BA46 (97-106)

Background: Disturbances in the processing and regulation of emotions are core symptoms of borderline personality disorder (BPD). To further elucidate neural underpinnings of BPD, the present meta-analysis summarizes functional neuroimaging findings of emotion processing tasks, as well as structural neuroimaging findings, and investigates multimodally affected brain regions. Methods: Combined coordinate- and image-based meta-analyses were calculated using anisotropic effect size signed differential mapping. Nineteen functional neuroimaging studies investigating the processing of negative compared with neutral stimuli in a total of 281 patients with BPD and 293 healthy control subjects (HC) were included. In addition, 10 studies investigating gray matter abnormalities in 263 patients with BPD and 278 HC were analyzed. Results: Compared with HC, BPD patients showed relatively increased activation of the left amygdala and posterior cingulate cortex, along with blunted responses of the bilateral dorsolateral prefrontal cortex, during the processing of negative emotional stimuli. The multimodal analysis identified the left amygdala to be characterized by a combination of functional hyperactivity and smaller gray matter volume compared with HC. Hyperresponsivity of the amygdala was moderated by medication status of the patient samples. Medication-free samples were characterized by limbic hyperactivity, whereas no such group differences were found in patients currently taking psychotropic medication. Conclusions: Results strengthen the assumption that dysfunctional dorsolateral prefrontal and limbic brain regions are a hallmark feature of BPD and therefore are consistent with the conceptualization of BPD as an emotion dysregulation disorder.

Rationale: Metabotropic glutamate type 5 receptor (mGluR5) antagonists are under development for treating cognitive disorders such as Fragile X syndrome and Alzheimer's disease, largely based on success in mouse models, where post-synaptic mGluR5 stimulation weakens synaptic functions in hippocampus. However, human trials of mGluR5 antagonists have yet to be successful. This may be due in part to the differing effects of mGluR5 in hippocampus vs. prefrontal cortex, as mGluR5 are primarily post-synaptic in rodent hippocampus, but are both pre- and post-synaptic in the dorsolateral prefrontal cortical (dlPFC) circuits known to subserve working memory. Objectives and methods: The current study examined the effects of the selective mGluR5 negative allosteric modulator, MTEP (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride), on neuronal firing and working memory performance in aging rhesus monkeys with naturally occurring impairments in neuronal firing and cognitive performance. Results: We found that iontophoresis of MTEP directly onto dlPFC "Delay cells" had an inverted U dose-response, where low doses tended to enhance task-related firing, but higher doses suppressed neuronal firing. Similar effects were seen on cognitive performance following systemic MTEP administration (0.0001-0.1 mg/kg), with MTEP producing erratic dose-response curves. In the subset of monkeys (50%) that showed replicable improvement with MTEP, co-administration with the mGluR5 PAM, CDPPB (3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), blocked MTEP beneficial effects, consistent with mGluR5 actions. Conclusions: The mixed effects of MTEP on cognitive performance may arise from opposing actions at pre- vs. post-synaptic mGluR5 in dlPFC. These data from monkeys suggest that future clinical trials should include low doses, and identification of potential subgroup responders.

Objectives: Periods of euthymia in bipolar disorder (BD) serve as a valuable time to study trait-based pathophysiology. The use of resting state functional connectivity (Rs-FC) can aid in the understanding of BD pathophysiology free of task or mood state biases. The present study investigated two unexplored areas of Rs-FC research in bipolar remission: (i) Rs-FC in women, controlling for the potential influence of premenstrual symptoms, and (ii) the use of both independent component analysis (ICA) and seed-based analysis (SBA) to investigate Rs-FC. Methods: We investigated Rs-FC of the default mode network, meso-paralimbic network and fronto-parietal network in a sample of 32 euthymic women with BD and 36 age-matched controls during the mid-follicular phase of their menstrual cycle. Rs-FC was assessed with ICA and SBA using the posterior cingulate cortex (PCC), amygdala and dorsolateral prefrontal cortex (dlPFC) as seed points for their respective resting state networks. Results: In BD, compared to controls, SBAs revealed increased coupling between the PCC and the angular gyrus (P=.002, false discovery rate [FDR]-corrected) and between the right dlPFC and the brainstem (P=.03, FDR-corrected). In BD only, PCC-angular gyrus coupling was correlated with anxiety symptoms. Group differences in Rs-FC using ICA did not survive multiple comparisons. Conclusions: Negative findings from whole-brain ICA Rs-FC may reflect a state of clinical remission in BD. Heightened activation between the PCC and the angular gyrus and between the dlPFC and the brainstem may reflect (i) an abnormal trait integration of affective information during clinical remission and/or (ii) an adaptive compensatory mechanism required for clinical stabilization.