Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Phase shift optimization of III/V-on-bulk-Si DFB LD for single-mode stability.

A III/V-on-Bulk-Si DFB laser with a long phase shift section optimized for single-mode stability is presented. The optimized phase shift allows stable single-mode operations up to 20 times a threshold current. This mode stability is achieved by a gain difference between fundamental and higher modes maximized by sub-wavelength-scale tuning of the phase shift section. In SMSR-based yield analyses, the long-phase-shifted DFB laser showed superior performance compared to the conventional λ/4-phase-shifted ones.

Diffusion tensor imaging-based pontine damage as a degeneration marker in synucleinopathy.

The pons is one of the earliest affected regions in patients with synucleinopathies. We aimed to investigate the diagnostic value of measuring pontine damage using diffusion tensor imaging (DTI) in these patients. We enrolled 49 patients with Parkinson's disease (PD), 16 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), 23 patients with multiple system atrophy (MSA), and 39 healthy controls in this study. All the participants underwent high-resolution T1-weighted imaging and DTI. Mean diffusivity (MD) and fraction anisotropy (FA) values in the pons were calculated to characterize structural damage. The discriminatory power of pontine MD and FA values to differentiate patients with synucleinopathies from healthy controls was examined using receiver operating characteristics (ROC) analyses. Compared to healthy controls, patients with PD, iRBD, and MSA had increased MD values and decreased FA values in the pons, although no correlation was observed between these DTI measures and disease severity. The ROC analyses showed that MD values in the pons had a fair discriminatory power to differentiate healthy controls from patients with PD (area under the curve [AUC], 0.813), iRBD (AUC, 0.779), and MSA (AUC, 0.951). The AUC for pontine FA values was smaller than that for pontine MD values when differentiating healthy controls from patients with PD (AUC, 0.713; p = 0.054) and iRBD (AUC, 0.686; p = 0.045). Our results suggest that MD values in the pons may be a useful marker of brain stem neurodegeneration in patients with synucleinopathies.

Spatiotemporal expression of RCAN1 and its isoform RCAN1-4 in the mouse hippocampus after pilocarpine-induced status epilepticus.

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, real-time reverse transcriptase-polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.

Distinct FP-CIT PET patterns of Alzheimer's disease with parkinsonism and dementia with Lewy bodies.

PURPOSE: Little is known regarding the clinical relevance or neurobiology of subtle motor disturbance in Alzheimer's disease (AD). This study aims to investigate the patterns of striatal 18F-FP-CIT uptake in patients with AD-related cognitive impairment (ADCI) with mild parkinsonism. METHODS: We recruited 29 consecutive patients with ADCI with mild parkinsonism. All patients underwent 18F-FP-CIT PET scans and dopamine transporter (DAT) availability in striatal subregions (anterior/posterior caudate, anterior/posterior putamen, ventral putamen, ventral striatum) was quantified. Additionally, 32 patients with dementia with Lewy bodies (DLB) and 21 healthy controls were included to perform inter-group comparative analyses of the striatal DAT availability. The discriminatory power of striatal DAT availability to differentiate ADCI from DLB was assessed using receiver operating characteristics (ROC) analyses. The Spearman's correlation coefficient was calculated to assess the relationship between motor severity and DAT availability in striatal subregions. RESULTS: Patients with ADCI with mild parkinsonism exhibited decreased DAT availability in the caudate that was intermediate between healthy controls and patients with DLB. The DAT availability in other striatal subregions, including the posterior putamen, did not differ between the ADCI with parkinsonism and healthy control groups. The ROC analysis showed that DAT availability of all striatal subregions, especially the whole striatum, had a fair discriminatory power. Parkinsonian motor severity did not correlate with the striatal DAT availability in ADCI with parkinsonism. CONCLUSIONS: The present study demonstrated that patients with ADCI with mild parkinsonism had distinct DAT scan patterns and suggests that parkinsonism is associated with the extranigral source of pathology.

O-band DFB laser heterogeneously integrated on a bulk-silicon platform.

An O-band DFB laser heterogeneously integrated on bulk-silicon platform is presented. A high wall plug efficiency of over 8% up to 70°C is achieved due to efficient heat dissipation from III/V active region to silicon platform. The single-mode operation is maintained in a wide current range with side-mode suppression ratio over 45dB. This result completes the optical device library suite for the bulk-silicon platform used in most semiconductor products.

Functional organization of the human posterior cingulate cortex, revealed by multiple connectivity-based parcellation methods.

