APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Alterations in patients with major depressive disorder before and after electroconvulsive therapy measured by fractional amplitude of low-frequency fluctuations (fALFF).

BACKGROUND: Electroconvulsive therapy (ECT) is an important treatment option for patients with major depressive disorder (MDD). However, the mechanisms of ECT in MDD are still unclear. METHODS: Twenty-four patients with severe MDD and 14 healthy controls were enrolled in this study. Eight ECT sessions were conducted for MDD patients using brief-pulse square-wave signal at bitemporal locations. To investigate the regional cerebral blood flow in MDD patients before and after ECT treatments by resting-state functional magnetic resonance imaging (rs-fMRI), the patients were scanned twice (before the first ECT and after the eighth ECT) for data acquisition. Afterward, we adopted fractional amplitude of low-frequency fluctuations (fALFF) to assess the alterations of regional brain activity. RESULTS: Compared with healthy controls, the fALFF in the cerebellum lobe, parahippocampal gyrus, fusiform gyrus, anterior cingulate gyrus, and thalamus in MDD patients before ECT (pre-ECT) was significantly increased. In another comparison, the fALFF in the cerebellum anterior lobe, fusiform gyrus, insula, parahippocampal gyrus, middle frontal gyrus, and inferior frontal gyrus in pre-ECT patients was significantly greater than the post-ECT fALFF. LIMITATIONS: Only two rs-fMRI scans were conducted at predefined times: before the first and after the eighth ECT treatment. More scans during the ECT sessions would yield more information. In addition, the sample size in this study was limited. The number of control subjects was relatively small. A larger number of subjects would produce more robust findings. CONCLUSIONS: The fALFF of both healthy controls and post-ECT patients in cerebellum anterior lobe, fusiform gyrus, and parahippocampal gyrus is significantly lower than the fALFF of pre-ECT patients. This finding demonstrates that ECT treatment is effective on these brain areas in MDD patients.

Non-infantile variant of desmoplastic ganglioglioma: Conventional and advanced MR imaging characteristics.

Desmoplastic infantile ganglioglioma is a paediatric brain tumor that is commonly seen in the infantile age group. Literature on the non-infantile variant of this low-grade supratentorial neoplasm is very scarce, except for a few case reports. Herein, we report a case of desmoplastic non-infantile ganglioglioma occurring at the age of 6 years and describe its conventional and advanced magnetic resonance imaging characteristics.

Seeing scenes: topographic visual hallucinations evoked by direct electrical stimulation of the parahippocampal place area.

In recent years, functional neuroimaging has disclosed a network of cortical areas in the basal temporal lobe that selectively respond to visual scenes, including the parahippocampal place area (PPA). Beyond the observation that lesions involving the PPA cause topographic disorientation, there is little causal evidence linking neural activity in that area to the perception of places. Here, we combined functional magnetic resonance imaging (fMRI) and intracranial EEG (iEEG) recordings to delineate place-selective cortex in a patient implanted with stereo-EEG electrodes for presurgical evaluation of drug-resistant epilepsy. Bipolar direct electrical stimulation of a cortical area in the collateral sulcus and medial fusiform gyrus, which was place-selective according to both fMRI and iEEG, induced a topographic visual hallucination: the patient described seeing indoor and outdoor scenes that included views of the neighborhood he lives in. By contrast, stimulating the more lateral aspect of the basal temporal lobe caused distortion of the patient's perception of faces, as recently reported (Parvizi et al., 2012). Our results support the causal role of the PPA in the perception of visual scenes, demonstrate that electrical stimulation of higher order visual areas can induce complex hallucinations, and also reaffirm direct electrical brain stimulation as a tool to assess the function of the human cerebral cortex.

Cerebral blood flow-based evidence for mechanisms of low- versus high-frequency transcutaneous electric acupoint stimulation analgesia: a perfusion fMRI study in humans.

