Prevent breaking bad: A proof of concept study of rebalancing the brain's rumination circuit with real‐time fMRI functional connectivity neurofeedback

Rumination, repetitively thinking about the causes, consequences, and one''s negative affect, has been considered as an important factor of depression. The intrusion of ruminative thoughts is not easily controlled, and it may be useful to visualize one''s neural activity related to rumination and to use that information to facilitate one''s self‐control. Real‐time fMRI neurofeedback (rtfMRI‐nf) enables one to see and regulate the fMRI signal from their own brain. This proof‐of concept study utilized connectivity‐based rtfMRI‐nf (cnf) to normalize brain functional connectivity (FC) associated with rumination. Healthy participants were instructed to brake or decrease FC between the precuneus and the right temporoparietal junction (rTPJ), associated with high levels of rumination, while engaging in a self‐referential task. The cnf group (n = 14) showed a linear decrease in the precuneus‐rTPJ FC across neurofeedback training (trend [112] = −0.180, 95% confidence interval [CI] −0.330 to −0.031, while the sham group (n = 14) showed a linear increase in the target FC (trend [112] = 0.151, 95% CI 0.017 to 0.299). Although the cnf group showed a greater reduction in state‐rumination compared to the sham group after neurofeedback training (p < .05), decoupled precuneus‐rTPJ FC did not predict attenuated state‐rumination. We did not find any significant aversive effects of rtfMRI‐nf in all study participants. These results suggest that cnf has the capacity to influence FC among precuneus and rTPJ of a ruminative brain circuit. This approach can be applied to mood and anxiety patients to determine the clinical benefits of reduction in maladaptive rumination.     

Comparison of two different analysis approaches for DTI free‐water corrected and uncorrected maps in the study of white matter microstructural integrity in individuals with depression

Diffusion tensor imaging (DTI) has often been used to examine white matter (WM) tract abnormalities in depressed subjects, but these studies have yielded inconsistent results, probably, due to gender composition or small sample size. In this study, we applied different analysis pipelines to a relatively large sample of individuals with depression to determine whether previous findings in depression can be replicated with these pipelines. We used a “standard” DTI algorithm and maps computed through a free‐water (FW) corrected DTI. This latter algorithm is able to identify and separate the effects of extracellular FW on DTI metrics. Additionally, skeletonized and WM voxel‐based analysis (VBA) methods were used. Using the skeletonized method, DTI maps showed lower fractional anisotropy (FA) in depressed subjects in the left brain hemisphere, including the anterior thalamic radiation (ATR L), cortical spinal tract (CST L), inferior fronto‐occipital fasciculus, inferior longitudinal fasciculus, and superior longitudinal fasciculus (SLF L). Differences in radial diffusivity (RD) were also found. For the VBA using RD, we found different results when we used FW uncorrected and corrected DTI metrics. Relative to the VBA approach, the skeletonized analysis was able to identify more clusters where WM integrity was altered in depressed individuals. Different significant correlations were found between RD and the Patient Health Questionnaire in the CST L, and SLF L. In conclusion, the skeletonized method revealed more clusters than the VBA and individuals with depression showed multiple WM abnormalities, some of which were correlated with disease severity Hum Brain Mapp 38:4690–4702, 2017. © 2017 Wiley Periodicals, Inc.     

Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma

Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p?=?0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies.     

Current intensity‐ and polarity‐specific online and aftereffects of transcranial direct current stimulation: An fMRI study

Transcranial direct current stimulation (tDCS) induces polarity‐ and dose‐dependent neuroplastic aftereffects on cortical excitability and cortical activity, as demonstrated by transcranial magnetic stimulation (TMS) and functional imaging (fMRI) studies. However, lacking systematic comparative studies between stimulation‐induced changes in cortical excitability obtained from TMS, and cortical neurovascular activity obtained from fMRI, prevent the extrapolation of respective physiological and mechanistic bases. We investigated polarity‐ and intensity‐dependent effects of tDCS on cerebral blood flow (CBF) using resting‐state arterial spin labeling (ASL‐MRI), and compared the respective changes to TMS‐induced cortical excitability (amplitudes of motor evoked potentials, MEP) in separate sessions within the same subjects (n = 29). Fifteen minutes of sham, 0.5, 1.0, 1.5, and 2.0‐mA anodal or cathodal tDCS was applied over the left primary motor cortex (M1) in a randomized repeated‐measure design. Time‐course changes were measured before, during and intermittently up to 120‐min after stimulation. ROI analyses indicated linear intensity‐ and polarity‐dependent tDCS after‐effects: all anodal‐M1 intensities increased CBF under the M1 electrode, with 2.0‐mA increasing CBF the greatest (15.3%) compared to sham, while all cathodal‐M1 intensities decreased left M1 CBF from baseline, with 2.0‐mA decreasing the greatest (?9.3%) from sham after 120‐min. The spatial distribution of perfusion changes correlated with the predicted electric field, as simulated with finite element modeling. Moreover, tDCS‐induced excitability changes correlated more strongly with perfusion changes in the left sensorimotor region compared to the targeted hand‐knob region. Our findings reveal lasting tDCS‐induced alterations in cerebral perfusion, which are dose‐dependent with tDCS parameters, but only partially account for excitability changes.     

