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1.  Development of a bipolar disorder biobank: differential phenotyping for subsequent biomarker analyses 
We aimed to establish a bipolar disorder biobank to serve as a resource for clinical and biomarker studies of disease risk and treatment response. Here, we describe the aims, design, infrastructure, and research uses of the biobank, along with demographics and clinical features of the first participants enrolled.
Patients were recruited for the Mayo Clinic Bipolar Biobank beginning in July 2009. The Structured Clinical Interview for DSM-IV was used to confirm bipolar diagnosis. The Bipolar Biobank Clinical Questionnaire and Participant Questionnaire were designed to collect detailed demographic and clinical data, including clinical course of illness measures that would delineate differential phenotypes for subsequent analyses. Blood specimens were obtained from participants, and various aliquots were stored for future research.
As of September 2014, 1363 participants have been enrolled in the bipolar biobank. Among these first participants, 69.0 % had a diagnosis of bipolar disorder type I. The group was 60.2 % women and predominantly white (90.6 %), with a mean (SD) age of 42.6 (14.9) years. Clinical phenotypes of the group included history of psychosis (42.3 %), suicide attempt (32.5 %), addiction to alcohol (39.1 %), addiction to nicotine (39.8 %), obesity (42.9 %), antidepressant-induced mania (31.7 %), tardive dyskinesia (3.2 %), and history of drug-related serious rash (5.7 %).
Quantifying phenotypic patterns of illness beyond bipolar subtype can provide more detailed clinical disease characteristics for biomarker research, including genomic-risk studies. Future research can harness clinically useful biomarkers using state-of-the-art research technology to help stage disease burden and better individualize treatment selection for patients with bipolar disorder.
PMCID: PMC4478187  PMID: 26105627
Biobank; Bipolar disorder; Phenotype
2.  Association of GATA4 sequence variation with alcohol dependence 
Addiction biology  2012;19(2):312-315.
To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis (PCA). Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene-level (p=0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.
PMCID: PMC3504631  PMID: 22862823
GATA4; Alcohol dependence; Genetic association; Gene level test
3.  Olfactory Neuromodulation of Motion Vision Circuitry in Drosophila 
Current Biology  2015;25(4):467-472.
It is well established that perception is largely multisensory [1]; often served by modalities such as touch, vision, and hearing that detect stimuli emanating from a common point in space [2, 3]; and processed by brain tissue maps that are spatially aligned [4]. However, the neural interactions among modalities that share no spatial stimulus domain yet are essential for robust perception within noisy environments remain uncharacterized. Drosophila melanogaster makes its living navigating food odor plumes. Odor acts to increase the strength of gaze-stabilizing optomotor reflexes [5] to keep the animal aligned within an invisible plume, facilitating odor localization in free flight [6–8]. Here, we investigate the cellular mechanism for cross-modal behavioral interactions. We characterize a wide-field motion-selective interneuron of the lobula plate that shares anatomical and physiological similarities with the “Hx” neuron identified in larger flies [9, 10]. Drosophila Hx exhibits cross-modal enhancement of visual responses by paired odor, and presynaptic inputs to the lobula plate are required for behavioral odor tracking but are not themselves the target of odor modulation, nor is the neighboring wide-field “HSE” neuron [11]. Octopaminergic neurons mediating increased visual responses upon flight initiation [12] also show odor-evoked calcium modulations and form connections with Hx dendrites. Finally, restoring synaptic vesicle trafficking within the octopaminergic neurons of animals carrying a null mutation for all aminergic signaling [13] is sufficient to restore odor-tracking behavior. These results are the first to demonstrate cellular mechanisms underlying visual-olfactory integration required for odor localization in fruit flies, which may be representative of adaptive multisensory interactions across taxa.
•Small-field motion detection neurons are required for odor-tracking behavior•Responses of a directional wide-field interneuron (Hx) increase with paired odor•Odor activates octopaminergic (OA) neurons that innervate the visual system•OA cells contact Hx; OA vesicle trafficking is required for odor-tracking behavior
Wasserman et al. report that a directionally selective wide-field motion-detecting neuron (Hx) in the fly increases response gain with paired odor. This multimodal interaction is dependent upon vesicle trafficking from octopaminergic neurons, which are themselves responsive to odor and make cell-cell contact with Hx.
PMCID: PMC4331282  PMID: 25619767
4.  Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals 
Biological psychiatry  2013;74(12):917-926.
Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome (TS). Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS.
The combination of DBS and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. Using a with-in subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n=5).
Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS.
Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of TS as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.
PMCID: PMC3910443  PMID: 23993641
Deep brain stimulation (DBS); Tourette syndrome; centromedian; parafascicular; functional magnetic resonance imaging (fMRI); swine model; neural circuitry
5.  Feasibility Evaluation of an Interpersonal and Social Rhythm Therapy Group Delivery Model 
Archives of psychiatric nursing  2013;27(6):271-277.
The effectiveness of psychotherapies, such as interpersonal and social rhythm therapy (IPSRT), is supported by randomized controlled trials. These trials provide minimal direction regarding feasibility of psychotherapy delivery models. The study purpose was to identify factors facilitating implementation and sustainability of an IPRST group for patients with bipolar disorder. Qualitative data were assessed by the normalization process model (NPM). The results demonstrate feasibility of implementation with experienced clinicians, program coordination, and leadership support. Sustainability challenges include aftercare groups, space, and clinician time. The NPM provides a useful framework for evaluation of factors influencing the feasibility of psychotherapy delivery models.
PMCID: PMC4020708  PMID: 24238006
6.  Every reason to discontinue lithium 
Lithium as a gold standard therapy for bipolar disorder is well known to have a number of medical comorbidities that impact renal, parathyroid, and thyroid function. Despite these medical comorbidities, there remains a group of lithium-responsive lithium-treated patients who have maintained mood stability for decades. The risk/benefit ratio of end organ toxicity/mood stability must be evaluated in each individual case.
PMCID: PMC4477477  PMID: 26092398
Lithium; Toxicity; Efficacy
7.  Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB 
Journal of affective disorders  2014;165:151-158.
Bipolar disorder (BD) is a highly heritable disease. While genome-wide association (GWA) studies have identified several genetic risk factors for BD, few of these studies have investigated the genetic etiology of specific disease subtypes. In particular, BD is positively associated with eating dysregulation traits such as binge eating behavior (BE), yet the genetic risk factors underlying BD with comorbid BE have not been investigated.
Utilizing data from the Genetic Association Information Network study of BD, which included 729,454 single nucleotide polymorphisms (SNPs) genotyped in 1001 European American bipolar cases and 1034 controls, we performed GWA analyses of bipolar subtypes defined by the presence or absence of BE history, and performed a case-only analysis comparing BD subjects with and without BE history. Association signals were refined using imputation, and network analysis was performed with Ingenuity Pathway Analysis software. Based on these results, candidate SNPs were selected for replication in an independent sample of 855 cases and 857 controls.
Top ranking SNPs in the discovery set included rs6006893 in PRR5, rs17045162 in ANK2, rs13233490 near PER4, rs4665788 and rs10198175 downstream of APOB, rs2367911 in CACNA2D1, and rs7249968 near ZNF536. Rs10198175 in APOB also demonstrated evidence of association in the replication sample and a meta-analysis of the two samples.
Without information of BE history in controls, it is not possible to determine whether the observed association with APOB reflects a risk factor for BE behavior in general or a risk factor for a subtype of BD with BE. Further longitudinal and functional studies are needed to determine the causal pathways underlying the observed associations.
This study identified new potential BD-susceptibility genes, highlighting the advantages of phenotypic sub-classification in genetic research and clinical practice.
PMCID: PMC4224146  PMID: 24882193
Bipolar disorder; Binge eating; Phenotypic subtypes; Network analysis; Genome-wide association study (GWAS); APOB
8.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
PMCID: PMC4091043  PMID: 24030475
10.  A Retrospective Study of Gender Differences in Depressive Symptoms and Risk of Relapse in Patients with Alcohol Dependence 
Background and Objectives
The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking
Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the Inventory of Drug Taking Situations (IDTS), Penn Alcohol Craving Scale (PACS), Patient Health Questionnaire (PHQ-9), and/ or Beck Depression Inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined.
Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = 0.0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = 0.035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4± 11.4 vs. 18.2± 9.8, p <.001). After controlling for depressive symptom severity as a covariate, the IDTS gender differences were no longer significant.
Conclusion and Scientific Significance
Our results suggest that unpleasant or temptation based emotional situations are a vulnerability risk factor for heavy drinking particularly in females. This risk appears to be at least partially driven by depressive symptom burden. Future research is needed to further investigate this finding.
