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1.  Neurophysiological Effects of Sleep Deprivation in Healthy Adults, a Pilot Study 
PLoS ONE  2015;10(1):e0116906.
Total sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied in concert. At baseline, after a regular night of sleep, and the next morning after TSD, 12 healthy subjects performed a semantic affective classification functional magnetic resonance imaging (fMRI) task, followed by a [11C]raclopride positron emission tomography (PET) scan. Saliva cortisol levels were acquired at 7 time points during both days. Affective symptoms were measured using Beck Depression Inventory (BDI), Spielberger State Trait Anxiety Index (STAI) and visual analogue scales. After TSD, perceived energy levels, concentration, and speed of thought decreased significantly, whereas mood did not. During fMRI, response speed decreased for neutral words and positive targets, and accuracy decreased trendwise for neutral words and for positive targets with a negative distracter. Following TSD, processing of positive words was associated with increased left dorsolateral prefrontal activation. Processing of emotional words in general was associated with increased insular activity, whereas contrasting positive vs. negative words showed subthreshold increased activation in the (para)hippocampal area. Cortisol secretion was significantly lower after TSD. Decreased voxel-by-voxel [11C]raclopride binding potential (BPND) was observed in left caudate. TSD induces widespread cognitive, neurophysiologic and endocrine changes in healthy adults, characterized by reduced cognitive functioning, despite increased regional brain activity. The blunted HPA-axis response together with altered [11C]raclopride binding in the basal ganglia indicate that sustained wakefulness requires involvement of additional adaptive biological systems.
doi:10.1371/journal.pone.0116906
PMCID: PMC4301911  PMID: 25608023
2.  Social support, oxytocin, and PTSD 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.26513.
Background
A lack of social support and recognition by the environment is one of the most consistent risk factors for posttraumatic stress disorder (PTSD), and PTSD patients will recover faster with proper social support. The oxytocin system has been proposed to underlie beneficial effects of social support as it is implicated in both social bonding behavior and reducing stress responsivity, notably amygdala reactivity (Koch et al., 2014; Olff et al., 2010; Olff, 2012). The amygdala is found to be hypersensitive in people with PTSD.
Method
In order to investigate neurobiological mechanisms underlying potential preventive and therapeutic effects of intranasal oxytocin, we performed a series of fMRI studies (funded with a prestigious NWO TOP grant): BONDS standing for “Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology” in acutely traumatized persons admitted to the emergency department (Frijling et al., 2014); BOOSTER “Boosting oxytocin after trauma: the effects of intranasal oxytocin administration on emotional and motivational processing and neural activity in PTSD” in police officers with and without PTSD.
Results
In this presentation, we present the BOOSTER results on the effects of a single oxytocin administration on amygdala reactivity in response to emotional faces in PTSD patients versus traumatized controls. We found significantly decreased bilateral amygdala reactivity towards emotional faces in PTSD patients compared to traumatized controls.
Conclusions
These promising results call for intervention studies such as studying the effects of medication (oxytocin) enhanced psychotherapy in PTSD patients.
doi:10.3402/ejpt.v5.26513
PMCID: PMC4265184  PMID: 25511718
oxytocin; social support; PTSD; trauma; fMRI; neuroimaging; amygdala
3.  Evidence-based treatment for adult women with child abuse-related Complex PTSD: a quantitative review 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.23613.
Introduction
Effective first-line treatments for posttraumatic stress disorder (PTSD) are well established, but their generalizability to child abuse (CA)-related Complex PTSD is largely unknown.
Method
A quantitative review of the literature was performed, identifying seven studies, with treatments specifically targeting CA-related PTSD or Complex PTSD, which were meta-analyzed, including variables such as effect size, drop-out, recovery, and improvement rates.
Results
Only six studies with one or more cognitive behavior therapy (CBT) treatment conditions and one with a present centered therapy condition could be meta-analyzed. Results indicate that CA-related PTSD patients profit with large effect sizes and modest recovery and improvement rates. Treatments which include exposure showed greater effect sizes especially in completers’ analyses, although no differential results were found in recovery and improvement rates. However, results in the subgroup of CA-related Complex PTSD studies were least favorable. Within the Complex PTSD subgroup, no superior effect size was found for exposure, and affect management resulted in more favorable recovery and improvement rates and less drop-out, as compared to exposure, especially in intention-to-treat analyses.
