A potential neuromodulation target for PTSD in Veterans derived from focal brain lesions.

Neuromodulation trials for PTSD have yielded mixed results, and the optimal neuroanatomical target remains unclear. We analyzed three datasets to study brain circuitry causally linked to PTSD in military Veterans. After penetrating traumatic brain injury (n=193), lesions that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex (mPFC), amygdala, and anterolateral temporal lobe (cross-validation p=0.01). In Veterans without lesions (n=180), PTSD was specifically associated with connectivity within this circuit (p<0.01). Connectivity change within this circuit correlated with PTSD improvement after transcranial magnetic stimulation (TMS) (n=20) (p<0.01), even though the circuit was not directly targeted. Finally, we directly targeted this circuit with fMRI-guided accelerated TMS, leading to rapid resolution of symptoms in a patient with severe lifelong PTSD. All results were independent of depression severity. This lesion-based PTSD circuit may serve as a neuromodulation target for Veterans with PTSD.

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment. RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a commonly- used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders.

OBJECTIVE: Disrupted emotional processing is a common feature of many psychiatric disorders. The authors investigated functional disruptions in neural circuitry underlying emotional processing across a range of tasks and across psychiatric disorders through a transdiagnostic quantitative meta-analysis of published neuroimaging data. METHODS: A PubMed search was conducted for whole-brain functional neuroimaging findings published through May 2018 that compared activation during emotional processing tasks in patients with psychiatric disorders (including schizophrenia, bipolar or unipolar depression, anxiety, and substance use) to matched healthy control participants. Activation likelihood estimation (ALE) meta-analyses were conducted on peak voxel coordinates to identify spatial convergence. RESULTS: The 298 experiments submitted to meta-analysis included 5,427 patients and 5,491 control participants. ALE across diagnoses and patterns of patient hyper- and hyporeactivity demonstrated abnormal activation in the amygdala, the hippocampal/parahippocampal gyri, the dorsomedial/pulvinar nuclei of the thalamus, and the fusiform gyri, as well as the medial and lateral dorsal and ventral prefrontal regions. ALE across disorders but considering directionality demonstrated patient hyperactivation in the amygdala and the hippocampal/parahippocampal gyri. Hypoactivation was found in the medial and lateral prefrontal regions, most pronounced during processing of unpleasant stimuli. More refined disorder-specific analyses suggested that these overall patterns were shared to varying degrees, with notable differences in patterns of hyper- and hypoactivation. CONCLUSIONS: These findings demonstrate a pattern of neurocircuit disruption across major psychiatric disorders in regions and networks key to adaptive emotional reactivity and regulation. More specifically, disruption corresponded prominently to the "salience" network, the ventral striatal/ventromedial prefrontal "reward" network, and the lateral orbitofrontal "nonreward" network. Consistent with the Research Domain Criteria initiative, these findings suggest that psychiatric illness may be productively formulated as dysfunction in transdiagnostic neurobehavioral phenotypes such as neurocircuit activation.

Identification of Common Neural Circuit Disruptions in Cognitive Control Across Psychiatric Disorders.

OBJECTIVE: Cognitive deficits are a common feature of psychiatric disorders. The authors investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis. METHOD: A PubMed search was conducted for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with axis I disorders and matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates. RESULTS: The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with various disorders (schizophrenia, bipolar or unipolar depression, anxiety disorders, and substance use disorders). Transdiagnostically abnormal activation was evident in the left prefrontal cortex as well as the anterior insula, the right ventrolateral prefrontal cortex, the right intraparietal sulcus, and the midcingulate/presupplementary motor area. Disruption was also observed in a more anterior cluster in the dorsal cingulate cortex, which overlapped with a network of structural perturbation that the authors previously reported in a transdiagnostic meta-analysis of gray matter volume. CONCLUSIONS: These findings demonstrate a common pattern of disruption across major psychiatric disorders that parallels the "multiple-demand network" observed in intact cognition. This network interfaces with the anterior-cingulo-insular or "salience network" demonstrated to be transdiagnostically vulnerable to gray matter reduction. Thus, networks intrinsic to adaptive, flexible cognition are vulnerable to broad-spectrum psychopathology. Dysfunction in these networks may reflect an intermediate transdiagnostic phenotype, which could be leveraged to advance therapeutics.

Formulation techniques for nanofluids.

Fluids with suspended nanoparticles, commonly known as nanofluids, may be formulated to improve the thermal performance of industrial heat transfer systems and applications. Nanofluids may show enhanced thermal and electrical properties such as thermal conductivity, viscosity, heat transfer coefficient, dielectric strength, etc. However, stability problems may arise as nanoparticles usually have the tendency to agglomerate and sediment producing deterioration in the increment of these properties. In this review, we discuss patents that report advances in the formulation of nanofluids including: production methods, selection of components (nanoparticles, base fluid and surfactants), their chemical compositions and morphologies, and characterization techniques. Finally, current and future directions in the development of nanofluid formulation are discussed.

Distinct contributions of microtubule subtypes to cell membrane shape and stability.

Microtubules (MTs) are linked to cell mechanobiology. "Stable" and "dynamically unstable" microtubule (MT) subtypes are differentially sensitive to growth and distribution in serum starved (SS) versus full serum (FS) conditions. Atomic Force and Immunofluorescence microscopies were used to study the nanomechanical properties of the cell membrane in response to serum conditions and nocodazole. Nanomechanical properties of the cell membrane remain unchanged under SS/FS conditions even though there are drastic MT changes. The cell membrane is shown to depend on unstable MTs and the intermediate filament (IF) networks to maintain local stiffness. Measurements of local membrane nanomechanics in response to nocodazole display characteristic serum dependent decays. The responses suggest that the cell exists in a mechanical transition state. Stiffness is shown to depend on the interplay between dynamically unstable MTs, stable MTs and IFs which all act to impart a distinct cellular type of transient "metastability".