Brain activities in response to acupuncture have been investigated in multiple studies; however, the neuromechanisms of low- and high-frequency transcutaneous electric acupoint stimulation (TEAS) analgesia are unclear. This work aimed to investigate how brain activity and the analgesic effect changed across 30-min low- versus high-frequency TEAS. Forty-six subjects received a 30-min 2, 100-Hz TEAS or mock TEAS (MTEAS) treatment on both behavior test and functional magnetic resonance imaging (fMRI) scan days. On the behavior test day, the pain thresholds and pain-related negative emotional feeling ratings were tested five times - at 4.5min before treatment, at 10, 20, and 30min during treatment and 4.5min after the treatment. On the fMRI scan day, to match the time-points in the behavioral testing session, the cerebral blood flow (CBF) signals were collected and incorporated with five independent runs before, during and after the treatment, each lasting 4.5min. The analgesic effect was observed in both the TEAS groups; the analgesic affect was not found in the MTEAS group. The effect started at 20min during the treatment and was maintained until the after-treatment states. In both TEAS groups, the regional CBF revealed a trend of early activation with later inhibition; also, a positive correlation between analgesia and the regional CBF change was observed in the anterior insula in the early stage, whereas a negative relationship was found in the parahippocampal gyrus in the later stage. The TEAS analgesia was specifically associated with the default mode network and other cortical regions in the 2-Hz TEAS group, ventral striatum and dorsal anterior cingulate cortex in the 100-Hz TEAS group, respectively. These findings suggest that the mechanisms of low- and high-frequency TEAS analgesia are distinct and partially overlapped, and they verify the treatment time as a notable factor for acupuncture studies.

Increased involvement of the parahippocampal gyri in a sad mood predicts future depressive symptoms.

Behavioral studies suggest a relationship between autobiographical memory, rumination and depression. The objective of this study was to determine whether remitted depressed patients show alterations in connectivity of the posterior cingulate cortex (PCC, a node in the default mode network) with the parahippocampal gyri (PHG, a region associated with autobiographical memory) while intensively recalling negative memories and whether this is related to daily life symptoms and to the further course of depression. Sad mood was induced with keywords of personal negative life events in participants with remitted depression (n = 29) and matched healthy controls (n = 29) during functional magnetic resonance imaging. Additionally, daily life assessments of mood and rumination and a 6-month follow-up were conducted. Remitted depressed participants showed greater connectivity than healthy controls of the PCC with the PHG, which was even stronger in patients with more previous episodes. Furthermore, patients with increased PCC-PHG connectivity showed a sadder mood and more rumination in daily life and a worsening of rumination and depression scores during follow-up. A relationship of negative autobiographical memory processing, rumination, sad mood and depression on a neural level seems likely. The identified increased connectivity probably indicates a 'scar' of recurrent depression and may represent a prognostic factor for future depression.

Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.

The effect of attention on repetition suppression and multivoxel pattern similarity.

Fundamental to our understanding of learning is the role of attention. We investigated how attention affects two fMRI measures of stimulus-specific memory: repetition suppression (RS) and pattern similarity (PS). RS refers to the decreased fMRI signal when a stimulus is repeated, and it is sensitive to manipulations of attention and task demands. In PS, region-wide voxel-level patterns of responses are evaluated for their similarity across repeated presentations of a stimulus. More similarity across presentations is related to better learning, but the role of attention on PS is not known. Here, we directly compared these measures during the visual repetition of scenes while manipulating attention. Consistent with previous findings, we observed RS in the scene-sensitive parahippocampal place area only when a scene was attended both at initial presentation and upon repetition in subsequent trials, indicating that attention is important for RS. Likewise, we observed greater PS in response to repeated pairs of scenes when both instances of the scene were attended than when either or both were ignored. However, RS and PS did not correlate on either a scene-by-scene or subject-by-subject basis, and PS measures revealed above-chance similarity even when stimuli were ignored. Thus, attention has different effects on RS and PS measures of perceptual repetition.

Selective role of lingual/parahippocampal gyrus and retrosplenial complex in spatial memory across viewpoint changes relative to the environmental reference frame.

Remembering object locations across different views is a fundamental competence for keeping oriented in large-scale space. Here we investigated such ability by comparing encoding and retrieval of locations across viewpoint changes relative to different spatial frames of reference. We acquired functional magnetic resonance images while subjects detected target displacements across consecutive views of a familiar virtual room, reporting changes in the target absolute position in the room (stable environmental frame), changes in its position relative to a set of movable objects (unstable object-based frame), and changes relative to their point of view (control viewer-centered frame). Behavioral costs were higher for the stable environmental frame, and a cortical network including the lingual/parahippocampal gyrus (LPHG) and the retrosplenial complex (RSC) selectively encoded spatial locations relative to this frame. Several regions, including the dorsal fronto-parietal cortex and the LPHG, were modulated by the amount of experienced viewpoint change, but only the RSC was selectively modulated by the amount of viewpoint change relative to the environmental frame, thus showing a special role in coding one's own position and heading in familiar environments.

Simultaneous CBF and BOLD mapping of high frequency acupuncture induced brain activity.

