Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in the European Populations.
Biol Psychiatry. 2016 Aug 11;:
Authors: Amin N, Belonogova NM, Jovanova O, Brouwer RW, van Rooij JG, van den Hout MC, Svishcheva GR, Kraaij R, Zorkoltseva IV, Kirichenko AV, Hofman A, Uitterlinden AG, van IJcken WF, Tiemeier H, Axenovich TI, van Duijn CM
BACKGROUND: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies.
METHODS: To identify genes associated with depressive symptomology, we performed a gene-based association analysis of nonsynonymous variation captured using exome-sequencing and exome-chip genotyping in a genetically isolated population from the Netherlands (n = 1999). Finally, we reproduced our significant findings in an independent population-based cohort (n = 1604).
RESULTS: We detected significant association of depressive symptoms with a gene NKPD1 (p = 3.7 × 10(-08)). Nonsynonymous variants in the gene explained 0.9% of sex- and age-adjusted variance of depressive symptoms in the discovery study, which is translated into 3.8% of the total estimated heritability (h(2) = 0.24). Significant association of depressive symptoms with NKPD1 was also observed (n = 1604; p = 1.5 × 10(-03)) in the independent replication sample despite little overlap with the discovery cohort in the set of nonsynonymous genetic variants observed in the NKPD1 gene. Meta-analysis of the discovery and replication studies improved the association signal (p = 1.0 × 10(-09)).
CONCLUSIONS: Our study suggests that nonsynonymous variation in the gene NKPD1 affects depressive symptoms in the general population. NKPD1 is predicted to be involved in the de novo synthesis of sphingolipids, which have been implicated in the pathogenesis of depression.
PMID: 27745872 [PubMed - as supplied by publisher]
CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.
Biol Psychiatry. 2016 Jul 16;:
Authors: Saravia R, Flores Á, Plaza-Zabala A, Busquets-Garcia A, Pastor A, de la Torre R, Di Marzo V, Marsicano G, Ozaita A, Maldonado R, Berrendero F
BACKGROUND: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans.
METHODS: We investigated in mice the role of CB1 cannabinoid receptors (CB1Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used.
RESULTS: Memory impairment during nicotine withdrawal was blocked by the CB1R antagonist rimonabant or the genetic deletion of CB1R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB1R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB1R conditional knockout mice and after subchronic treatment with rimonabant.
CONCLUSIONS: These findings underline the interest of CB1R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.
PMID: 27737762 [PubMed - as supplied by publisher]
Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation.
Biol Psychiatry. 2016 Jul 14;:
Authors: Simpson EH, Kellendonk C
The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. We review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients.
PMID: 27720388 [PubMed - as supplied by publisher]
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Connectome Disconnectivity and Cortical Gene Expression in Patients With Schizophrenia.
Biol Psychiatry. 2016 Jul 27;:
Authors: Romme IA, de Reus MA, Ophoff RA, Kahn RS, van den Heuvel MP
BACKGROUND: Genome-wide association studies have identified several common risk loci for schizophrenia (SCZ). In parallel, neuroimaging studies have shown consistent findings of widespread white matter disconnectivity in patients with SCZ.
METHODS: We examined the role of genes in brain connectivity in patients with SCZ by combining transcriptional profiles of 43 SCZ risk genes identified by the recent genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium with data on macroscale connectivity reductions in patients with SCZ. Expression profiles of 43 Psychiatric Genomics Consortium SCZ risk genes were extracted from the Allen Human Brain Atlas, and their average profile across the cortex was correlated to the pattern of cortical disconnectivity as derived from diffusion-weighted magnetic resonance imaging data of patients with SCZ (n = 48) and matched healthy controls (n = 43).
RESULTS: The expression profile of SCZ risk genes across cortical regions was significantly correlated with the regional macroscale disconnectivity (r = .588; p = .017). In addition, effects were found to be potentially specific to SCZ, with transcriptional profiles not related to cortical disconnectivity in patients with bipolar I disorder (diffusion-weighted magnetic resonance imaging data; 216 patients, 144 controls). Further examination of correlations across all 20,737 genes present in the Allen Human Brain Atlas showed the set of top 100 strongest correlating genes to display significant enrichment for the disorder, potentially identifying new genes involved in the pathophysiology of SCZ.