Based on cytoarchitecture, the posterior cingulate cortex (PCC) is thought to be comprised of two distinct functional subregions: the dorsal and ventral PCC (dPCC and vPCC). However, functional subregions do not completely match anatomical boundaries in the human brain. To understand the relationship between the functional organization of regions and anatomical features, it is necessary to apply parcellation algorithms based on functional properties. We therefore defined functionally informed subregions in the human PCC by parcellation of regions with similar patterns of functional connectivity in the resting brain. We used various patterns of functional connectivity, namely local, whole-brain and diffuse functional connections of the PCC, and various clustering methods, namely hierarchical, spectral, and k-means clustering to investigate the subregions of the PCC. Overall, the approximate anatomical boundaries and predicted functional regions were highly overlapped to each other. Using hierarchical clustering, the PCC could be clearly separated into two anatomical subregions, namely the dPCC and vPCC, and further divided into four subregions segregated by local functional connectivity patterns. We show that the PCC could be separated into two (dPCC and vPCC) or four subregions based on local functional connections and hierarchical clustering, and that subregions of PCC display differential global functional connectivity, particularly along the dorsal-ventral axis. These results suggest that differences in functional connectivity between dPCC and vPCC may be due to differences in local connectivity between these functionally hierarchical subregions of the PCC. Hum Brain Mapp 38:2808-2818, 2017. © 2017 Wiley Periodicals, Inc.

Nigrostriatal dopamine-independent resting-state functional networks in Parkinson's disease.

As an indicator of synchronous neural activity, resting-state functional networks are influenced by neuropathological and neurochemical changes in degenerative diseases. To further advance understanding about neurochemical and neuropathological basis for resting-state functional maps, we performed a comparative analysis of resting-state functional connectivity in patients with Parkinson's disease (PD) and drug induced parkinsonism (DIP). Resting-state neuroimaging data were analyzed with a seed-based approach to investigate striatocortical functional connectivity and cortical functional connectivity within the default mode network, executive control network, and the dorsal attention network. The striatal subregions were divided into the more or less affected sides in terms of dopamine transporter uptake. Compared with DIP, PD exhibited an increased cerebellar connectivity from the more affected side of the caudate and the less affected sides of the anterior and the posterior putamen. Additionally, PD showed increased functional connectivity in the anterior prefrontal areas from the more affected side of the anterior putamen and from the less affected side of the posterior putamen. However, PD exhibited decreased cortical functional connectivity from the posterior cingulate cortex in the left temporal area. Finally, DIP patients showed decreased cortical functional connectivity from the dorsolateral prefrontal cortex in frontal and parietal areas compared with PD patients. In summary, the present study demonstrates that PD patients exhibited a unique resting state functional connectivity that may be associated with PD-related pathological changes beyond the dopaminergic system, whereas DIP patients showed altered functional connectivity within executive control network.

Olfactory performance and resting state functional connectivity in non-demented drug naïve patients with Parkinson's disease.

Olfactory performance in Parkinson's disease (PD) is closely associated with subsequent cognitive decline. In the present study, we analyzed the olfaction-dependent functional connectivity with a hypothesis that olfactory performance would influence functional connectivity within key brain areas of PD. A total of 110 nondemented drug-naïve patients with PD were subdivided into three groups of high score (PD-H, n = 23), middle score (PD-M, n = 64), and low score (PD-L, n = 23) based on olfactory performance. We performed the resting-state functional connectivity with seed region of interest in the posterior cingulate cortex (PCC) and caudate. An analysis of functional connectivity revealed that PD-L patients exhibited a significant attenuation of cortical functional connectivity with the PCC in the bilateral primary sensory areas, right frontal areas, and right parietal areas compared to PD-H or PD-M patients. Meanwhile, PD-L patients exhibited a significant enhancement of striatocortical functional connectivity in the bilateral occipital areas and right frontal areas compared to PD-H or PD-M patients. In the voxel-wise correlation analysis, olfactory performance was positively associated with cortical functional connectivity with the PCC in similar areas of attenuated cortical connectivity in PD-L patients relative to PD-H patients. On the other hand, the cortical functional connectivity with the caudate was negatively correlated with olfactory performance in similar areas of increased connectivity in PD-L patients relative to PD-H patients. The present study demonstrated that resting state functional connectivity exhibits a distinctive pattern depending on olfactory performance, which might shed light on a meaningful relationship between olfactory impairment and cognitive dysfunction in PD.