problems
Studies of copy number variation (CNV) have successfully characterized loci and molecular pathways involved in a range of neuropsychiatric conditions. We conducted an analysis of rare CNVs in Tourette Syndrome (TS) to identify novel risk regions and relevant molecular pathways, evaluate the burden of structural variation in cases versus controls, and to assess the overlap of identified variations with those implicated in other neuropsychiatric syndromes.
We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370K to 1M probe arrays, and genome-wide genotyping data was used to match cases and controls for ancestry. Transmitted and de novo CNVs present in < 1% of the population were evaluated.
While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (H1R and H2R) signaling pathways (p=5.8×10-4-1.6×10-2) as well as “axon guidance”, “cell adhesion”, “nervous system development” and “synaptic structure and function” processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders (ASD), but not intellectual disability or schizophrenia. Three large, likely-pathogenic, de novo events were identified, including one disrupting multiple gamma-Aminobutyric acid (GABA) receptor genes.
We identify further evidence supporting recent findings regarding the involvement of histaminergic and GABAergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and ASD.
Tourette syndrome; copy number variation; CNV; histamine; GABA; autism
Studies have shown that schizophrenia patients have motion perception deficit, which was thought to cause eye-tracking abnormality in schizophrenia. However, eye movement closely interacts with motion perception. The known eye-tracking difficulties in schizophrenia patients may interact with their motion perception.
Two speed discrimination experiments were conducted in a within-subject design. In experiment 1, the stimulus duration was 150 msec to minimize the chance of eye-tracking occurrence. In experiment 2, the duration was increased to 300 msec, increasing the possibility of eye movement intrusion. Regular eye-tracking performance was evaluated in a third experiment.
At 150 msec, speed discrimination thresholds did not differ between schizophrenia patients (n = 38) and control subjects (n = 33). At 300 msec, patients had significantly higher thresholds than control subjects (p =.03). Furthermore, frequencies of eye tracking during the 300 msec stimulus were significantly correlated with speed discrimination in control subjects (p = .01) but not in patients, suggesting that eye-tracking initiation may benefit control subjects but not patients. The frequency of eye tracking during speed discrimination was not significantly related to regular eye-tracking performance.
Speed discrimination, per se, is not impaired in schizophrenia patients. The observed abnormality appears to be a consequence of impairment in generating or integrating the feedback information from eye movements. This study introduces a novel approach to motion perception studies and highlights the importance of concurrently measuring eye movements to understand interactions between these two systems; the results argue for a conceptual revision regarding motion perception abnormality in schizophrenia.
Corollary discharge; efference copy; extraretinal; eye movement; eye tracking; frontal eye field; motion perception; MST; retinal; schizophrenia; smooth pursuit; speed discrimination; SPEM
Food restriction is known to enhance learning and motivation. The neural mechanisms underlying these responses likely involve alterations in gene expression in brain regions mediating the motivation to feed.
Analysis of gene expression profiles in male C57BL6/J mice using whole-genome microarrays was completed in the medial prefrontal cortex, nucleus accumbens, ventral tegmental area, and the hypothalamus following a five day food restriction. Quantitative PCR was used to validate these findings and determine the time-course of expression changes. Plasma levels of the stress hormone corticosterone (CORT) were measured by ELISA. Expression changes were measured in adrenalectomized animals that underwent food restriction, as well as in animals receiving daily injections of CORT. Progressive ratio responding for food, a measure of motivated behavior, was assessed after CORT treatment in restricted and fed animals.
Brief food restriction results in an upregulation of peripheral stress responsive genes in the mammalian brain. Time-course analysis demonstrated rapid and persistent expression changes in all four brain regions under study. Administration of CORT to non-restricted animals was sufficient to induce a subset of the genes, and alterations in gene expression after food restriction were dependent on intact adrenal glands. CORT can increase the motivation to work for food only in the restricted state.