Conclusion
Limited evidence suggests that predominantly CBT treatments are effective, but do not suffice to achieve satisfactory end states, especially in Complex PTSD populations. Moreover, we propose that future research should focus on direct comparisons between types of treatment for Complex PTSD patients, thereby increasing generalizability of results.
doi:10.3402/ejpt.v5.23613
PMCID: PMC4199330  PMID: 25563302
Review; meta-analysis; PTSD; psychotherapy; cognitive behavioral therapy; cognitive behavioral treatment; child abuse; childhood abuse; adult survivors of child abuse
4.  Systematic review of ERP and fMRI studies investigating inhibitory control and error processing in people with substance dependence and behavioural addictions 
Background
Several current theories emphasize the role of cognitive control in addiction. The present review evaluates neural deficits in the domains of inhibitory control and error processing in individuals with substance dependence and in those showing excessive addiction-like behaviours. The combined evaluation of event-related potential (ERP) and functional magnetic resonance imaging (fMRI) findings in the present review offers unique information on neural deficits in addicted individuals.
Methods
We selected 19 ERP and 22 fMRI studies using stop-signal, go/no-go or Flanker paradigms based on a search of PubMed and Embase.
Results
The most consistent findings in addicted individuals relative to healthy controls were lower N2, error-related negativity and error positivity amplitudes as well as hypoactivation in the anterior cingulate cortex (ACC), inferior frontal gyrus and dorsolateral prefrontal cortex. These neural deficits, however, were not always associated with impaired task performance. With regard to behavioural addictions, some evidence has been found for similar neural deficits; however, studies are scarce and results are not yet conclusive. Differences among the major classes of substances of abuse were identified and involve stronger neural responses to errors in individuals with alcohol dependence versus weaker neural responses to errors in other substance-dependent populations.
Limitations
Task design and analysis techniques vary across studies, thereby reducing comparability among studies and the potential of clinical use of these measures.
Conclusion
Current addiction theories were supported by identifying consistent abnormalities in prefrontal brain function in individuals with addiction. An integrative model is proposed, suggesting that neural deficits in the dorsal ACC may constitute a hallmark neurocognitive deficit underlying addictive behaviours, such as loss of control.
doi:10.1503/jpn.130052
PMCID: PMC3997601  PMID: 24359877
5.  Effects of Insulin Detemir and NPH Insulin on Body Weight and Appetite-Regulating Brain Regions in Human Type 1 Diabetes: A Randomized Controlled Trial 
PLoS ONE  2014;9(4):e94483.
Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli.
Trial Registration
ClinicalTrials.gov NCT00626080.
doi:10.1371/journal.pone.0094483
PMCID: PMC3989203  PMID: 24739875
6.  Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment 
In the context of chronic childhood emotional maltreatment (CEM; emotional abuse and/or neglect), adequately responding to facial expressions is an important skill. Over time, however, this adaptive response may lead to a persistent vigilance for emotional facial expressions. The amygdala and the medial prefrontal cortex (mPFC) are key regions in face processing. However, the neurobiological correlates of face processing in adults reporting CEM are yet unknown. We examined amydala and mPFC reactivity to emotional faces (Angry, Fearful, Sad, Happy, Neutral) vs scrambled faces in healthy controls and unmedicated patients with depression and/or anxiety disorders reporting CEM before the age of 16 years (n = 60), and controls and patients who report no childhood abuse (n = 75). We found that CEM was associated with enhanced bilateral amygdala reactivity to emotional faces in general, and independent of psychiatric status. Furthermore, we found no support for differential mPFC functioning, suggesting that amygdala hyper-responsivity to emotional facial perception in adults reporting CEM may be independent from top–down influences of the mPFC. These findings may be key in understanding the increased emotional sensitivity and interpersonal difficulties, that have been reported in individuals with a history of CEM.
doi:10.1093/scan/nss007
PMCID: PMC3624946  PMID: 22258799
Amygdala; childhood emotional maltreatment; fMRI; mPFC; stress
7.  Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial 
BMC Psychiatry  2014;14:92.
Background
Currently few evidence based interventions are available for the prevention of PTSD within the first weeks after trauma. Increased risk for PTSD development is associated with dysregulated fear and stress responses prior to and shortly after trauma, as well as with a lack of perceived social support early after trauma. Oxytocin is a potent regulator of these processes. Therefore, we propose that oxytocin may be important in reducing adverse consequences of trauma. The ‘BONDS’ study is conducted in order to assess the efficacy of an early intervention with intranasal oxytocin for the prevention of PTSD.
