A Low-Intensity Transcranial Focused Ultrasound Parameter Exploration Study of the Ventral Capsule/Ventral Striatum.

OBJECTIVES: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is effective for treatment-resistant obsessive-compulsive disorder (OCD); however, DBS is associated with neurosurgical risks. Transcranial focused ultrasound (tFUS) is a newer form of noninvasive (ie, nonsurgical) stimulation that can modulate deeper regions, such as the VC/VS. tFUS parameters have just begun to be studied and have often not been compared in the same participants. We explored the effects of three VC/VS tFUS protocols and an entorhinal cortex (ErC) tFUS session on the VC/VS and cortico-striato-thalamo-cortical circuit (CSTC) in healthy individuals for later application to patients with OCD. MATERIALS AND METHODS: Twelve individuals participated in a total of 48 sessions of tFUS in this exploratory multisite, within-subject parameter study. We collected resting-state, reward task, and arterial spin-labeled (ASL) magnetic resonance imaging scans before and after ErC tFUS and three VC/VS tFUS sessions with different pulse repetition frequencies (PRFs), pulse widths (PWs), and duty cycles (DCs). RESULTS: VC/VS protocol A (PRF = 10 Hz, PW = 5 ms, 5% DC) was associated with increased putamen activation during a reward task (p = 0.003), and increased VC/VS resting-state functional connectivity (rsFC) with the anterior cingulate cortex (p = 0.022) and orbitofrontal cortex (p = 0.004). VC/VS protocol C (PRF = 125 Hz, PW = 4 ms, 50% DC) was associated with decreased VC/VS rsFC with the putamen (p = 0.017), and increased VC/VS rsFC with the globus pallidus (p = 0.008). VC/VS protocol B (PRF = 125 Hz, PW = 0.4 ms, 5% DC) was not associated with changes in task-related CSTC activation or rsFC. None of the protocols affected CSTC ASL perfusion. CONCLUSIONS: This study began to explore the multidimensional parameter space of an emerging form of noninvasive brain stimulation, tFUS. Our preliminary findings in a small sample suggest that VC/VS tFUS should continue to be investigated for future noninvasive treatment of OCD.

Rumination in bipolar disorder associated with brain network and behavioural measures of inhibitory executive control.

OBJECTIVE: Rumination is a passive form of negative self-focused cognition that predicts depressive episodes for individuals with bipolar disorder (BD). Individuals with BD also have impaired inhibitory executive control; rumination in BD may therefore reflect executive dysfunction. We investigated the relationship between a neural measure of executive functioning (functional connectivity between the frontoparietal control network [FPCN] and the default mode network [DMN] during an effortful task), behavioural measures of executive functioning (the Behavior Rating Inventory of Executive Function) and rumination (the Ruminative Responses Scale). METHODS: Fifteen individuals with BD and fifteen healthy controls underwent MRI scans during mental distraction. Using CONN toolbox, between-network FPCN-DMN connectivity values were calculated. We conducted Pearson's r bivariate correlations between connectivity values, BRIEF and RRS scores. RESULTS: RRS scores were positively correlated with BRIEF Behavioral Regulation Index (BRI) scores. In individuals with BD, there was a positive correlation between FPCN-DMN functional connectivity during distraction and BRIEF BRI scores. FPCN-DMN functional connectivity was also positively correlated with RRS ruminative brooding scores. Healthy controls did not show significant correlations between these behavioural and neural measures of executive functioning and rumination. CONCLUSION: For individuals with BD, the greater the tendency to ruminate and the higher the executive dysfunction, the stronger the connectivity between an executive control network and a network involved in rumination during an unrelated cognitive task. This could reflect continual attempts to inhibit ruminative thinking and shift back to the distraction task. Therefore, engagement in rumination may reflect failed inhibitory executive control.

Neural correlates of learning accommodation and consolidation in generalised anxiety disorder.