These data demonstrate a central role for CORT in mediating both molecular and behavioral responses to food restriction. The stress hormone-induced alterations in gene expression described here may be relevant for both adaptive and pathological responses to stress.
transcription; neural plasticity; starvation; obesity; motivation; stress hormones
Can stressful events in early life alter the response characteristics of the human stress axis? Individual differences in stress reactivity are considered potentially important in long-term health and disease, however little is known about the sources of these individual differences. We present evidence that adverse experience in childhood and adolescence can alter core components of the stress axis, including cortisol and heart rate reactivity.
We exposed 354 healthy young adults (196 women) to public speaking and mental arithmetic stressors in the laboratory. Stress responses were indexed by self-report, heart rate, and cortisol levels relative to measures on a nonstress control day. Subjects were grouped into those who had experienced 0, 1, or 2 or more significant adverse life events including Physical or Sexual Adversity (mugged, threatened with a weapon, experienced a break-in or robbery; or raped or sexually assaulted by a relative or nonrelative) or Emotional Adversity (separation from biological mother or father for at least 6 months prior to age 15).
Experience of adversity predicted smaller heart rate and cortisol responses to the stressors in a dose-dependent fashion (0 > 1 > 2 or more events; (Fs = 5.79 and 8.11, ps < .004) for both men and women. This was not explained by differences in socioeconomic status, the underlying cortisol diurnal cycle, or subjective experience during the stress procedure.
The results indicate a long-term impact of stressful life experience on the reactivity of the human stress axis.
gender; heart rate; cortisol; stress reactivity; lifetime adversity; mental stress
Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a Cognitive-Behavioral Stress Management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat.
199 women undergoing primary treatment of Stage 0–III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. 79 provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-, and 12-month follow-ups.
Baseline negative affect was associated with > 50% differential expression of 201 leukocyte transcripts, including up-regulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by > 50% at follow-up (Group × Time interaction), including down-regulation of pro-inflammatory and metastasis-related genes and up-regulation of Type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of Interferon Response Factors and the Glucocorticoid Receptor (GR) as potential mediators of CBSM-induced transcriptional alterations.
In early stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related up-regulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes.
threat/anxiety; cognitive-behavioral stress management; gene expression; immune system; inflammation; cancer; stress
Mild traumatic brain injury (mTBI; cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders including post-traumatic stress disorder (PTSD). However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether TBI itself is a cause of augmented fear and anxiety.
Rats were trained with one of five fear conditioning procedures (N = 105) two days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring NMDA receptor subunits and GAD-67 protein levels in the hippocampus and basolateral amygdala complex (BLA).
Injured rats exhibited an overall increase in fear conditioning regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to over generalize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant up-regulation of excitatory NMDA receptors in the BLA. There was a trend toward decreased GABA related inhibition (GAD-67) in the BLA and hippocampus.
These results suggest that mTBI predisposes the brain toward heightened fear learning during stressful post-injury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the co-morbidity of PTSD and TBI.
traumatic brain injury; concussion; PTSD; fear conditioning; NMDA; GAD-67
Traditionally, norepinephrine has been associated with stress responses while dopamine has been associated with reward. Both of these catecholamines are found within the bed nucleus of the stria terminalis (BNST), a brain relay nucleus in the extended amygdala between cortical/limbic centers, and the hypothalamic-pituitary-adrenal axis. Despite this colocalization, little is known about subsecond catecholamine signaling in subregions of the BNST in response to salient stimuli.
Changes in extracellular catecholamine concentration in subregions of the BNST in response to salient stimuli were measured within the rat BNST using fast-scan cyclic voltammetry at carbon-fiber microelectrodes.
A discrete subregional distribution of release events was observed for different catecholamines in this nucleus. In addition, rewarding and aversive tastants evoked inverse patterns of norepinephrine and dopamine release in the BNST. An aversive stimulus, quinine, activated noradrenergic signaling but inhibited dopaminergic signaling, while a palatable stimulus, sucrose, inhibited norepinephrine while causing dopamine release.
This reciprocal relationship, coupled with their different time courses, can provide integration of opposing hedonic states to influence response outputs appropriate for survival.