Methods/Design
In this multicenter double-blind randomized placebo-controlled trial we will recruit 220 Emergency Department patients at increased risk of PTSD. Trauma-exposed patients are screened for increased PTSD risk with questionnaires assessing peri-traumatic distress and acute PTSD symptoms within 7 days after trauma. Baseline PTSD symptom severity scores and neuroendocrine and psychophysiological measures will be collected within 10 days after trauma. Participants will be randomized to 7.5 days of intranasal oxytocin (40 IU) or placebo twice a day. Follow-up measurements at 1.5, 3 and 6 months post-trauma are collected to assess PTSD symptom severity (the primary outcome measure). Other measures of symptoms of psychopathology, and neuroendocrine and psychophysiological disorders are secondary outcome measures.
Discussion
We hypothesize that intranasal oxytocin administered early after trauma is an effective pharmacological strategy to prevent PTSD in individuals at increased risk, which is both safe and easily applicable. Interindividual and contextual factors that may influence the effects of oxytocin treatment will be considered in the analysis of the results.
Trial registration
Netherlands Trial Registry: NTR3190.
doi:10.1186/1471-244X-14-92
PMCID: PMC3986606  PMID: 24679046
Post-traumatic disorder; PTSD; Early intervention; Oxytocin; Neurobiology; Randomized controlled trial; Prevention
9.  Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words 
Post-traumatic stress disorder (PTSD) is associated with impaired memory performance coupled with functional changes in brain areas involved in declarative memory and emotion regulation. It is not yet clear how symptom severity and comorbidity affect neurocognitive functioning in PTSD. We performed a functional magnetic resonance imaging (fMRI) study with an emotional declarative memory task in 28 Complex PTSD patients with comorbid depressive and personality disorders, and 21 healthy non-trauma-exposed controls. In Complex PTSD patients—compared to controls—encoding of later remembered negative words vs baseline was associated with increased blood oxygenation level dependent (BOLD) response in the left ventral anterior cingulate cortex (ACC) and dorsal ACC extending to the dorsomedial prefrontal cortex (dmPFC) together with a trend for increased left hippocampus activation. Patients tended to commit more False Alarms to negative words compared to controls, which was associated with enhanced left ventrolateral prefrontal and orbitofrontal cortex (vlPFC/OFC) responses. Severity of child abuse was positively correlated with left ventral ACC activity and severity of depression with (para) hippocampal and ventral ACC activity. Presented results demonstrate functional abnormalities in Complex PTSD in the frontolimbic brain circuit also implicated in fear conditioning models, but generally in the opposite direction, which may be explained by severity of the trauma and severity of comorbid depression in Complex PTSD.
doi:10.1093/scan/nsr084
PMCID: PMC3575721  PMID: 22156722
anterior cingulate cortex; hippocampus; memory; complex post-traumatic stress disorder; childhood abuse
10.  The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data 