OBJECTIVE.: Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD). METHODS.: Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS. RESULTS.: Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal. CONCLUSION.: Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

Open-label study of duloxetine for the treatment of obsessive-compulsive disorder.

BACKGROUND: This study sought to investigate the efficacy of duloxetine for the treatment of obsessive-compulsive disorder (DSM-IV). METHODS: Twenty individuals were enrolled in a 17-week, open-label trial of duloxetine at Massachusetts General Hospital. Data were collected between March 2007 and September 2012. Study measures assessing obsessive-compulsive disorder symptoms, quality of life, depression, and anxiety were administered at baseline and weeks 1, 5, 9, 13, and 17. The primary outcome measures were the Yale-Brown Obsessive Compulsive Scale and Clinical Global Improvement scale. RESULTS: For the 12 study completers, pre- and posttreatment analyses revealed significant improvements (P<.05) on clinician- and self-rated measures of obsessive-compulsive disorder symptoms and quality of life. Among the 12 completers, more than one-half (n=7) satisfied full medication response criteria. Intention-to-treat analyses (n=20) showed similar improvements (P<.05) on primary and secondary study outcome measures. CONCLUSION: The results of this study suggest that duloxetine may provide a significant reduction in symptoms for patients with obsessive-compulsive disorder. ClinicalTrials.gov NCT00464698; http://clinicaltrials.gov/ct2/show/NCT00464698?term=NCT00464698&rank=1.

Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment.

The microenvironment of human follicular lymphoma (FL), an incurable B cell non-Hodgkin's lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular Th cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17 but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17, but not CCL22, in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-γ-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk among TFH, tumor cells, and Tregs in FL, and offer potential targets for development of therapeutic strategies to overcome immune evasion.

EEG complexity in emotion conflict task in individuals with psychiatric disorders.

Analyzing EEG complexity may help to elucidate complex brain dynamics in individuals with psychiatric disorders and provide insight into neural connectivity and its relationship with deficits such as emotion-related impulsivity. EEG complexity was calculated through multiscale entropy and compared between a heterogeneous psychiatric patient group and a healthy control group during the emotion conflict resolution task. Twenty-eight healthy adults and ten psychiatric patients were recruited and compared on the multiscale entropy of EEG acquired in the task. Our results revealed a lower multiscale entropy in the psychiatric patient group compared to the healthy group during the task. This decrease in multiscale entropy suggests reduced long-range interaction between the left frontal region and other brain regions during the emotion conflict resolution task among psychiatric patients. Notably, a positive correlation was observed between multiscale entropy and impulsivity measures in the psychiatric patient group, where the higher the EEG complexity during the emotion regulation task, the higher the level of self-reported impulsivity in the psychiatric patients. Such impulsivity was evident in both healthy individuals and psychiatric patients, with healthy individuals showing shorter reaction times on incongruent conditions compared to congruent conditions and psychiatric patients displaying similar reaction times in both conditions, This study highlights the significance of investigating EEG complexity and its potential applications in the transdiagnostic exploration of impulsivity in psychiatric disorders.

A Review of Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation Combined with Medication and Psychotherapy for Depression.

LEARNING OBJECTIVES: After participating in this CME activity, the psychiatrist should be better able to:• Compare and contrast therapies used in combination with transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) for treating MDD. BACKGROUND: Noninvasive neuromodulation, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), has emerged as a major area for treating major depressive disorder (MDD). This review has two primary aims: (1) to review the current literature on combining TMS and tDCS with other therapies, such as psychotherapy and psychopharmacological interventions, and (2) to discuss the efficacy, feasibility, limitations, and future directions of these combined treatments for MDD. METHOD: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched three databases: PubMed, PsycInfo, and Cochrane Library. The last search date was December 5, 2023. RESULTS: The initial search revealed 2,519 records. After screening and full-text review, 58 studies (7 TMS plus psychotherapy, 32 TMS plus medication, 7 tDCS plus psychotherapy, 12 tDCS plus medication) were included. CONCLUSIONS: The current literature on tDCS and TMS paired with psychotherapy provides initial support for integrating mindfulness interventions with both TMS and tDCS. Adding TMS or tDCS to stable doses of ongoing medications can decrease MDD symptoms; however, benzodiazepines may interfere with TMS and tDCS response, and antipsychotics can interfere with TMS response. Pairing citalopram with TMS and sertraline with tDCS can lead to greater MDD symptom reduction compared to using these medications alone. Future studies need to enroll larger samples, include randomized controlled study designs, create more uniform protocols for combined treatment delivery, and explore mechanisms and predictors of change.