CONCLUSIONS: Our results suggest that under disease conditions, cortical areas with pronounced expression of risk genes implicated in SCZ form central areas for white matter disconnectivity.
PMID: 27720199 [PubMed - as supplied by publisher]
The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.
Biol Psychiatry. 2016 Aug 6;:
Authors: Howes OD, McCutcheon R, Owen MJ, Murray RM
The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.
PMID: 27720198 [PubMed - as supplied by publisher]
Molecular Histochemistry Identifies Peptidomic Organization and Reorganization Along Striatal Projection Units.
Biol Psychiatry. 2016 Mar 1;79(5):415-20
Authors: Hishimoto A, Nomaru H, Ye K, Nishi A, Lim J, Aguilan JT, Nieves E, Kang G, Angeletti RH, Hiroi N
Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) (MALDI-IMS) provides a technical means for simultaneous analysis of precise anatomic localization and regulation of peptides. We explored the technical capability of matrix-assisted laser desorption ionization mass spectrometry for characterization of peptidomic regulation by an addictive substance along two distinct projection systems in the mouse striatum. The spatial expression patterns of substance P and proenkephalin, marker neuropeptides of two distinct striatal projection neurons, were negatively correlated at baseline. We detected 768 mass/charge (m/z) peaks whose expression levels were mostly negatively and positively correlated with expression levels of substance P and proenkephalin A (amino acids 218-228), respectively, within the dorsal striatum. After nicotine administration, there was a positive shift in correlation of mass/charge peak expression levels with substance P and proenkephalin A (218-228). Our exploratory analyses demonstrate the technical capacity of MALDI-IMS for comprehensive identification of peptidomic regulation patterns along histochemically distinguishable striatal projection pathways.
PMID: 26520239 [PubMed - indexed for MEDLINE]
Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.
Biol Psychiatry. 2016 Mar 1;79(5):383-91
Authors: Bertelsen B, Stefánsson H, Riff Jensen L, Melchior L, Mol Debes N, Groth C, Skov L, Werge T, Karagiannidis I, Tarnok Z, Barta C, Nagy P, Farkas L, Brøndum-Nielsen K, Rizzo R, Gulisano M, Rujescu D, Kiemeney LA, Tosato S, Nawaz MS, Ingason A, Unnsteinsdottir U, Steinberg S, Ludvigsson P, Stefansson K, Kuss AW, Paschou P, Cath D, Hoekstra PJ, Müller-Vahl K, Stuhrmann M, Silahtaroglu A, Pfundt R, Tümer Z
BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations.
METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues.
RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology.
CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
PMID: 26444075 [PubMed - indexed for MEDLINE]
Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.
Biol Psychiatry. 2016 Mar 1;79(5):402-14
Authors: Tozzi A, de Iure A, Bagetta V, Tantucci M, Durante V, Quiroga-Varela A, Costa C, Di Filippo M, Ghiglieri V, Latagliata EC, Wegrzynowicz M, Decressac M, Giampà C, Dalley JW, Xia J, Gardoni F, Mellone M, El-Agnaf OM, Ardah MT, Puglisi-Allegra S, Björklund A, Spillantini MG, Picconi B, Calabresi P
BACKGROUND: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate.
METHODS: We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons.
RESULTS: We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models.
CONCLUSIONS: We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease.
PMID: 26392130 [PubMed - indexed for MEDLINE]
Deep Brain Stimulation for Treatment-Resistant Psychiatric Illnesses: What Has Gone Wrong and What Should We Do Next?
Biol Psychiatry. 2016 Feb 15;79(4):e9-10
Authors: Widge AS, Deckersbach T, Eskandar EN, Dougherty DD
PMID: 26212895 [PubMed - indexed for MEDLINE]
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Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue.
Biol Psychiatry. 2016 Feb 15;79(4):320-8
Authors: Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M, Harrison NA
BACKGROUND: Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear.
METHODS: Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24.
RESULTS: IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms.
CONCLUSIONS: Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.
PMID: 26169252 [PubMed - indexed for MEDLINE]
Anterior Cortical Development During Adolescence in Bipolar Disorder.