Thompson, Paul M. | Stein, Jason L. | Medland, Sarah E. | Hibar, Derrek P. | Vasquez, Alejandro Arias | Renteria, Miguel E. | Toro, Roberto | Jahanshad, Neda | Schumann, Gunter | Franke, Barbara | Wright, Margaret J. | Martin, Nicholas G. | Agartz, Ingrid | Alda, Martin | Alhusaini, Saud | Almasy, Laura | Almeida, Jorge | Alpert, Kathryn | Andreasen, Nancy C. | Andreassen, Ole A. | Apostolova, Liana G. | Appel, Katja | Armstrong, Nicola J. | Aribisala, Benjamin | Bastin, Mark E. | Bauer, Michael | Bearden, Carrie E. | Bergmann, Ørjan | Binder, Elisabeth B. | Blangero, John | Bockholt, Henry J. | Bøen, Erlend | Bois, Catherine | Boomsma, Dorret I. | Booth, Tom | Bowman, Ian J. | Bralten, Janita | Brouwer, Rachel M. | Brunner, Han G. | Brohawn, David G. | Buckner, Randy L. | Buitelaar, Jan | Bulayeva, Kazima | Bustillo, Juan R. | Calhoun, Vince D. | Cannon, Dara M. | Cantor, Rita M. | Carless, Melanie A. | Caseras, Xavier | Cavalleri, Gianpiero L. | Chakravarty, M. Mallar | Chang, Kiki D. | Ching, Christopher R. K. | Christoforou, Andrea | Cichon, Sven | Clark, Vincent P. | Conrod, Patricia | Coppola, Giovanni | Crespo-Facorro, Benedicto | Curran, Joanne E. | Czisch, Michael | Deary, Ian J. | de Geus, Eco J. C. | den Braber, Anouk | Delvecchio, Giuseppe | Depondt, Chantal | de Haan, Lieuwe | de Zubicaray, Greig I. | Dima, Danai | Dimitrova, Rali | Djurovic, Srdjan | Dong, Hongwei | Donohoe, Gary | Duggirala, Ravindranath | Dyer, Thomas D. | Ehrlich, Stefan | Ekman, Carl Johan | Elvsåshagen, Torbjørn | Emsell, Louise | Erk, Susanne | Espeseth, Thomas | Fagerness, Jesen | Fears, Scott | Fedko, Iryna | Fernández, Guillén | Fisher, Simon E. | Foroud, Tatiana | Fox, Peter T. | Francks, Clyde | Frangou, Sophia | Frey, Eva Maria | Frodl, Thomas | Frouin, Vincent | Garavan, Hugh | Giddaluru, Sudheer | Glahn, David C. | Godlewska, Beata | Goldstein, Rita Z. | Gollub, Randy L. | Grabe, Hans J. | Grimm, Oliver | Gruber, Oliver | Guadalupe, Tulio | Gur, Raquel E. | Gur, Ruben C. | Göring, Harald H. H. | Hagenaars, Saskia | Hajek, Tomas | Hall, Geoffrey B. | Hall, Jeremy | Hardy, John | Hartman, Catharina A. | Hass, Johanna | Hatton, Sean N. | Haukvik, Unn K. | Hegenscheid, Katrin | Heinz, Andreas | Hickie, Ian B. | Ho, Beng-Choon | Hoehn, David | Hoekstra, Pieter J. | Hollinshead, Marisa | Holmes, Avram J. | Homuth, Georg | Hoogman, Martine | Hong, L. Elliot | Hosten, Norbert | Hottenga, Jouke-Jan | Hulshoff Pol, Hilleke E. | Hwang, Kristy S. | Jack, Clifford R. | Jenkinson, Mark | Johnston, Caroline | Jönsson, Erik G. | Kahn, René S. | Kasperaviciute, Dalia | Kelly, Sinead | Kim, Sungeun | Kochunov, Peter | Koenders, Laura | Krämer, Bernd | Kwok, John B. J. | Lagopoulos, Jim | Laje, Gonzalo | Landen, Mikael | Landman, Bennett A. | Lauriello, John | Lawrie, Stephen M. | Lee, Phil H. | Le Hellard, Stephanie | Lemaître, Herve | Leonardo, Cassandra D. | Li, Chiang-shan | Liberg, Benny | Liewald, David C. | Liu, Xinmin | Lopez, Lorna M. | Loth, Eva | Lourdusamy, Anbarasu | Luciano, Michelle | Macciardi, Fabio | Machielsen, Marise W. J. | MacQueen, Glenda M. | Malt, Ulrik F. | Mandl, René | Manoach, Dara S. | Martinot, Jean-Luc | Matarin, Mar | Mather, Karen A. | Mattheisen, Manuel | Mattingsdal, Morten | Meyer-Lindenberg, Andreas | McDonald, Colm | McIntosh, Andrew M. | McMahon, Francis J. | McMahon, Katie L. | Meisenzahl, Eva | Melle, Ingrid | Milaneschi, Yuri | Mohnke, Sebastian | Montgomery, Grant W. | Morris, Derek W. | Moses, Eric K. | Mueller, Bryon A. | Muñoz Maniega, Susana | Mühleisen, Thomas W. | Müller-Myhsok, Bertram | Mwangi, Benson | Nauck, Matthias | Nho, Kwangsik | Nichols, Thomas E. | Nilsson, Lars-Göran | Nugent, Allison C. | Nyberg, Lars | Olvera, Rene L. | Oosterlaan, Jaap | Ophoff, Roel A. | Pandolfo, Massimo | Papalampropoulou-Tsiridou, Melina | Papmeyer, Martina | Paus, Tomas | Pausova, Zdenka | Pearlson, Godfrey D. | Penninx, Brenda W. | Peterson, Charles P. | Pfennig, Andrea | Phillips, Mary | Pike, G. Bruce | Poline, Jean-Baptiste | Potkin, Steven G. | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rietschel, Marcella | Rijpkema, Mark | Risacher, Shannon L. | Roffman, Joshua L. | Roiz-Santiañez, Roberto | Romanczuk-Seiferth, Nina | Rose, Emma J. | Royle, Natalie A. | Rujescu, Dan | Ryten, Mina | Sachdev, Perminder S. | Salami, Alireza | Satterthwaite, Theodore D. | Savitz, Jonathan | Saykin, Andrew J. | Scanlon, Cathy | Schmaal, Lianne | Schnack, Hugo G. | Schork, Andrew J. | Schulz, S. Charles | Schür, Remmelt | Seidman, Larry | Shen, Li | Shoemaker, Jody M. | Simmons, Andrew | Sisodiya, Sanjay M. | Smith, Colin | Smoller, Jordan W. | Soares, Jair C. | Sponheim, Scott R. | Sprooten, Emma | Starr, John M. | Steen, Vidar M. | Strakowski, Stephen | Strike, Lachlan | Sussmann, Jessika | Sämann, Philipp G. | Teumer, Alexander | Toga, Arthur W. | Tordesillas-Gutierrez, Diana | Trabzuni, Daniah | Trost, Sarah | Turner, Jessica | Van den Heuvel, Martijn | van der Wee, Nic J. | van Eijk, Kristel | van Erp, Theo G. M. | van Haren, Neeltje E. M. | van ‘t Ent, Dennis | van Tol, Marie-Jose | Valdés Hernández, Maria C. | Veltman, Dick J. | Versace, Amelia | Völzke, Henry | Walker, Robert | Walter, Henrik | Wang, Lei | Wardlaw, Joanna M. | Weale, Michael E. | Weiner, Michael W. | Wen, Wei | Westlye, Lars T. | Whalley, Heather C. | Whelan, Christopher D. | White, Tonya | Winkler, Anderson M. | Wittfeld, Katharina | Woldehawariat, Girma | Wolf, Christiane | Zilles, David | Zwiers, Marcel P. | Thalamuthu, Anbupalam | Schofield, Peter R. | Freimer, Nelson B. | Lawrence, Natalia S. | Drevets, Wayne
Brain Imaging and Behavior  2014;8(2):153-182.
The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
doi:10.1007/s11682-013-9269-5
PMCID: PMC4008818  PMID: 24399358
Genetics; MRI; GWAS; Consortium; Meta-analysis; Multi-site
11.  Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study 
PLoS ONE  2014;9(1):e84560.
Introduction
With the progression of substance dependence, drug cue-related brain activation is thought to shift from motivational towards habit pathways. However, a direct association between cue-induced brain activation and dependence duration has not yet been shown. We therefore examined the relationship between alcohol cue-reactivity in the brain, cue-induced subjective craving and alcohol dependence duration and severity. Since alcohol dependence is highly comorbid with depression/anxiety, which may modulate brain responses to alcohol cues, we also examined the relation between comorbid depression/anxiety and cue-reactivity.
Methods
We compared 30 alcohol dependent patients with 15 healthy controls and 15 depression/anxiety patients during a visual alcohol cue-reactivity task using functional magnetic resonance imaging blood oxygenated level-dependent responses and subjective craving as outcomes. Within the alcohol dependent group we correlated cue-reactivity with alcohol dependence severity and duration, with cue-induced craving and with depression/anxiety levels.
Results
Alcohol dependent patients showed greater cue-reactivity in motivational brain pathways and stronger subjective craving than depression/anxiety patients and healthy controls. Depression/anxiety was not associated with cue-reactivity, but depression severity in alcohol dependent patients was positively associated with craving. Within alcohol dependence, longer duration of alcohol dependence was associated with stronger cue-related activation of the posterior putamen, a structure involved in habits, whereas higher alcohol dependence severity was associated with lower cue-reactivity in the anterior putamen, an area implicated in goal-directed behavior preceding habit formation.