This study mapped brain activity elicited by high frequency electroacupuncture by simultaneously using blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) contrasts. Forty subjects participated in the study, in which twenty ones were imaged during electrical acupoint stimulation (EAS) to the left LI4 acupoint at a maximal intensity without pain, and the others were with a minimal-EAS at a just detectible intensity. Both BOLD and CBF data were acquired simultaneously during alternating blocks of rest and stimulation. The results showed that the minimal-EAS mostly induced the activities in somatosensory region, including those in inferior parietal lobule, SII, insula, and thalamus. On the other hand, EAS activated more including also posterior middle cingulate cortex (pMCC), and deactivated superior temporal gyrus. Moreover, deactivation was found in posterior cingulated cortex (PCC), precuneus from BOLD and in culmen of cerebellum, caudate from CBF. The comparison between EAS and minimal-EAS revealed deactivation in the default mode network in both BOLD and CBF signals, activation in thalamus, insula, and caudal anterior cingulate cortex (ACC) in the CBF signal alone, and deactivation in putamen, rostral ACC and parahippocampal gyrus in the BOLD signal alone. This study provides, for the first time, simultaneous CBF and BOLD responses to high frequency EAS at the LI4 acupoint, revealing concordant and complementary insights into the neural effects of EAS, including modulation of subcortical structures and limbic system.

Regional cerebral blood flow differences in patients with mild cognitive impairment between those who did and did not develop Alzheimer's disease.

Mild cognitive impairment (MCI) is a heterogeneous condition associated with increased risk of Alzheimer's disease (AD) and other dementias. This study aimed to identify areas of initial hypoperfusion in MCI conversion to AD using technetium (Tc-99m) hexamethylpropyleneamine oxime (TC-99m HMPAO) single photon emission computed tomography (SPECT) to compare baseline cerebral hypoperfusion in converted MCI and non-converted MCI patients and normal controls. Forty-nine MCI patients were recruited for brain magnetic resonance imaging (MRI), detailed neuropsychological testing, Tc-99m HMPAO SPECT, and 1- to 2-year periodic follow-up to monitor progression to dementia status. We processed SPECT images with Statistical Parametric Mapping 8 (SPM8) software and performed voxel-based statistical parametric mapping analysis. Thirty-nine of 49 MCI patients were included in our analysis. Nine patients were diagnosed with conversion to AD, on average 19.0±6.6 months after initial assessment. Compared with normal controls, converted MCI patients demonstrated perfusion deficits in both parahippocampal gyri and right precuneus, and non-converted MCI patients demonstrated hypoperfusion in the left parahippocampal gyrus. Compared with non-converted MCI patients, converted MCI patients demonstrated significant hypoperfusion in both cingulate gyri and right precuneus. Our study suggests that using brain SPECT to identify initial hypoperfusion in patients with MCI may be helpful for predicting MCI patients likely to develop AD.

Exploring the parahippocampal cortex response to high and low spatial frequency spaces.

The posterior parahippocampal cortex (PHC) supports a range of cognitive functions, in particular scene processing. However, it has recently been suggested that PHC engagement during functional MRI simply reflects the representation of three-dimensional local space. If so, PHC should respond to space in the absence of scenes, geometric layout, objects or contextual associations. It has also been reported that PHC activation may be influenced by low-level visual properties of stimuli such as spatial frequency. Here, we tested whether PHC was responsive to the mere sense of space in highly simplified stimuli, and whether this was affected by their spatial frequency distribution. Participants were scanned using functional MRI while viewing depictions of simple three-dimensional space, and matched control stimuli that did not depict a space. Half the stimuli were low-pass filtered to ascertain the impact of spatial frequency. We observed a significant interaction between space and spatial frequency in bilateral PHC. Specifically, stimuli depicting space (more than nonspatial stimuli) engaged the right PHC when they featured high spatial frequencies. In contrast, the interaction in the left PHC did not show a preferential response to space. We conclude that a simple depiction of three-dimensional space that is devoid of objects, scene layouts or contextual associations is sufficient to robustly engage the right PHC, at least when high spatial frequencies are present. We suggest that coding for the presence of space may be a core function of PHC, and could explain its engagement in a range of tasks, including scene processing, where space is always present.

Category-selective background connectivity in ventral visual cortex.