Transcranial focused ultrasound of the amygdala modulates fear network activation and connectivity.

BACKGROUND: Current noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. OBJECTIVE: We investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS' effects on amygdala-fear circuit resting-state functional connectivity. METHODS: Thirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. RESULTS: Compared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F(1,25) = 4.86, p = 0.04, η2 = 0.16) during the fear task, and lower hippocampal (F(1,27) = 4.41, p = 0.05, η2 = 0.14), and dorsal anterior cingulate cortex (F(1,27) = 6.26, p = 0.02; η2 = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F(1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F(1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F(1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F(1,28) = 3.52, p = 0.05) resting-state functional connectivity. CONCLUSIONS: tFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS' therapeutic potential for individuals with clinical levels of anxiety.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Differential patterns of default mode network activity associated with negative and positive rumination in bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) engage in both negative and positive rumination, defined as maladaptive self-focused thinking, and this tendency predicts depressive and manic episodes, respectively. Prior research in patients with major depression implicates regions of the default mode network (DMN) consistent with the self-focused nature of rumination. Little is known about the neural correlates of rumination in bipolar disorder. METHODS: Fifteen euthymic patients with BD (twelve with Type I) and 17 healthy controls (HC) performed negative and positive rumination induction tasks, as well as a distraction task, followed by a self-related trait judgment task while undergoing functional magnetic resonance imaging (fMRI). Participants also underwent resting state scans. We examined functional connectivity at rest and during the induction tasks, as well as task-based activation during the trait judgment task, in core regions of the DMN. RESULTS: Compared to HC, patients with BD showed greater functional connectivity between the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) at rest and during positive rumination, compared to distraction. They also showed greater activity in the PCC and MPFC during processing of positive traits, following positive rumination. At rest and during negative rumination compared to distraction, patients with BD showed greater functional connectivity between the PCC and inferior parietal lobule than HC. CONCLUSIONS: These findings demonstrate that negative and positive rumination are subserved by different patterns of connectivity within the DMN in BD. Additionally, the PCC and MPFC are key regions involved in the processing of positive self-relevant traits following positive rumination.

The default mode network and rumination in individuals at risk for depression.

The default mode network (DMN) is a network of brain regions active during rest and self-referential thinking. Individuals with major depressive disorder (MDD) show increased or decreased DMN activity relative to controls. DMN activity has been linked to a tendency to ruminate in MDD. It is unclear if individuals who are at risk for, but who have no current or past history of depression, also show differential DMN activity associated with rumination. We investigated whether females with high levels of neuroticism with no current or lifetime mood or anxiety disorders (n = 25) show increased DMN activation, specifically when processing negative self-referential information, compared with females with average levels of neuroticism (n = 28). Participants heard criticism and praise during functional magnetic resonance imaging (MRI) scans in a 3T Siemens Prisma scanner. The at-risk group showed greater activation in two DMN regions, the medial prefrontal cortex and the inferior parietal lobule (IPL), after hearing criticism, but not praise (relative to females with average levels of neuroticism). Criticism-specific activation in the IPL was significantly correlated with rumination. Individuals at risk for depression may, therefore, have an underlying neurocognitive vulnerability to use a brain network typically involved in thinking about oneself to preferentially ruminate about negative, rather than positive, information.

Neuroticism modulates the qualitative effects of inferior parietal tDCS on negatively-valenced memories.