PMCID: PMC3748388  PMID: 23952888
11.  Figure–ground discrimination behavior in Drosophila. I. Spatial organization of wing-steering responses 
The Journal of Experimental Biology  2014;217(4):558-569.
The behavioral algorithms and neural subsystems for visual figure–ground discrimination are not sufficiently described in any model system. The fly visual system shares structural and functional similarity with that of vertebrates and, like vertebrates, flies robustly track visual figures in the face of ground motion. This computation is crucial for animals that pursue salient objects under the high performance requirements imposed by flight behavior. Flies smoothly track small objects and use wide-field optic flow to maintain flight-stabilizing optomotor reflexes. The spatial and temporal properties of visual figure tracking and wide-field stabilization have been characterized in flies, but how the two systems interact spatially to allow flies to actively track figures against a moving ground has not. We took a systems identification approach in flying Drosophila and measured wing-steering responses to velocity impulses of figure and ground motion independently. We constructed a spatiotemporal action field (STAF) – the behavioral analog of a spatiotemporal receptive field – revealing how the behavioral impulse responses to figure tracking and concurrent ground stabilization vary for figure motion centered at each location across the visual azimuth. The figure tracking and ground stabilization STAFs show distinct spatial tuning and temporal dynamics, confirming the independence of the two systems. When the figure tracking system is activated by a narrow vertical bar moving within the frontal field of view, ground motion is essentially ignored despite comprising over 90% of the total visual input.
PMCID: PMC3922833  PMID: 24198267
Fly vision; Flight control; Figure tracking; Optomotor response
12.  Figure–ground discrimination behavior in Drosophila. II. Visual influences on head movement behavior 
The Journal of Experimental Biology  2014;217(4):570-579.
Visual identification of small moving targets is a challenge for all moving animals. Their own motion generates displacement of the visual surroundings, inducing wide-field optic flow across the retina. Wide-field optic flow is used to sense perturbations in the flight course. Both ego-motion and corrective optomotor responses confound any attempt to track a salient target moving independently of the visual surroundings. What are the strategies that flying animals use to discriminate small-field figure motion from superimposed wide-field background motion? We examined how fruit flies adjust their gaze in response to a compound visual stimulus comprising a small moving figure against an independently moving wide-field ground, which they do by re-orienting their head or their flight trajectory. We found that fixing the head in place impairs object fixation in the presence of ground motion, and that head movements are necessary for stabilizing wing steering responses to wide-field ground motion when a figure is present. When a figure is moving relative to a moving ground, wing steering responses follow components of both the figure and ground trajectories, but head movements follow only the ground motion. To our knowledge, this is the first demonstration that wing responses can be uncoupled from head responses and that the two follow distinct trajectories in the case of simultaneous figure and ground motion. These results suggest that whereas figure tracking by wing kinematics is independent of head movements, head movements are important for stabilizing ground motion during active figure tracking.
PMCID: PMC3922834  PMID: 24198264
Fly vision; Gaze control; Figure tracking; Optomotor response
13.  Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states 
Synthetic kappa-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects, and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol dependent subjects and investigated their association with (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations (IDTS); (2), a self-reported history of depression; and, (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II (BDI). In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p=0.00079) and with negative craving (p=0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p=0.024) and alcohol dependence (p=0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol dependent subjects.
PMCID: PMC3901318  PMID: 23101464
OPRK1; PDYN; Alcohol dependence; Craving; Depression
14.  Method and software for using m-sequences to characterize parallel components of higher-order visual tracking behavior in Drosophila 
A moving visual figure may contain first-order signals defined by variation in mean luminance, as well as second-order signals defined by constant mean luminance and variation in luminance envelope, or higher-order signals that cannot be estimated by taking higher moments of the luminance distribution. Separating these properties of a moving figure to experimentally probe the visual subsystems that encode them is technically challenging and has resulted in debated mechanisms of visual object detection by flies. Our prior work took a white noise systems identification approach using a commercially available electronic display system to characterize the spatial variation in the temporal dynamics of two distinct subsystems for first- and higher-order components of visual figure tracking. The method relied on the use of single pixel displacements of two visual stimuli according to two binary maximum length shift register sequences (m-sequences) and cross-correlation of each m-sequence with time-varying flight steering measurements. The resultant spatio-temporal action fields represent temporal impulse responses parameterized by the azimuthal location of the visual figure, one STAF for first-order and another for higher-order components of compound stimuli. Here we review m-sequence and reverse correlation procedures, then describe our application in detail, provide Matlab code, validate the STAFs, and demonstrate the utility and robustness of STAFs by predicting the results of other published experimental procedures. This method has demonstrated how two relatively modest innovations on classical white noise analysis—the inclusion of space as a way to organize response kernels and the use of linear decoupling to measure the response to two channels of visual information simultaneously—could substantially improve our basic understanding of visual processing in the fly.