Ventral visual cortex contains specialized regions for particular object categories, but little is known about how these regions interact during object recognition. Here we examine how the face-selective fusiform gyrus (FG) and the scene-selective parahippocampal cortex (PHC) interact with each other and with the rest of the brain during different visual tasks. To assess these interactions, we developed a novel approach for identifying patterns of connectivity associated with specific task sets, independent of stimulus-evoked responses. We tested whether this "background connectivity" between the FG and PHC was modulated when subjects engaged in face and scene processing tasks. In contrast to what would be predicted from biased competition or intrinsic activity accounts, we found that the strength of FG-PHC background connectivity depended on which category was task relevant: connectivity increased when subjects attended to scenes (irrespective of whether a competing face was present) and decreased when subjects attended to faces (irrespective of competing scenes). We further discovered that posterior occipital cortex was correlated selectively with the FG during face tasks and the PHC during scene tasks. These results suggest that category specificity exists not only in which regions respond most strongly but also in how these and other regions interact.

Double dissociation between hippocampal and parahippocampal responses to object-background context and scene novelty.

Several recent models of medial temporal lobe (MTL) function have proposed that the parahippocampal cortex processes context information, the perirhinal cortex processes item information, and the hippocampus binds together items and contexts. While evidence for a clear functional distinction between the perirhinal cortex and other regions within the MTL has been well supported, it has been less clear whether such a dissociation exists between the hippocampus and parahippocampal cortex. In the current study, we use a novel approach applying a functional magnetic resonance imaging adaptation paradigm to address these issues. During scanning, human subjects performed an incidental target detection task while viewing trial-unique sequentially presented pairs of natural scenes, each containing a single prominent object. We observed a striking double dissociation between the hippocampus and parahippocampal cortex, with the former showing a selective sensitivity to changes in the spatial relationship between objects and their background context and the latter engaged only by scene novelty. Our findings provide compelling support for the hypothesis that rapid item-context binding is a function of the hippocampus, rather than the parahippocampal cortex, with the former acting to detect relational novelty of this nature through its function as a match-mismatch detector.

Shared neural activity in panic disorder and undifferentiated somatoform disorder compared with healthy controls.

OBJECTIVE: In previous studies, some brain areas, including parahippocampal gyrus, were suggested to be associated with panic disorder. Both panic disorder and somatoform disorders are associated with anxiety. This study sought to determine if there are shared neural activity underlying panic disorder and undifferentiated somatoform disorder. METHOD: Sixteen nonmedicated patients with panic disorder, 16 nonmedicated patients with undifferentiated somatoform disorder, and 10 healthy subjects were scanned between February 2005 and August 2006. Diagnoses were made according to the Korean version of the Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient/Non-Patient Edition. Regional cerebral perfusion was measured by 99 m-Tc-ethyl cysteinate dimer single photon emission computed tomography (SPECT). Using statistical parametric mapping analysis, we compared the SPECT images between the groups. RESULTS: Significant hyperperfusion was found at the left superior temporal gyrus and the left supramarginal gyrus in the panic disorder patients when compared to the controls (family-wise error [FWE], P < .001). The somatoform disorder patients showed hyperperfusion in the left hemisphere at the superior temporal gyrus, inferior parietal lobule, middle occipital gyrus, precentral gyrus, postcentral gyrus, and, in the right hemisphere, at the superior temporal gyrus when compared to the controls (false discovery rate [FDR], P < .001). In contrast, significant hypoperfusion was found at the right parahippocampal gyrus in each of panic disorder (FWE, P = .001) and somatoform disorder (FWE, P < .001) groups compared to healthy controls. However, no significant differences were found in regional cerebral perfusion between the 2 disorder groups. CONCLUSIONS: Both panic disorder and undifferentiated somatoform disorder showed hyperperfusion in the left superior temporal gyrus and hypoperfusion in the right parahippocampal gyrus, which suggests that the 2 disorders are likely to share neural activity.

Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia.

OBJECTIVE: Activation in a network of language-related regions has been reported during auditory verbal hallucinations. It remains unclear, however, how this activation is triggered. Identifying brain regions that show significant signal changes preceding auditory hallucinations might reveal the origin of these hallucinations. METHOD: Twenty-four patients with a psychotic disorder indicated the presence of auditory verbal hallucinations during 3-Tesla functional magnetic resonance imaging by squeezing a handheld balloon. A one-sample t test was performed to reveal groupwise activation during hallucinations. To enable analysis of brain activation 6 to 0 seconds preceding hallucinations, a tailored 'selective averaging' method, without any a priori assumptions concerning the hemodynamic response profile, was performed. To control for motor-related activation, 15 healthy comparison subjects squeezed a balloon at matched time intervals. RESULTS: Groupwise analysis during auditory verbal hallucinations revealed brain activation in bilateral (right more than left) language-related regions and bilateral motor regions. Prominent deactivation preceding these hallucinations was observed in the left parahippocampal gyrus. In addition, significant deactivation preceding hallucinations was found in the left superior temporal, right inferior frontal, and left middle frontal gyri as well as in the right insula and left cerebellum. No significant signal changes were revealed prior to the matched balloon squeezing among the comparison subjects. CONCLUSION: Auditory verbal hallucinations in patients with a psychotic disorder are consistently preceded by deactivation of the parahippocampal gyrus. The parahippocampus has been hypothesized to play a central role in memory recollection, sending information from the hippocampus to the association areas. Dysfunction of this region could trigger inadequate activation of right language areas during auditory hallucinations.