For individuals with increased levels of neuroticism, experiencing criticism or receiving negative feedback has been associated with worse psychological and cognitive outcomes. Transcranial direct current stimulation (tDCS) can change cognitive processes in clinical populations. We bilaterally stimulated the posterior inferior parietal lobule (pIPL), a critical superficial node of the default model network. We investigated how baseline neuroticism modulates the impact of bilateral tDCS to pIPL on qualitative measures of memory after hearing criticism, hypothesizing that cathodal stimulation of the IPL would offer qualitative memory improvements for individuals with higher levels of neuroticism. Ninety individuals from the community were randomly assigned to receive anodal, cathodal, or sham stimulation while they were exposed to critical comments before and after stimulation. Participants then recalled the critical comments, and their linguistic responses were analyzed using Pennebaker's Linguistic Inquiry and Word Count software, a quantitative analysis software for linguistic data. Results showed that for individuals receiving cathodal tDCS, higher neuroticism scores corresponded with greater proportions of non-personal language (i.e., words such as "us," "they," or "other" instead of "I" or "me") when recalling negative feedback. For individuals with higher neuroticism, cathodal tDCS stimulation, rather than anodal or sham, of the pIPL prompted increased emotional distancing and perspective taking strategies when recalling criticism. These results further highlight the state-dependent nature of tDCS effects and the role of the IPL in interpersonal processing - a clinically meaningful outcome that current tDCS studies solely examining quantitative measures of memory (e.g., task-based accuracy or speed) do not reveal.

Brivanib: a review of development.

The development of new agents in oncology has focused on disrupting key pathways in oncogenesis. Both malignant angiogenesis and peptide growth factor signaling have been studied extensively and have been validated for cancer treatment. While antibody-directed therapeutics offer increased specificity, small-molecule tyrosine kinase inhibitors often have the ability to hit multiple targets. Brivanib alaninate (BMS582664) is an oral, potent selective inhibitor of both the FGF and VEGF family of receptors. It is a first-in-class FGF/VEGF inhibitor now in late-phase clinical trials. Besides its antiangiogenic activity from blocking VEGF receptor 1-3, its ability to disrupt FGF receptors 1-3 has been suggested to add additional antiangiogenic activity, overcome resistance from VEGF blockade, and block FGF-dependent tumor proliferation. In this review, we will discuss the preclinical science driving brivanib's development and the clinical data generated to date.

Perception of racial discrimination and psychopathology across three U.S. ethnic minority groups.

To examine the association between the perception of racial discrimination and the lifetime prevalence rates of psychological disorders in the three most common ethnic minorities in the United States, we analyzed data from a sample consisting of 793 Asian Americans, 951 Hispanic Americans, and 2,795 African Americans who received the Composite International Diagnostic Interview through the Collaborative Psychiatric Epidemiology Studies. The perception of racial discrimination was associated with the endorsement of major depressive disorder, panic disorder with agoraphobia, agoraphobia without history of panic disorder, posttraumatic stress disorder, and substance use disorders in varying degrees among the three minority groups, independent of the socioeconomic status, level of education, age, and gender of participants. The results suggest that the perception of racial discrimination is associated with psychopathology in the three most common U.S. minority groups.

Restoration of default mode network and task positive network anti-correlation associated with mindfulness-based cognitive therapy for bipolar disorder.