PMCID: PMC4215624  PMID: 25400550
vision; optomotor; psychophysics; fixation; attention; Drosophila; system identification; dynamics
15.  Drosophila Tracks Carbon Dioxide in Flight 
Current biology : CB  2013;23(4):10.1016/j.cub.2012.12.038.
Carbon dioxide (CO2) elicits an attractive host-seeking response from mosquitos [1–3] yet is innately aversive to Drosophila melanogaster [4, 5] despite being a plentiful byproduct of attractive fermenting food sources. Prior studies used walking flies exclusively, yet adults track distant food sources on the wing [6]. Here we show that a fly tethered within a magnetic field allowing free rotation about the yaw axis [7] actively seeks a narrow CO2 plume during flight. Genetic disruption of the canonical CO2-sensing olfactory neurons does not alter in-flight attraction to CO2; however, antennal ablation and genetic disruption of the Ir64a acid sensor do. Surprisingly, mutation of the obligate olfactory coreceptor (Orco [8]) does not abolish CO2 aversion during walking [4] yet eliminates CO2 tracking in flight. The biogenic amine octopamine regulates critical physiological processes during flight [9–11], and blocking synaptic output from octopamine neurons inverts the valence assigned to CO2 and elicits an aversive response in flight. Combined, our results suggest that a novel Orco-mediated olfactory pathway that gains sensitivity to CO2 in flight via changes in octopamine levels, along with Ir64a, quickly switches the valence of a key environmental stimulus in a behavioral-state-dependent manner.
PMCID: PMC3810385  PMID: 23352695
16.  An Olfactory Circuit Increases the Fidelity of Visual Behavior 
Multimodal integration allows neural circuits to be activated in a behaviorally context-specific manner. In the case of odor plume tracking by Drosophila, an attractive odorant increases the influence of yaw-optic flow on steering behavior in flight, which enhances visual stability reflexes, resulting in straighter flight trajectories within an odor plume. However, it is not well understood whether context-specific changes in optomotor behavior are the result of an increased sensitivity to motion inputs (e.g., through increased visual attention) or direct scaling of motor outputs (i.e., increased steering gain). We address this question by examining the optomotor behavior of Drosophila melanogaster in a tethered flight assay and demonstrate that whereas olfactory cues decrease the gain of the optomotor response to sideslip optic flow, they concomitantly increase the gain of the yaw optomotor response by enhancing the animal's ability to follow transient visual perturbations. Furthermore, ablating the mushroom bodies (MBs) of the fly brain via larval hydroxyurea (HU) treatment results in a loss of olfaction-dependent increase in yaw optomotor fidelity. By expressing either tetanus toxin light chain or diphtheria toxin in gal4-defined neural circuits, we were able to replicate the loss of function observed in the HU treatment within the lines expressing broadly in the mushroom bodies, but not within specific mushroom body lobes. Finally, we were able to genetically separate the yaw responses and sideslip responses in our behavioral assay. Together, our results implicate the MBs in a fast-acting, memory-independent olfactory modification of a visual reflex that is critical for flight control.