Immunohistochemical demonstration of mitochondria in routinely processed tissue using a monoclonal antibody

We report results obtained using the monoclonal antibody M-II 68, which recognizes inner mitochondrial membrane in routinely processed (formalin-fixed and paraffin-embedded) tissue by light microscopic immunohistochemistry. In ten normal brains, the range of immunoreactivity in various cell types and locations was defined. The most intense staining was observed in Purkinje cells, in neurons of cranial nerve nuclei, pons and substantia nigra, as well as in choroid plexus epithelial cells. By comparison with this control group, one case of primary mitochondrial encephalomyopathy exhibited increased staining of endothelial and vascular smooth muscle cells, choroid plexus epithelial cells, and neurons of various locations. Scattered ragged-red fibres were heavily labelled in one case of mitochondrial myopathy, while ten muscles without mitochondriopathy were left unstained. Our method is able to detect accumulations of mitochondria and increases in mitochondrial cristae density. It could prove useful for differential diagnosis of routine biopsy material and for clarification of cell types involved in mitochondrial cytopathies.     

Regional modulation of BOLD MRI responses to human sensorimotor activation by transcranial direct current stimulation.

Blood oxygenation level dependent (BOLD) MRI was used to monitor modulations of human sensorimotor activity by prior transcranial direct current stimulation (tDCS). Activation maps for a right hand sequential finger opposition task were obtained for six subjects before as well as 0-5 min and 15-20 min after a 5-min period of 1 mA cathodal and, in a separate session, anodal tDCS of the left-hemispheric motor cortex. Cathodal tDCS resulted in a global decrease of the mean number of activated pixels by 38% (P < 0.01) 0-5 min after stimulation, which reduced to 28% (P < 0.05) 15-20 min after stimulation. A region-of-interest analysis revealed a 57% decrease of activated pixels (P < 0.001) in the supplementary motor area, but no change in the hand area of the primary motor cortex. Anodal tDCS yielded a nonsignificant 5% increase of activated pixels with no regional differences. These findings support the view that reduced neuroaxonal excitability after cathodal tDCS causes reduced brain activity. However, rather than affecting the primary sensorimotor input of an active task, the process appears to dampen those responses that rely on cortico-cortical connections and related processing. Magn Reson Med 45:196-201, 2001.     

Early Outcome Comparison Between the Direct Anterior Approach and the Mini-Incision Posterior Approach for Primary Total Hip Arthroplasty: 150 Consecutive Cases

This study evaluated early postoperative results of 150 consecutive primary total hip arthroplasties performed by a single surgeon; 50 from mini-incision posterior approach, 50 during the learning curve for the direct anterior approach, and 50 subsequent cases when the approach was routine. The anterior approach groups had significantly reduced hospital length of stays (2.9 and 2.7 days versus 3.9 days for the posterior group; P < 0.0001) and discharge to home versus rehab was more likely (80% and 84% in anterior groups, 56% in posterior group; P = 0.0028). In the anterior groups, there was significantly less use of assistive devices and narcotics at 6 weeks, and pain was significantly lower. Primary total hip arthroplasty using the anterior approach allows for superior recovery in a matched cohort of patients.     

Sequential scintigraphic strategy for the differentiation of brain tumours

Both thallium-201 and iodine-123 α-methyltyrosine (¹²³I-IMT) have been shown to be useful in the diagnostic evaluation of brain tumours. The aim of this study was to investigate the respective contributions of ²⁰¹Tl and ¹²³I-IMT single-photon emission tomography (SPET) in the non-invasive evaluation of intracerebral tumours. We analysed 65 patients with the following brain tumours: 8 non-neoplastic lesions, 4 meningiomas, 12 low-grade gliomas, 28 high-grade gliomas, 11 metastases and 2 high-grade lymphomas. ²⁰¹Tl SPET and ¹²³I-IMT SPET were performed [start of ²⁰¹Tl SPET: 15 min p.i. (early) and 180 min p.i. (delayed); start of ¹²³I-IMT SPET: 15 min p.i.]. The intensity of uptake was quantified as the ratio between tracer accumulation in the tumour and in the contralateral hemisphere. None of the non-neoplastic lesions or low-grade gliomas expressed marked ²⁰¹Tl uptake. All malignant tumours except one small metastasis and all meningiomas except one small, cystic and degenerated lesion showed significant ²⁰¹Tl accumulation [Tl(15’)>2.0]; ¹²³I-IMT uptake was either absent or intermediate in non-malignant lesions except in two low-grade gliomas; the highest levels were observed in high-grade gliomas followed by metastases and lymphomas (mean IMT: 2.7 vs 2.1 vs 1.8), with metastases showing a high variability in ¹²³I-IMT uptake (range: 0.8–3.6). Using ²⁰¹Tl to distinguish non-neoplastic lesions from malignant tumours and meningiomas, 63 of 65 patients were characterised correctly. In the latter group, high-grade gliomas were correctly identified in 27 of 28 cases by their amino acid uptake. It is concluded that the combination of ²⁰¹Tl and ¹²³I-IMT surpasses the accuracy of each single test in the differentiation of space-occupying lesions of the brain. Based on these preliminary results, a sequential strategy is proposed involving an initial ²⁰¹Tl SPET study and an additional ¹²³I-IMT SPET study in the event of positive ²⁰¹Tl uptake. Received 1 October 1999 and in revised form 8 January 2000