Individuals with bipolar disorder (BP) show abnormalities in the default mode network (DMN), a brain network active at rest and during self-referential cognition. In healthy individuals, the DMN is anti-correlated (strongly negatively correlated) with the task positive network (TPN), a brain network that is active during attention demanding tasks. Mindfulness has been linked to changes in DMN connectivity. We investigated the effects of mindfulness-based cognitive therapy (MBCT) versus supportive psychotherapy (SP) on the relationship between these two networks in individuals with BP. We identified differences in BOLD resting state DMN-TPN connectivity between healthy controls (HC; n = 22) and individuals with DSM-IV BP before treatment (n = 22) using a seed region in the dorsolateral prefrontal cortex (DLPFC), a key TPN node. We then explored changes in DMN-TPN connectivity after 12 weeks of MBCT or SP. Before treatment, BP individuals showed positively correlated activity and the HC group showed negatively correlated activity between the DLPFC and the posterior cingulate cortex (PCC). After treatment, BP individuals who received MBCT showed negatively correlated DLPFC-PCC activity. BP individuals who received SP did not show a significant change. Mindfulness-based cognitive therapy can restore the anti-correlation between the DMN and TPN in individuals with BP.

Convergence between behavioral, neural, and self-report measures of cognitive control: The Frontal Systems Behavior Scale in bipolar disorder.

The Frontal Systems Behavior Scale (FrSBe) is a self-report measure that assesses difficulties with cognitive and emotional control such as apathetic behavior, lack of inhibitory control, and executive dysfunction. Previous neuroimaging studies highlight the involvement of the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex (DLPFC) in these processes. In this study, we investigated whether there was convergence across subjective and objective measures of apathy, disinhibition, and executive dysfunction. Specifically, we studied whether ACC, OFC, and DLPFC activation during a modified version of the Multi-Source Interference Task (MSIT), is associated with FrSBe apathy, disinhibition, and executive dysfunction scores, in healthy controls (HC) and individuals with Bipolar Disorder (BD), who commonly exhibit difficulties in these domains. Individuals with BD (n = 31) and HCs (n = 31) with no current or past psychiatric illness completed the FrSBe and the MSIT during fMRI scanning. We investigated task-specific changes in the ACC, DLPFC, and OFC and their correlations with FrSBe apathy, disinhibition, and executive dysfunction subscale scores, respectively. Individuals with BD and the HC group demonstrated greater ACC, DLPFC, and OFC activation during MSIT interference conditions compared with non-interference conditions. Furthermore, there was a significant negative correlation between OFC activation and disinhibition scores, which remained significant after accounting for medication load. Together, these results demonstrate the FrSBe disinhibition subscale, in particular, can be a self-report measure that converges with behavioral and neural markers of disinhibition in BD.

Dimensional Affective Processing in BD.

Bipolar Disorder (BD) involves altered neural affective processing, but studies comparing BD patients to controls have yielded inconsistent results. This might relate to substantial variability in the nature and severity of mood symptoms among individuals with BD. Hence, we dimensionally examined the relationship between depressive and manic symptom severity and neural responses to positive and negative affective stimuli. 39 Participants with BD completed measures of depression and mania severity prior to completing a cognitive-affective processing task during fMRI. A multiple regression model was run in SPM to identify brain regions correlated with depressive and manic symptoms during positive-neutral and negative-neutral contrasts. A-priori anatomical ROIs were defined bilaterally in frontal, parietal and limbic regions. Results showed that depression severity was associated with increased activation in frontal, parietal, and limbic ROIs, regardless of valence. Mania severity was correlated with both increased and decreased activation, particularly within frontal subdivisions and during the processing of positively valenced images. In conclusion, dimensional modeling of symptom severity captures variance in neural responses to affect, which may have been previously undetected due to heterogeneity when examined at the group level. Future fMRI studies comparing BD patients and controls should account for symptom variability in BD.

Neural basis of associative learning in Trichotillomania and skin-picking disorder.