Biol Psychiatry. 2016 Feb 15;79(4):303-10
Authors: Najt P, Wang F, Spencer L, Johnston JA, Cox Lippard ET, Pittman BP, Lacadie C, Staib LH, Papademetris X, Blumberg HP
BACKGROUND: Increasing evidence supports a neurodevelopmental model for bipolar disorder (BD), with adolescence as a critical period in its development. Developmental abnormalities of anterior paralimbic and heteromodal frontal cortices, key structures in emotional regulation processes and central in BD, are implicated. However, few longitudinal studies have been conducted, limiting understanding of trajectory alterations in BD. In this study, we performed longitudinal neuroimaging of adolescents with and without BD and assessed volume changes over time, including changes in tissue overall and within gray and white matter. Larger decreases over time in anterior cortical volumes in the adolescents with BD were hypothesized. Gray matter decreases and white matter increases are typically observed during adolescence in anterior cortices. It was hypothesized that volume decreases over time in BD would reflect alterations in those processes, showing larger gray matter contraction and decreased white matter expansion.
METHODS: Two high-resolution magnetic resonance imaging scans were obtained approximately 2 years apart for 35 adolescents with bipolar I disorder (BDI) and 37 healthy adolescents. Differences over time between groups were investigated for volume overall and specifically for gray and white matter.
RESULTS: Relative to healthy adolescents, adolescents with BDI showed greater volume contraction over time in a region including insula and orbitofrontal, rostral, and dorsolateral prefrontal cortices (p < .05, corrected), including greater gray matter contraction and decreased white matter expansion over time, in the BD compared with the healthy group.
CONCLUSIONS: The findings support neurodevelopmental abnormalities during adolescence in BDI in anterior cortices, including altered developmental trajectories of anterior gray and white matter.
PMID: 26033826 [PubMed - indexed for MEDLINE]
Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder.
Biol Psychiatry. 2016 Feb 15;79(4):266-73
Authors: Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, Zhang G, Chen X, Shi S, Wang L, Liu R, Hwang J, Li Z, Tao J, Wang Y, Zhu B, Kong J
BACKGROUND: Depression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is a Food and Drug Administration approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, noninvasive VNS method based on the rationale that there is afferent/efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS.
METHODS: In this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments.
RESULTS: Thirty-four patients completed the study and were included in data analysis. After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale score reduced significantly in the tVNS group as compared with the stVNS group. The FC between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased compared with stVNS. All these FC increases are also associated with 24-item Hamilton Depression Rating Scale reduction.
CONCLUSIONS: tVNS can significantly modulate the DMN FC of MDD patients; our results provide insights to elucidate the brain mechanism of tVNS treatment for MDD patients.
PMID: 25963932 [PubMed - indexed for MEDLINE]
Frontoparietal Activation During Response Inhibition Predicts Remission to Antidepressants in Patients With Major Depression.
Biol Psychiatry. 2016 Feb 15;79(4):274-81
Authors: Gyurak A, Patenaude B, Korgaonkar MS, Grieve SM, Williams LM, Etkin A
BACKGROUND: Despite cognitive function impairment in depression, its relationship to treatment outcome is not well understood. Here, we examined whether pretreatment activation of cortical circuitry during test of cognitive functions predicts outcomes for three commonly used antidepressants.
METHODS: Eighty medication-free outpatients with major depression and 34 matched healthy controls were included as participants in the International Study to Predict Optimized Treatment in Depression (iSPOT-D) trial. During functional magnetic resonance imaging, participants completed three tasks that assessed core domains of cognitive functions: response inhibition (Go/NoGo), selective attention (oddball), and selective working memory updating (1-back). Participants were randomized to 1 of 3 arms: escitalopram, sertraline (serotonin-specific reuptake inhibitors [SSRI]), or venlafaxine-extended release (serotonin and norepinephrine reuptake inhibitor [SNRI]) therapy. Functional magnetic resonance imaging scans were repeated after 8 weeks of treatment, and remission was assessed using the Hamilton Rating Scale for Depression.