Conclusion
Cue-reactivity in alcohol dependence is not modulated by comorbid depression or anxiety. More importantly, the current data confirm the hypothesis of a ventral to dorsal striatal shift of learning processes with longer dependence duration, which could underlie increasingly habitual substance use with progressing substance dependence.
doi:10.1371/journal.pone.0084560
PMCID: PMC3882248  PMID: 24400099
12.  Hypothalamic Response to the Chemo-Signal Androstadienone in Gender Dysphoric Children and Adolescents 
The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.
doi:10.3389/fendo.2014.00060
PMCID: PMC4037295  PMID: 24904525
androstadienone; chemo-signal; fMRI; gender dysphoria; hypothalamus; puberty; sex difference
13.  On the connection between level of education and the neural circuitry of emotion perception 
Through education, a social group transmits accumulated knowledge, skills, customs, and values to its members. So far, to the best of our knowledge, the association between educational attainment and neural correlates of emotion processing has been left unexplored. In a retrospective analysis of The Netherlands Study of Depression and Anxiety (NESDA) functional magnetic resonance imaging (fMRI) study, we compared two groups of fourteen healthy volunteers with intermediate and high educational attainment, matched for age and gender. The data concerned event-related fMRI of brain activation during perception of facial emotional expressions. The region of interest (ROI) analysis showed stronger right amygdala activation to facial expressions in participants with lower relative to higher educational attainment (HE). The psychophysiological interaction analysis revealed that participants with HE exhibited stronger right amygdala—right insula connectivity during perception of emotional and neutral facial expressions. This exploratory study suggests the relevance of educational attainment on the neural mechanism of facial expressions processing.
doi:10.3389/fnhum.2014.00866
PMCID: PMC4209829  PMID: 25386133
emotion; facial expressions; educational attainment; neural response; psychophysiological interaction
14.  Brain Activation Associated with Attentional Bias in Smokers is Modulated by a Dopamine Antagonist 
Neuropsychopharmacology  2012;37(13):2772-2779.
Attentional bias in substance-dependent individuals is the tendency to automatically direct the attention to substance-related cues in the environment. Attentional bias is known to be associated with clinical measures such as relapse or successful quitting in smokers. It has been suggested that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The current functional magnetic resonance imaging study employed a dopaminergic challenge in order to test whether brain activation associated with attentional bias in smokers could be modulated by a dopamine antagonist. A total of 25 smokers were compared with 24 controls. Participants were scanned twice while performing a pictorial attentional bias task. Haloperidol (2 mg), a selective D2/D3 dopamine antagonist, or placebo was orally administered 4 h before each scanning session in a double-blind randomized cross-over design. Imaging analyses were performed in a priori selected regions of interest. Results showed that smokers had enhanced brain activation compared with controls in the dorsal anterior cingulate cortex (dACC), right dorsolateral prefrontal cortex (r-DLPFC), and left superior parietal lobe (I-SPL) after placebo. Group × medication interactions were found in the dACC and r-DLPFC, with no differences between groups in these regions after haloperidol. The current findings suggest that a pharmacologically induced reduction in dopamine normalizes brain activation associated with attentional bias in the dACC and DLPFC in smokers, probably because salience of these cues is no longer detected when dopamine activity is reduced.
doi:10.1038/npp.2012.143
PMCID: PMC3499728  PMID: 22850734
attentional bias; dopamine; smokers; functional magnetic resonance imaging; addiction and substance abuse; attentional bias; cognition; dopamine; imaging; clinical or preclinical; smokers
15.  Treatment compliance and effectiveness in complex PTSD patients with co-morbid personality disorder undergoing stabilizing cognitive behavioral group treatment: a preliminary study 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.21171.
Background
In the empirical and clinical literature, complex posttraumatic stress disorder (PTSD) and personality disorders (PDs) are suggested to be predictive of drop-out or reduced treatment effectiveness in trauma-focused PTSD treatment.
Objective
In this study, we aimed to investigate if personality characteristics would predict treatment compliance and effectiveness in stabilizing complex PTSD treatment.
Method
In a randomized controlled trial on a 20-week stabilizing group cognitive behavioral treatment (CBT) for child-abuse-related complex PTSD, we included 71 patients of whom 38 were randomized to a psycho-educational and cognitive behavioral stabilizing group treatment. We compared the patients with few PD symptoms (adaptive) (N=14) with the non-adaptive patients (N=24) as revealed by a cluster analysis.