Disorders such as Trichotillomania (TTM) and skin-picking disorder (SPD) are associated with reduced flexibility and increased internally focused attention. While the basal ganglia have been hypothesized to play a key role, the mechanisms underlying learning and flexible accommodation of new information is unclear. Using a Bayesian Learning Model, we evaluated the neural basis of learning and accommodation in individuals with TTM and/or SPD. Participants were 127 individuals with TTM and/or SPD (TTM/SPD) recruited from three sites (age 18-57, 84% female) and 26 healthy controls (HC). During fMRI, participants completed a shape-button associative learning and reversal fMRI task. Above-threshold clusters were identified where the Initial Learning-Reversals BOLD activation contrast differed significantly (p < .05 FDR-corrected) between the two groups. A priori, effects were anticipated in predefined ROIs in bilateral basal ganglia, with exploratory analyses in the hippocampus, dorsolateral prefrontal cortex (dlPFC), and dorsal anterior cingulate cortex (dACC). Relative to HC, individuals with TTM/SPD demonstrated reduced activation during initial learning compared to reversal learning in the right basal ganglia. Similarly, individuals with TTM/SPD demonstrated reduced activation during initial learning compared to reversal learning in several clusters in the dlPFC and dACC compared to HC. Individuals with TTM/SPD may form or reform visual stimulus-motor response associations through different brain mechanisms than healthy controls. The former exhibit altered activation within the basal ganglia, dlPFC, and dACC during an associative learning task compared to controls, reflecting reduced frontal-subcortical activation during initial learning. Future work should determine whether these neural deficits may be restored with targeted treatment.

Analysis of human meiotic recombination events with a parent-sibling tracing approach.

BACKGROUND: Meiotic recombination ensures that each child inherits distinct genetic materials from each parent, but the distribution of crossovers along meiotic chromosomes remains difficult to identify. In this study, we developed a parent-sibling tracing (PST) approach from previously reported methods to identify meiotic crossover sites of GEO GSE6754 data set. This approach requires only the single nucleotide polymorphism (SNP) data of the pedigrees of both parents and at least two of children. RESULTS: Compared to other SNP-based algorithms (identity by descent or pediSNP), fewer uninformative SNPs were derived with the use of PST. Analysis of a GEO GSE6754 data set containing 2,145 maternal and paternal meiotic events revealed that the pattern and distribution of paternal and maternal recombination sites vary along the chromosomes. Lower crossover rates near the centromeres were more prominent in males than in females. Based on analysis of repetitive sequences, we also showed that recombination hotspots are positively correlated with SINE/MIR repetitive elements and negatively correlated with LINE/L1 elements. The number of meiotic recombination events was positively correlated with the number of shorter tandem repeat sequences. CONCLUSIONS: The advantages of the PST approach include the ability to use only two-generation pedigrees with two siblings and the ability to perform gender-specific analyses of repetitive elements and tandem repeat sequences while including fewer uninformative SNP regions in the results.

Targeted proteomics using selected reaction monitoring reveals the induction of specific terpene synthases in a multi-level study of methyl jasmonate-treated Norway spruce (Picea abies).

Induction of terpene synthase (TPS) gene expression and enzyme activity is known to occur in response to various chemical and biological stimuli in several species of spruce (genus Picea). However, high sequence identity between TPS family members has made it difficult to determine the induction patterns of individual TPS at the protein and transcript levels and whether specific TPS enzymes respond differentially to treatment. In the present study we used a multi-level approach to measure the induction and activity of TPS enzymes in protein extracts of Norway spruce (Picea abies) bark tissue following treatment with methyl jasmonate (MeJA). Measurements were made on the transcript, protein, enzyme activity and metabolite levels. Using a relatively new proteomics application, selective reaction monitoring (SRM), it was possible to differentiate and quantitatively measure the abundance of several known TPS proteins and three 1-deoxy-D-xylulose 5-phosphate synthase (DXS) isoforms in Norway spruce. Protein levels of individual TPS and DXS enzymes were differentially induced upon MeJA treatment and good correlation was generally observed between induction of transcripts, proteins, and enzyme activities. Most of the mono- and diterpenoid metabolites accumulated with similar temporal patterns of induction as part of the coordinated multi-compound chemical defense response. Protein and enzyme activity levels of the monoTPS (+)-3-carene synthase and the corresponding accumulation of (+)-3-carene was induced to a higher fold change than any other TPS or metabolite measured, indicating an important role in the induced terpenoid defense response in Norway spruce.