PMCID: PMC3749065  PMID: 22016537
17.  Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report 
Manchia, Mirko | Adli, Mazda | Akula, Nirmala | Ardau, Raffaella | Aubry, Jean-Michel | Backlund, Lena | Banzato, Claudio EM. | Baune, Bernhard T. | Bellivier, Frank | Bengesser, Susanne | Biernacka, Joanna M. | Brichant-Petitjean, Clara | Bui, Elise | Calkin, Cynthia V. | Cheng, Andrew Tai Ann | Chillotti, Caterina | Cichon, Sven | Clark, Scott | Czerski, Piotr M. | Dantas, Clarissa | Zompo, Maria Del | DePaulo, J. Raymond | Detera-Wadleigh, Sevilla D. | Etain, Bruno | Falkai, Peter | Frisén, Louise | Frye, Mark A. | Fullerton, Jan | Gard, Sébastien | Garnham, Julie | Goes, Fernando S. | Grof, Paul | Gruber, Oliver | Hashimoto, Ryota | Hauser, Joanna | Heilbronner, Urs | Hoban, Rebecca | Hou, Liping | Jamain, Stéphane | Kahn, Jean-Pierre | Kassem, Layla | Kato, Tadafumi | Kelsoe, John R. | Kittel-Schneider, Sarah | Kliwicki, Sebastian | Kuo, Po-Hsiu | Kusumi, Ichiro | Laje, Gonzalo | Lavebratt, Catharina | Leboyer, Marion | Leckband, Susan G. | López Jaramillo, Carlos A. | Maj, Mario | Malafosse, Alain | Martinsson, Lina | Masui, Takuya | Mitchell, Philip B. | Mondimore, Frank | Monteleone, Palmiero | Nallet, Audrey | Neuner, Maria | Novák, Tomás | O’Donovan, Claire | Ösby, Urban | Ozaki, Norio | Perlis, Roy H. | Pfennig, Andrea | Potash, James B. | Reich-Erkelenz, Daniela | Reif, Andreas | Reininghaus, Eva | Richardson, Sara | Rouleau, Guy A. | Rybakowski, Janusz K. | Schalling, Martin | Schofield, Peter R. | Schubert, Oliver K. | Schweizer, Barbara | Seemüller, Florian | Grigoroiu-Serbanescu, Maria | Severino, Giovanni | Seymour, Lisa R. | Slaney, Claire | Smoller, Jordan W. | Squassina, Alessio | Stamm, Thomas | Steele, Jo | Stopkova, Pavla | Tighe, Sarah K. | Tortorella, Alfonso | Turecki, Gustavo | Wray, Naomi R. | Wright, Adam | Zandi, Peter P. | Zilles, David | Bauer, Michael | Rietschel, Marcella | McMahon, Francis J. | Schulze, Thomas G. | Alda, Martin
PLoS ONE  2013;8(6):e65636.
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods
Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
PMCID: PMC3686769  PMID: 23840348
18.  Ethanol withdrawal-induced brain metabolites and the pharmacological effects of acamprosate in mice lacking ENT1 
Neuropharmacology  2012;62(8):2480-2488.
Acamprosate is clinically used to treat alcohol-dependent patients. While the molecular and pharmacological mechanisms of acamprosate remain unclear, it has been shown to regulate γ-aminobutyric acid (GABA) or glutamate levels in the cortex and striatum. To investigate the effect of acamprosate on brain metabolites in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), we employed in vivo 16.4T proton magnetic resonance spectroscopy. We utilized type 1 equilibrative nucleoside transporter (ENT1) null mice since acamprosate attenuates ethanol drinking in these mice. Our findings demonstrated that ethanol withdrawal reduced GABA levels and increased phosphorylated choline compounds in the mPFC of both wild-type and ENT1 null mice. Notably, acamprosate normalized these withdrawal-induced changes only in ENT1 null mice. In the NAc, ethanol withdrawal increased glutamate and glutamine (Glx) levels only in wild-type mice. Interestingly, acamprosate reduced Glx levels in the NAc compared to the withdrawal state in both genotypes. These results provide a molecular basis for the pharmacological effect of acamprosate in the cortical-striatal circuit.
PMCID: PMC3531991  PMID: 22616110
acamprosate; ENT1; ethanol withdrawal; [1H] MRS; GABA; glutamate
19.  Multisensory systems integration for high-performance motor control in flies 
Current opinion in neurobiology  2010;20(3):347-352.
Engineered tracking systems ‘fuse’ data from disparate sensor platforms, such as radar and video, to synthesize information that is more reliable than any single input. The mammalian brain registers visual and auditory inputs to directionally localize an interesting environmental feature. For a fly, sensory perception is challenged by the extreme performance demands of high speed flight. Yet even a fruit fly can robustly track a fragmented odor plume through varying visual environments, outperforming any human engineered robot. Flies integrate disparate modalities, such as vision and olfaction, which are neither related by spatiotemporal spectra nor processed by registered neural tissue maps. Thus, the fly is motivating new conceptual frameworks for how low-level multisensory circuits and functional algorithms produce high-performance motor control.