The selective amygdalohippocampectomy for intractable temporal limbic seizures.

OBJECT: The proximal (anterior) transsylvian approach through a pterional craniotomy was developed by the senior author (M.G.Y.) in 1967 for the microsurgical treatment of saccular aneurysms of the circle of Willis, frontoorbital and temporobasal arteriovenous malformations, cavernomas, and extrinsic and intrinsic tumors. The acquired positive surgical experiences on this large series enabled the senior author, in 1973, to apply this approach for the selective amygdalohippocampectomy in patients with intractable mesial temporal lobe epilepsy. METHODS: The proximal (anterior) transsylvian-transamygdala approach to the mesial temporal structures permits the selective two-thirds resection of the amygdala and hippocampus-parahippocampus in an anteroinferior to posteroinferior exploration axis along the base of the semicircular temporal horn. This strategy ensures preservation of the overlying neopallial temporal convolutions such as the T1, T2, T3, and T4 gyri as well as the related subcortical connective fiber systems and other essential components of the temporal white matter. The application of rigid brain self-retaining retractor systems was strictly avoided during the entire procedure. Computer-assisted navigation was never used. On routine postoperative CT scanning and MR imaging studies, infarction was not observed in any patient. The availability of tractography technology has proven that the connective fiber system around the resected mesial temporal area remains intact. RESULTS: The surgical outcome and results on neoplastic and vascular lesions of the mesiobasal temporal region have been presented in Volumes II, IIIB, and IVB of Microneurosurgery. The surgical outcomes and results in 102 patients with mesial temporal seizures who underwent surgery performed by the senior author in Zürich have been previously published. In this paper, 73 patients who underwent surgery between 1994 and September 2006 in Little Rock, Arkansas, are presented, and 13 other patients are excluded who underwent surgery after September 2006. Altogether, among 188 patients who underwent surgery, there was no surgical mortality or morbidity, and no neurological deficits, new neurocognitive dysfunction, or impairments of the preoperative incapacities. CONCLUSIONS: The surgical outcome in terms of seizures was rewarding in the majority of patients, particularly in those who exhibited the following irregularities on preoperative investigations: regular local dysfunctions on electroencephalography, dysmorphic changes in the mesiobasal temporal parenchyma on MR imaging studies, and hypometabolism in the anterior third of the temporal lobe on PET studies.

Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder.

Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18-56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG-sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG-sgCG signaling in BD than HC. There was no between-group difference in sgCG-DLPFC effective connectivity. In BD, abnormally increased right PHG-sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD.

Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake phobia.

The objective was to study effects of fear on brain activity, functional connectivity and brain-behavior relationships during symptom provocation in subjects with specific phobia. Positron emission tomography (PET) and (15)O water was used to measure regional cerebral blood flow (rCBF) in 16 women phobic of either snakes or spiders but not both. Subjects watched pictures of snakes and spiders serving either as phobic or fear-relevant, but non-phobic, control stimuli depending on phobia type. Presentation of phobic as compared with non-phobic cues was associated with increased activation of the right amygdala and cerebellum as well as the left visual cortex and circumscribed frontal areas. Activity decreased in the prefrontal, orbitofrontal and ventromedial cortices as well as in the primary somatosensory cortex and auditory cortices. Furthermore, amygdala activation correlated positively with the subjective experience of distress. Connectivity analyses of activity in the phobic state revealed increased functional couplings between voxels in the right amygdala and the periamygdaloid area, fusiform gyrus and motor cortex. During non-phobic stimulation, prefrontal activity correlated negatively with amygdala rCBF, suggesting a phobia-related functional decoupling. These results suggest that visually elicited phobic reactions activate object recognition areas and deactivate prefrontal areas involved in cognitive control over emotion-triggering areas like the amygdala, resulting in motor readiness to support fight or flight.