RESULTS: Dorsolateral prefrontal cortex activation during inhibitory "no go" responses was a general predictor of remission, with remitters having the same pretreatment activation as control participants and nonremitters hypoactivating relative to controls. Posttreatment dorsolateral prefrontal cortex activation was reduced in both remitters and controls but not in nonremitters. By contrast, inferior parietal activation differentially predicted remission between SSRI and SNRI medications, with SSRI remitters showing greater pretreatment activation than SSRI nonremitters and the SNRI group showing the opposite pattern.
CONCLUSIONS: Intact activation in the frontoparietal network during response inhibition, a core cognitive function, predicts remission with antidepressant treatment, particularly for SSRIs, and may be a potential substrate of the clinical effect of treatment.
PMID: 25891220 [PubMed - indexed for MEDLINE]
Voxel-Based Meta-Analytical Evidence of Structural Disconnectivity in Major Depression and Bipolar Disorder.
Biol Psychiatry. 2016 Feb 15;79(4):293-302
Authors: Wise T, Radua J, Nortje G, Cleare AJ, Young AH, Arnone D
BACKGROUND: Identification of white matter microstructure differences and similarities between major depression and bipolar disorder is a necessary step to better understand the underlying brain abnormalities in affective disorders and target more effective treatments. However, research has not yet yielded robust conclusions. We report here a meta-analysis of diffusion tensor imaging studies in these conditions.
METHODS: A comprehensive literature search was conducted up to 2014 to identify studies comparing fractional anisotropy (FA) between patients and control subjects. Results were combined to identify white matter abnormalities in major depression (736 patients vs. 668 control subjects) and bipolar disorder (536 patients vs. 489 control subjects). Effect size comparison and conjunction analysis allowed identification of similarities and differences between the disorders.
RESULTS: A significant decrease in FA in the genu of the corpus callosum characterized both conditions. The comparison between unipolar and bipolar disorders revealed a greater decrease in FA in the left posterior cingulum in bipolar disorder. Studies that adopted tract-based spatial statistics methodology showed more pronounced reductions in these regions compared with voxel-based analyses.
CONCLUSIONS: Major depression and bipolar disorder are characterized by abnormalities in white matter tracts of the genu of the corpus callosum that connect the two hemispheres of the prefrontal cortex implicated in mood regulation. Bipolar disorder was associated with reduced white matter integrity in the left posterior cingulum, which may contribute to cognitive impairment described in this condition. Tract-based spatial statistics may be a more sensitive technique to detect white matter abnormalities in these regions compared with voxel-based analyses.
PMID: 25891219 [PubMed - indexed for MEDLINE]
Attentional Bias Predicts Increased Reward Salience and Risk Taking in Bipolar Disorder.
Biol Psychiatry. 2016 Feb 15;79(4):311-9
Authors: Mason L, Trujillo-Barreto NJ, Bentall RP, El-Deredy W
BACKGROUND: There is amassing evidence that risky decision-making in bipolar disorder is related to reward-based differences in frontostriatal regions. However, the roles of early attentional and later cognitive processes remain unclear, limiting theoretical understanding and development of targeted interventions.
METHODS: Twenty euthymic bipolar disorder and 19 matched control participants played a Roulette task in which they won and lost money. Event-related potentials and source analysis were used to quantify predominantly sensory-attentional (N1), motivational salience (feedback-related negativities [FRN]), and cognitive appraisal (P300) stages of processing. We predicted that the bipolar disorder group would show increased N1, consistent with increased attentional orienting, and reduced FRN, consistent with a bias to perceive outcomes more favorably.
RESULTS: As predicted, the bipolar disorder group showed increased N1 and reduced FRN but no differences in P300. N1 amplitude was additionally associated with real-life risk taking, and N1 source activity was reduced in visual cortex but increased activity in precuneus, frontopolar, and premotor cortex, compared to those of controls.
CONCLUSIONS: These findings demonstrate an early attentional bias to reward that potentially drives risk taking by priming approach behavior and elevating reward salience in the frontostriatal pathway. Although later cognitive appraisals of these inputs may be relatively intact in remission, interventions targeting attention orienting may also be effective in long-term reduction of relapse.
PMID: 25863360 [PubMed - indexed for MEDLINE]
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Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder.