PMCID: PMC3635923  PMID: 20202821
20.  Replication of Genome Wide Association Studies of Alcohol Dependence: Support for Association with Variation in ADH1C 
PLoS ONE  2013;8(3):e58798.
Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.
PMCID: PMC3596339  PMID: 23516558
21.  Baseline thyroid indices and the subsequent response to citalopram treatment, a pilot study 
Brain and Behavior  2013;3(2):89-94.
The lack of reliable outcome predictors and the delayed onset of therapeutic response to antidepressants are among the clinical challenges in the treatment of depression. Identifying clinical correlates associated with antidepressant response would reduce symptom severity and morbidity for patients with depression. Twenty-three subjects with major depression were treated with citalopram 20 mg/day in a 6-week open trial and were also simultaneously randomized to either adjunctive triiodothyronine (T3) 25 μg BID (n = 7), pindolol 5 mg BID (n = 8), or placebo (n = 8). Baseline thyroid-stimulating hormone (TSH), FT4, FT3, and TT3 were measured for potential relationships to treatment response across groups. In males only, there was a significant inverse correlation between baseline free T4 and time to response (r = −0.7, P = 0.034). In both males and females across all treatment conditions, as measured by Kaplan–Meier (K–M) maintenance failure time, baseline TSH below the mean (1.5 ng/dL) was associated with a shorter time to response (50% reduction in Montgomery and Asberg Depression Rating Scale [MADRS] score) (χ2 = 4.53, df = 1, P = 0.03). Patients with baseline TSH above the mean were less likely to reach full remission (MADRS ≤ 7) (χ2 = 4.38, df = 1, P = 0.03). No significant differences between groups emerged in the mean response time. Baseline thyroid function, as measured by serum free T4 and TSH, may predict a patient's response time to antidepressant treatment with citalopram.
PMCID: PMC3607150  PMID: 23533025
Acceleration; antidepressant response; citalopram; free thyroxine; thyroid; thyroid-stimulating hormone; triiodothyronine
22.  Nucleus Accumbens Deep Brain Stimulation Results in Insula and Prefrontal Activation: A Large Animal fMRI Study 
PLoS ONE  2013;8(2):e56640.
Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model
Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan
We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation
Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS
PMCID: PMC3575484  PMID: 23441210
23.  Underlying Neurobiology and Clinical Correlates of Mania Status-Post Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s disease: A Review of the Literature 
Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson’s disease (PD).
We review the current literature to identify the clinical correlates associated with STN DBS-induced hypomania/mania in PD patients.
Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male patients and/or early onset PD.
STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanism(s) of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight towards development of future DBS mood stabilization therapies.
PMCID: PMC3570815  PMID: 22450620
Parkinson’s disease; mania; subthalamic nucleus (STN); deep brain stimulation (DBS)
24.  Review of Pharmacological Treatment in Mood Disorders and Future Directions for Drug Development 
Neuropsychopharmacology  2011;37(1):77-101.
After a series of serendipitous discoveries of pharmacological treatments for mania and depression several decades ago, relatively little progress has been made for novel hypothesis-driven drug development in mood disorders. Multifactorial etiologies of, and lack of a full understanding of, the core neurobiology of these conditions clearly have contributed to these development challenges. There are, however, relatively novel targets that have raised opportunities for progress in the field, such as glutamate and cholinergic receptor modulators, circadian regulators, and enzyme inhibitors, for alternative treatment. This review will discuss these promising new treatments in mood disorders, the underlying mechanisms of action, and critical issues of their clinical application. For these new treatments to be successful in clinical practice, it is also important to design innovative clinical trials that identify the specific actions of new drugs, and, ideally, to develop biomarkers for monitoring individualized treatment response. It is predicted that future drug development will identify new agents targeting the molecular mechanisms involved in the pathophysiology of mood disorders.
PMCID: PMC3238080  PMID: 21900884
mood disorders; clinical pharmacology; clinical trials; neurotransmission; circadian; signal transduction
25.  Impact of sunlight on the age of onset of bipolar disorder 
Bipolar disorders  2012;14(6):654-663.
Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.
Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.
The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= −4.724, 95% CI: −8.124 to −1.323, p = 0.006), controlling for each country’s median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.
The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.
PMCID: PMC3525652  PMID: 22612720 CAMSID: cams2451
age of onset; bipolar disorder; solar insolation; sunlight

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