Norepinephrine; dopamine; dorsolateral bed nucleus of the stria terminalis (dlBNST); ventral bed nucleus of the stria terminalis (vBNST); fast-scan cyclic voltammetry (FSCV); tastant stimuli
Studies have examined the interaction of MAOA genotype with childhood maltreatment in relation to depressive symptomatology and alcohol abuse with conflicting findings. Both high and low activity allele combinations have been shown to be protective for maltreated children with direction of findings varying by study methodology and participant’s sex.
Participants in a prospective cohort design study involving court substantiated cases of child abuse and neglect and a matched comparison group were followed up into adulthood and interviewed (N = 802). Eighty-two percent consented to provide blood, 631 gave permission for DNA extraction and analyses, and 575 were included in the final sample. This sample included male, female, White, and Non-White (primarily Black) participants. Symptoms of dysthymia, major depression and alcohol abuse were assessed using the NIMH Diagnostic Interview Schedule-III-R.
Significant three-way interactions, MAOA genotype by abuse by sex, predicted dysthymic symptoms. Low-activity MAOA genotype buffered against symptoms of dysthymia in physically abused and multiply maltreated women. Significant three-way interactions, MAOA genotype by sexual abuse by race, predicted all outcomes. Low-activity MAOA genotype buffered against symptoms of dysthymia, major depressive disorder and alcohol abuse for sexually abused White participants. The high-activity genotype was protective in the Non-White sexually abused group.
This prospective study provides evidence that MAOA interacts with child maltreatment to predict mental health outcomes. Reasons for sex differences and race findings are discussed.
Child abuse and neglect; MAOA genotype; depression; dysthymia; alcohol abuse; prospective longitudinal design
The last three decades has seen a steady growth of neuroscience research aimed at understanding the functions and sources of top-down attentional modulation in the brain. This correlates with recognition that attention may be a necessary component of sensory systems to support natural behaviors in natural environments. Complexity and clutter are two of the most recognizable hallmarks of natural environments, which can simultaneously contain vitally important and completely irrelevant stimuli. Attention serves as an adaptive filter allowing each sensory modality preferential processing routes for important stimuli while suppressing responses to distracters, thus optimizing use of limited neural resources. In other words, “attention” is the family of mechanisms by which organisms are able to effectively and selectively allocate limited neural resources to achieve specific behavioral goals. This review provides some historical context for considering attentional frameworks and modern neurophysiological attention research, focusing on visual attention. A taxonomy of common attentional effects and neural mechanisms is provided, along with consideration of the specific relationship between attention and saccade planning. We examine the validity of premotor theories of attention, which posit that attention and saccade planning are one and the same. While there is strong evidence that attention and oculomotor planning are similar, with shared neural substrates, there is also evidence that these two functions are not synonymous. Finally, we examine neurophysiological explanations for dysfunction in Attention Deficit Hyperactivity Disorder (ADHD) and the hypothesis that social impairment in Autism Spectrum Disorders (ASD) is partially attributable to perturbations of attentional control circuitry.
Neuregulin 1 (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia (Stefansson et al 2002). PPI is a widely used surrogate measure of psychosis in animal models and is considered a schizophrenia endophenotype. We hypothesized that if NRG1 influences PPI in rodents, then it should have a similar effect on PPI in humans.
We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms (SNPs) located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping were completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls.
Rs3924999 genotype was significantly associated with PPI (p=0.003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p=0.02) and controls (p=0.02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p=0.85). Schizophrenia patients had reduced PPI compared to control subjects (p=0.04). Neither SNP was associated with schizophrenia (all p>0.37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p=0.05).
A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations.
schizophrenia; glutamatergic; psychosis; endophenotype; nonsynonymous; polymorphism; PPI; NRG; NMDA; SNP
Emerging neuroscientific and genetic findings emphasize the dimensional rather than the categorical aspects of psychiatric disorders. However, the integration of dimensional approaches within the current categorical diagnostic framework remains unclear. Here, we used resting state fMRI (R-fMRI) to examine whether dimensional measures of psychiatric symptomatology capture brain-behavior relationships unaccounted for by categorical diagnoses. Additionally, we examined whether dimensional brain-behavior relationships are modified by the presence of a categorically defined illness, Attention-Deficit/Hyperactivity Disorder (ADHD).