Biol Psychiatry. 2016 Feb 15;79(4):329-36
Authors: Rucker JJ, Tansey KE, Rivera M, Pinto D, Cohen-Woods S, Uher R, Aitchison KJ, Craddock N, Owen MJ, Jones L, Jones I, Korszun A, Barnes MR, Preisig M, Mors O, Maier W, Rice J, Rietschel M, Holsboer F, Farmer AE, Craig IW, Scherer SW, McGuffin P, Breen G
BACKGROUND: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.
METHODS: In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.
RESULTS: We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).
CONCLUSIONS: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.
PMID: 25861698 [PubMed - indexed for MEDLINE]
Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression.
Biol Psychiatry. 2016 Feb 15;79(4):282-92
Authors: Joshi SH, Espinoza RT, Pirnia T, Shi J, Wang Y, Ayers B, Leaver A, Woods RP, Narr KL
BACKGROUND: Electroconvulsive therapy (ECT) elicits a rapid and robust clinical response in patients with refractory depression. Neuroimaging measurements of structural plasticity relating to and predictive of ECT response may point to the mechanisms underlying rapid antidepressant effects and establish biomarkers to inform other treatments. Here, we determine the effects of diagnosis and of ECT on global and local variations of hippocampal and amygdala structures in major depression and predictors of ECT-related clinical response.
METHODS: Longitudinal changes in hippocampal and amygdala structures were examined in patients with major depression (N = 43, scanned three times: prior to ECT, after the second ECT session, and within 1 week of completing the ECT treatment series), referred for ECT as part of their standard clinical care. Cross-sectional comparisons with demographically similar controls (N = 32, scanned twice) established effects of diagnosis.
RESULTS: Patients showed smaller hippocampal volumes than controls at baseline (p < .04). Both the hippocampal and the amygdala volumes increased with ECT (p < .001) and in relation to symptom improvement (p < .01). Hippocampal volume at baseline predicted subsequent clinical response (p < .05). Shape analysis revealed pronounced morphometric changes in the anterior hippocampus and basolateral and centromedial amygdala. All structural measurements remained stable across time in controls.
CONCLUSIONS: ECT-induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and is pronounced in regions with prominent connections to ventromedial prefrontal cortex and other limbic structures. Smaller hippocampal volumes at baseline predict a more robust clinical response. Neurotrophic processes including neurogenesis shown in preclinical studies may underlie these structural changes.
PMID: 25842202 [PubMed - indexed for MEDLINE]
Successful Treatment of Tourette Syndrome With Electroconvulsive Therapy: A Case Report.
Biol Psychiatry. 2016 Mar 1;79(5):e13-4
Authors: Guo JN, Kothari JS, Leckman JF, Ostroff RB
PMID: 25481620 [PubMed - indexed for MEDLINE]
A Case of Quetiapine-Induced Rapid Eye Movement Sleep Behavior Disorder.
Biol Psychiatry. 2016 Mar 1;79(5):e11-2
Authors: Tan L, Zhou J, Liang B, Li Y, Lei F, Du L, Yang L, Li T, Tang X
PMID: 25444160 [PubMed - indexed for MEDLINE]
Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia.
Biol Psychiatry. 2016 Mar 1;79(5):345-53
Authors: Bastide MF, de la Crompe B, Doudnikoff E, Fernagut PO, Gross CE, Mallet N, Boraud T, Bézard E
BACKGROUND: A systematic search of brain nuclei putatively involved in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ∆FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID.
METHODS: ∆FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson's disease and LID. ΔFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used.
RESULTS: LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6-hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with ß-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA-induced rotations. Inactivation of ∆FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with ΔFosB, suggesting a D1 receptor-mediated mechanism supporting the LHb involvement in AIMs.
CONCLUSIONS: This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID.
PMID: 25442003 [PubMed - indexed for MEDLINE]
Transcriptome Analysis of the Human Striatum in Tourette Syndrome.
Biol Psychiatry. 2016 Mar 1;79(5):372-82
Authors: Lennington JB, Coppola G, Kataoka-Sasaki Y, Fernandez TV, Palejev D, Li Y, Huttner A, Pletikos M, Sestan N, Leckman JF, Vaccarino FM
BACKGROUND: Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to investigate the pathophysiology of this disorder.
METHODS: We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects.
RESULTS: We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients' striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module.
CONCLUSIONS: Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction.
PMID: 25199956 [PubMed - indexed for MEDLINE]
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A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FosB Expression.