Results
We found that non-adaptive patients compared to the adaptive patients showed very low drop-out rates. Both non-adaptive patients, classified with highly different personality profiles “withdrawn” and “aggressive,” were equally compliant. With regard to symptom reduction, we found no significant differences between subtypes. Post-hoc, patients with a PD showed lower drop-out rates and higher effect sizes in terms of complex PTSD severity, especially on domains that affect regulation and interpersonal problems.
Conclusions
Contrary to our expectations, these preliminary findings indicate that this treatment is well tolerated by patients with a variety of personality pathology. Larger sample sizes are needed to study effectiveness for subgroups of complex PTSD patients.
doi:10.3402/ejpt.v4i0.21171
PMCID: PMC3820917  PMID: 24224077
Personality disorders; treatment outcome; child abuse; posttraumatic stress disorder; cognitive behavioral treatment; complex PTSD; dissociative subtype
16.  Influence of COMT val158met Genotype on the Depressed Brain during Emotional Processing and Working Memory 
PLoS ONE  2013;8(9):e73290.
Major depressive disorder (MDD) has been associated with abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI-neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met-alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory.
doi:10.1371/journal.pone.0073290
PMCID: PMC3772077  PMID: 24069183
18.  N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study 
Neuropsychopharmacology  2012;37(9):2143-2152.
Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy (1H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.
doi:10.1038/npp.2012.66
PMCID: PMC3398721  PMID: 22549117
cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity; cocaine dependence; N-acetylcysteine; glutamate; magnetic resonance spectroscopy; impulsivity
19.  Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: Abnormal salience circuitry and relations to positive emotionality☆ 
NeuroImage : Clinical  2013;2:790-796.
Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n = 25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject's connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic–cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.
Highlights
•We studied whole-brain functional connectivity in MDD during an emotional task.•We used a set of independent template networks, corresponding to various task demands.•We showed lower connectivity of reward related regions with a salience network in MDD.•Lower salience connectivity specifically related to extraversion in patients•Results may reflect vulnerability for MDD via a circuit vital for rewarding behavior.
doi:10.1016/j.nicl.2013.05.012
PMCID: PMC3777780  PMID: 24179829
Depression; Extraversion; Functional magnetic resonance imagint; Salience network; Whole-brain functional connectivity
20.  Identification of common variants associated with human hippocampal and intracranial volumes 
Stein, Jason L | Medland, Sarah E | Vasquez, Alejandro Arias | Hibar, Derrek P | Senstad, Rudy E | Winkler, Anderson M | Toro, Roberto | Appel, Katja | Bartecek, Richard | Bergmann, Ørjan | Bernard, Manon | Brown, Andrew A | Cannon, Dara M | Chakravarty, M Mallar | Christoforou, Andrea | Domin, Martin | Grimm, Oliver | Hollinshead, Marisa | Holmes, Avram J | Homuth, Georg | Hottenga, Jouke-Jan | Langan, Camilla | Lopez, Lorna M | Hansell, Narelle K | Hwang, Kristy S | Kim, Sungeun | Laje, Gonzalo | Lee, Phil H | Liu, Xinmin | Loth, Eva | Lourdusamy, Anbarasu | Mattingsdal, Morten | Mohnke, Sebastian | Maniega, Susana Muñoz | Nho, Kwangsik | Nugent, Allison C | O’Brien, Carol | Papmeyer, Martina | Pütz, Benno | Ramasamy, Adaikalavan | Rasmussen, Jerod | Rijpkema, Mark | Risacher, Shannon L | Roddey, J Cooper | Rose, Emma J | Ryten, Mina | Shen, Li | Sprooten, Emma | Strengman, Eric | Teumer, Alexander | Trabzuni, Daniah | Turner, Jessica | van Eijk, Kristel | van Erp, Theo G M | van Tol, Marie-Jose | Wittfeld, Katharina | Wolf, Christiane | Woudstra, Saskia | Aleman, Andre | Alhusaini, Saud | Almasy, Laura | Binder, Elisabeth B | Brohawn, David G | Cantor, Rita