R-fMRI scans were collected from 37 typically developing children (aged 10.2±2; 21 females) and 37 children meeting DSM-IV-TR criteria for ADHD (9.7±2; 11 females). Parent-rated Child Behavior Checklist Externalizing and Internalizing scores served as dimensional measures in our analyses of default network (DN) resting state functional connectivity (RSFC).
Regardless of diagnosis, we observed several significant relationships between DN RSFC and both Internalizing and Externalizing scores. Increased Internalizing scores were associated with stronger positive intra-DN RSFC, while increased Externalizing scores were associated with reduced negative RSFC between DN and “task-positive” regions such as dorsal anterior cingulate cortex. Several of these brain-behavior relationships differed depending on the categorical presence of ADHD.
Our findings suggest that while categorical diagnostic boundaries provide an inadequate basis for understanding the pathophysiology of psychiatric disorders, psychiatric illness cannot be viewed simply as an extreme of typical neural or behavioral function. Efforts to understand the neural underpinnings of psychiatric illness should incorporate both categorical and dimensional clinical assessments.
ADHD; children; functional magnetic resonance imaging (fMRI); functional connectivity; dimensional scale; default network
Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of α2A-adrenoceptors in postmortem frontal cortex of depressed subjects.
G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α2-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects.
Basal [35S] guanosine γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [35S] GTPγS binding potency (EC50 = .58 μmol/L vs. EC50 = 3.31 μmol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (Imax = 27 ± 4% vs. Imax = 47 ± 5%; p < .01) were observed after incubation with the α2-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [35S] GTPγS and Imax values for AC assay was found (n = 30; r = −.43; p < .05).
The dual regulation of α2A-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gαi/o–protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α2A-adrenoceptors in the pathogenesis of depression.
adenylyl cyclase; α2-adrenoceptor; cAMP; depression; G-protein; human brain
Illicit anabolic-androgenic steroid (AAS) abuse, though an important public health problem, remains inadequately studied. Almost all AAS abusers are male and lift weights, but the risk factors for AAS use among male weightlifters remain poorly understood.
We recruited 233 experienced male weightlifters, of whom 102 (44%) reported lifetime AAS use, and assessed their childhood and adolescent attributes retrospectively using structured clinical interviews and computerized questionnaires. This “cross-sectional cohort” approach—a design that we have formally presented in the recent methodological literature—utilizes a study cohort, not selected for outcomes of interest, and assesses exposures and outcomes retrospectively. We hypothesized that conduct disorder and body-image concerns would be major risk factors for subsequent AAS use among male weightlifters.
Within our study population, many attributes showed little association with AAS use, but conduct disorder and body-image concerns showed strong associations. For individuals with prior conduct disorder vs. those without, the hazard ratio [95% confidence interval] for subsequent AAS use was 2.2 [1.5, 3.4]. For individuals in the middle vs. lowest tertile of scores on a retrospective adolescent “muscle-dysmorphia” scale, the hazard ratio was 1.5 [0.84, 2.6]; for the highest vs. lowest tertile, the hazard ratio was 3.3 [2.0, 5.3]; and for the linear trend of hazard ratios, P < 0.001.
Conduct disorder and body-image concerns represent important risk factors for AAS use among male weightlifters. Thus, assessment of these attributes may help to identify individuals most likely to require interventions to discourage this form of substance abuse.
Anabolic-androgenic steroids; substance abuse; risk factors; body-image disorders; conduct disorder; men
Ethanol modulates glutamate and GABA function. However, little is known about the acute pharmacologic effects of ethanol on levels of GABA, glutamate, and other metabolites measurable in the human cortex in vivo using 1H magnetic resonance spectroscopy (MRS).