Biol Psychiatry. 2016 Mar 1;79(5):362-71
Authors: Feyder M, Södersten E, Santini E, Vialou V, LaPlant Q, Watts EL, Spigolon G, Hansen K, Caboche J, Nestler EJ, Fisone G
BACKGROUND: Abnormal regulation of extracellular signal-regulated kinases 1 and 2 has been implicated in 3,4-dihydroxy-l-phenylalanine (L-DOPA)-induced dyskinesia (LID), a motor complication affecting Parkinson's disease patients subjected to standard pharmacotherapy. We examined the involvement of mitogen- and stress-activated kinase 1 (MSK1), a downstream target of extracellular signal-regulated kinases 1 and 2, and an important regulator of transcription in LID.
METHODS: 6-Hydroxydopamine was used to produce a model of Parkinson's disease in MSK1 knockout mice and in ∆FosB- or ∆cJun-overexpressing transgenic mice, which were assessed for LID following long-term L-DOPA administration. Biochemical processes were evaluated by Western blotting or immunofluorescence. Histone H3 phosphorylation was analyzed by chromatin immunoprecipitation followed by promotor-specific quantitative polymerase chain reaction.
RESULTS: Genetic inactivation of MSK1 attenuated LID and reduced the phosphorylation of histone H3 at Ser10 in the striatum. Chromatin immunoprecipitation analysis showed that this reduction occurred at the level of the fosB gene promoter. In line with this observation, the accumulation of ∆FosB produced by chronic L-DOPA was reduced in MSK1 knockout. Moreover, inducible overexpression of ∆FosB in striatonigral medium spiny neurons exacerbated dyskinetic behavior, whereas overexpression of ∆cJun, which reduces ∆FosB-dependent transcriptional activation, counteracted LID.
CONCLUSIONS: Results indicate that abnormal regulation of MSK1 contributes to the development of LID and to the concomitant increase in striatal ∆FosB, which may occur via increased histone H3 phosphorylation at the fosB promoter. Results also show that accumulation of ∆FosB in striatonigral neurons is causally related to the development of dyskinesia.
PMID: 25193242 [PubMed - indexed for MEDLINE]
Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA-Induced Dyskinesia.
Biol Psychiatry. 2016 Mar 1;79(5):354-61
Authors: Engeln M, Bastide MF, Toulmé E, Dehay B, Bourdenx M, Doudnikoff E, Li Q, Gross CE, Boué-Grabot E, Pisani A, Bezard E, Fernagut PO
BACKGROUND: ΔFosB is a surrogate marker of L-DOPA-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-DOPA long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown.
METHODS: We used the Daun02 prodrug-inactivation method associated with lentiviral expression of β-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability.
RESULTS: We first show that daunorubicin, the active product of Daun02 metabolism by β-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing β-galactosidase upon D1 dopamine receptor stimulation. We then demonstrate that the selective, and reversible, inhibition of FosB/ΔFosB-expressing striatal neurons with Daun02 decreases the severity of LID while improving the beneficial effect of L-DOPA.
CONCLUSIONS: These results establish that FosB/ΔFosB accumulation ultimately results in altered neuronal electrical properties sustaining maladaptive circuits leading not only to LID but also to a blunted response to L-DOPA. These findings further reveal that targeting dyskinesia can be achieved without reducing the antiparkinsonian properties of L-DOPA when specifically inhibiting FosB/ΔFosB-accumulating neurons.
PMID: 25146322 [PubMed - indexed for MEDLINE]
Motor Improvement and Emotional Stabilization in Patients With Tourette Syndrome After Deep Brain Stimulation of the Ventral Anterior and Ventrolateral Motor Part of the Thalamus.
Biol Psychiatry. 2016 Mar 1;79(5):392-401
Authors: Huys D, Bartsch C, Koester P, Lenartz D, Maarouf M, Daumann J, Mai JK, Klosterkötter J, Hunsche S, Visser-Vandewalle V, Woopen C, Timmermann L, Sturm V, Kuhn J
BACKGROUND: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS.
METHODS: In this prospective open-label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset.
RESULTS: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome.
CONCLUSIONS: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS.
PMID: 25034948 [PubMed - indexed for MEDLINE]