M | Carless, Melanie A | Corvin, Aiden | Czisch, Michael | Curran, Joanne E | Davies, Gail | de Almeida, Marcio A A | Delanty, Norman | Depondt, Chantal | Duggirala, Ravi | Dyer, Thomas D | Erk, Susanne | Fagerness, Jesen | Fox, Peter T | Freimer, Nelson B | Gill, Michael | Göring, Harald H H | Hagler, Donald J | Hoehn, David | Holsboer, Florian | Hoogman, Martine | Hosten, Norbert | Jahanshad, Neda | Johnson, Matthew P | Kasperaviciute, Dalia | Kent, Jack W | Kochunov, Peter | Lancaster, Jack L | Lawrie, Stephen M | Liewald, David C | Mandl, René | Matarin, Mar | Mattheisen, Manuel | Meisenzahl, Eva | Melle, Ingrid | Moses, Eric K | Mühleisen, Thomas W | Nauck, Matthias | Nöthen, Markus M | Olvera, Rene L | Pandolfo, Massimo | Pike, G Bruce | Puls, Ralf | Reinvang, Ivar | Rentería, Miguel E | Rietschel, Marcella | Roffman, Joshua L | Royle, Natalie A | Rujescu, Dan | Savitz, Jonathan | Schnack, Hugo G | Schnell, Knut | Seiferth, Nina | Smith, Colin | Steen, Vidar M | Valdés Hernández, Maria C | Van den Heuvel, Martijn | van der Wee, Nic J | Van Haren, Neeltje E M | Veltman, Joris A | Völzke, Henry | Walker, Robert | Westlye, Lars T | Whelan, Christopher D | Agartz, Ingrid | Boomsma, Dorret I | Cavalleri, Gianpiero L | Dale, Anders M | Djurovic, Srdjan | Drevets, Wayne C | Hagoort, Peter | Hall, Jeremy | Heinz, Andreas | Jack, Clifford R | Foroud, Tatiana M | Le Hellard, Stephanie | Macciardi, Fabio | Montgomery, Grant W | Poline, Jean Baptiste | Porteous, David J | Sisodiya, Sanjay M | Starr, John M | Sussmann, Jessika | Toga, Arthur W | Veltman, Dick J | Walter, Henrik | Weiner, Michael W | Bis, Joshua C | Ikram, M Arfan | Smith, Albert V | Gudnason, Vilmundur | Tzourio, Christophe | Vernooij, Meike W | Launer, Lenore J | DeCarli, Charles | Seshadri, Sudha | Andreassen, Ole A | Apostolova, Liana G | Bastin, Mark E | Blangero, John | Brunner, Han G | Buckner, Randy L | Cichon, Sven | Coppola, Giovanni | de Zubicaray, Greig I | Deary, Ian J | Donohoe, Gary | de Geus, Eco J C | Espeseth, Thomas | Fernández, Guillén | Glahn, David C | Grabe, Hans J | Hardy, John | Hulshoff Pol, Hilleke E | Jenkinson, Mark | Kahn, René S | McDonald, Colm | McIntosh, Andrew M | McMahon, Francis J | McMahon, Katie L | Meyer-Lindenberg, Andreas | Morris, Derek W | Müller-Myhsok, Bertram | Nichols, Thomas E | Ophoff, Roel A | Paus, Tomas | Pausova, Zdenka | Penninx, Brenda W | Potkin, Steven G | Sämann, Philipp G | Saykin, Andrew J | Schumann, Gunter | Smoller, Jordan W | Wardlaw, Joanna M | Weale, Michael E | Martin, Nicholas G | Franke, Barbara | Wright, Margaret J | Thompson, Paul M
Nature genetics  2012;44(5):552-561.
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer’s disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).
doi:10.1038/ng.2250
PMCID: PMC3635491  PMID: 22504417
21.  Cognitive Inflexibility in Obsessive-Compulsive Disorder and Major Depression Is Associated with Distinct Neural Correlates 
PLoS ONE  2013;8(4):e59600.
Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD.
doi:10.1371/journal.pone.0059600
PMCID: PMC3634812  PMID: 23637737
22.  Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression 
PLoS ONE  2013;8(4):e61494.
Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD.
doi:10.1371/journal.pone.0061494
PMCID: PMC3631241  PMID: 23620758
23.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Background
Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.
Methods
We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.
Results
Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.
Conclusions
During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.
doi:10.1371/journal.pone.0049923
PMCID: PMC3509135  PMID: 23209619
24.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019
25.  The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity 
Brain and Behavior  2012;2(5):553-562.
Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.
doi:10.1002/brb3.74
PMCID: PMC3489808  PMID: 23139901
Anterior cingulate cortex; delay discounting; glutamate; impulsive decision making; magnetic resonance spectroscopy; resting state fMRI

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