Eleven healthy social drinkers received two intravenous ethanol infusions that raised breath alcohol levels to a clamped plateau of 60 mg/dL over 60–70 minutes. The first infusion established tolerability of the procedure, and the second procedure, conducted 15±12 days later, was performed during 1H MRS of occipital GABA, glutamate, and other metabolites.
The time course of brain ethanol approximated that of breath ethanol, but venous ethanol lagged by about 7 minutes. GABA fell 13±8% after 5 minutes of the ethanol infusion and remained reduced (p=0.003) throughout the measurement. The combination of N-acetylaspartate and N-acetylaspartyl glutamate (summed as NAA) fell steadily during the infusion by 8±3% (p=0.0036).
Ethanol reduced cortical GABA and NAA levels in humans. Reductions in GABA levels are consistent with facilitation of GABAA receptor function by ethanol. The gradual decline in NAA levels suggests inhibition of neural or metabolic activity in the brain.
1H MRS; GABA; alcohol; NAA; glutamate; brain
Unaided attempts to quit smoking commonly fail during the first two weeks of the nicotine withdrawal syndrome. Alterations in dopamine (DA) signaling correlate with withdrawal from chronic nicotine exposure, but those changes have not been well characterized.
Mice were administered nicotine in their drinking water for 4 or 12 weeks. Then nicotine was withheld for 1 to 10 days while DA signaling was characterized using in vivo microdialysis or fast-scan cyclic voltammetry.
Upon withdrawal of nicotine, the basal DA concentration in the nucleus accumbens decreased as measured by microdialysis. The length of time that the low basal DA state lasted depended on the length of the chronic nicotine treatment. Microdialysis indicated that acute re-exposure to nicotine during withdrawal temporarily reversed this hypodopaminergic state. Voltammetry measurements supported the microdialysis results by showing that nicotine withdrawal decreased tonic and phasic DA release. The basal DA concentration and tonic DA signals, however, were disproportionately lower than the phasic DA signals. Therefore, the phasic/tonic DA signaling ratio was increased during the withdrawal period.
The relative increase in the sensitivity of DA release to phasic stimulation suggests an increase in the signal-to-noise relationship of DA signaling during the withdrawal period. Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that may reinforce relapse to drug use (i.e., smoking). Because the basal DA concentration is low during withdrawal, therapies aimed at elevating the background DA signal represent a reasonable treatment strategy for nicotine dependent individuals attempting to quit.
Chronic Nicotine; Tonic; Phasic; Dopamine; Withdrawal; Nucleus Accumbens
Genetic factors and early life adversity are critical in the etiology of mood disorders and substance abuse. Because of their role in the transduction of stress responses, glucocorticoid hormones and their receptors could serve as both genetic factors and mediators of environmental influences. We have shown that constitutive overexpression of the glucocorticoid receptor (GR) in forebrain results in increased emotional reactivity and “lability” in mice. Here we asked whether there was a critical period for the emergence of this phenotype.
We generated a mouse line with inducible GR overexpression specifically in forebrain (GRov). Anxiety-like behaviors and cocaine-induced sensitization were assessed in adult mice following GR overexpression during different periods in development. The molecular basis of the behavioral phenotype was examined using microarray analyses of dentate gyrus and nucleus accumbens.
Transient overexpression of GR during early life led to increased anxiety and cocaine sensitization, paralleling the phenotype of lifelong GR overexpression. This increased emotional reactivity was not observed when GR overexpression was induced after weaning. GR overexpression in early life is sufficient to alter gene expression patterns for the rest of the animal’s life, with dentate gyrus being more responsive than nucleus accumbens. The altered transcripts are implicated in GR and axonal guidance signaling in dentate gyrus and dopamine receptor signaling in nucleus accumbens.
Transient overexpression of GR early in life is both necessary and sufficient for inducing transcriptome-wide changes in the brain and producing a lifelong increase in vulnerability to anxiety and drugs of abuse.
Glucocorticoid receptor; early life; forebrain; anxiety; sensitization; cocaine