Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia

Background and Purpose-Both transcranial Doppler (TCD) and spiral computed tomography angiography (CTA) are used for noninvasive vascular assessment tools in acute stroke. We aimed to evaluate the diagnostic accuracy of TCD against CTA in patients with acute cerebral ischemia. Methods-Consecutive patients presenting to the Emergency Department with symptoms of acute (< 24 hours) cerebral ischemia underwent emergent high-resolution brain CTA with a multidetector helical scanner. TCD was performed at bedside with a standardized, fast-track insonation protocol before or shortly (< 2 hours) after completion of the CTA. Previously published diagnostic criteria were prospectively applied for TCD interpretation independent of angiographic findings. Results-A total of 132 patients (74 men, mean +/- SD age 63 +/- 15 years) underwent emergent neurovascular assessment with brain CTA and TCD. Compared with CTA, TCD showed 34 true-positive, 9 false-negative, 5 false-positive, and 84 true-negative studies (sensitivity 79.1%, specificity 94.3%, positive predictive value 87.2%, negative predictive value 90.3%, and accuracy 89.4%). In 9 cases (7%), TCD showed findings complementary to the CTA (real-time embolization, collateralization of flow with extracranial internal carotid artery disease, alternating flow signals indicative of steal phenomenon). Conclusions-Bedside TCD examination yields satisfactory agreement with urgent brain CTA in the evaluation of patients with acute cerebral ischemia. TCD can provide real-time flow findings that are complementary to information provided by CTA

Noninvasive detection of diffuse intracranial disease

Background and Purpose - Intracranial arterial stenosis increases flow velocities on the upslope of the Spencer’s curve of cerebral hemodynamics. However, the velocity can decrease with long and severely narrowed vessels. We assessed the frequency and accuracy for detection of focal and diffuse intracranial stenoses using novel diagnostic criteria that take into account increased resistance to flow with widespread lesions. Methods - We evaluated consecutive patients referred to a neurovascular ultrasound laboratory with symptoms of cerebral ischemia. Transcranial Doppler mean flow velocities were classified as normal (30 to 99 cm/s), high and low. Pulsatility index >= 1.2 was considered high. Focal intracranial disease was defined as >= 50% diameter reduction by the Warfarin Aspirin in Symptomatic Intracranial Disease criteria. Diffuse disease was defined as stenoses in multiple intracranial arteries, multiple segments of one artery, or a long (> 1 cm) stenosis in one major artery on contrast angiography (CT angiography or digital subtraction angiography) as the gold standard. Results - One hundred fifty-three patients (96 men, 76% white, age 62 +/- 15 years) had previous strokes (n=135) or transient ischemic attack (n=18). Transcranial Doppler detection of focal and diffuse intracranial disease had sensitivity 79.4% (95% CI: 65.8% to 93%), specificity 92.4% (95% CI: 87.7% to 97.2%), positive predictive value 75.0% (95% CI: 60.9% to 89.2%), negative predictive value 94.0% (95% CI: 89.7% to 98.3%), and overall accuracy 89.5% (95% CI: 84.5% to 94.4%). After adjustment for stroke risk factors, transcranial Doppler findings of low mean flow velocities and high pulsatility index in a single vessel were independently associated with angiographically demonstrated diffuse single vessel intracranial disease, whereas low mean flow velocities/high pulsatility index in multiple vessels were related to multivessel intracranial disease (OR: 19.7, 95% CI: 4.8 to 81.2, P < 0.001). Conclusions - Diffuse intracranial disease may have a higher than expected frequency in a select stroke population and can be detected with noninvasive screening

Quantification of microspheres appearance in brain vessels: Implications for residual flow velocity measurements, dose calculations, and potential drug delivery

Background and Purpose: Characteristics of ultrasound-activated gaseous microspheres (μS) reflective of their size and quantities are needed for future dose-escalation and drug delivery trials. Methods: A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler μS traces included large ( > 8μ) μS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small ( < 5μ) μS from acute patients without shunts receiving thrombolysis and perflutren-lipid μS. Results: In 101 μS traces from 50 RLS-positive and 10 thrombolysis+μS treated patients, a large μS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small μS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P < 0.001. Small μS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P < 0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P < 0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265–588) small μS can produce continuous flow enhancement for 4 seconds. Small μS velocities on m-mode in obstructed vessels (39.8±11.3 cm/s) were similar to large μS in patent vessels (40.8±11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8±13.8 cm/s, P < 0.001). Conclusions: With normal or reduced flow, activated μS passage duration through a small power motion Doppler gate can quantify the dose of delivered μS. Ultrasound can determine a minimum number of μS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of μS smaller than red blood cells may reflect plasma flow velocities around acute occlusions

Family presence during brain death evaluation: a randomized controlled trial

Objective: To evaluate if a family presence educational intervention during brain death evaluation improves understanding of brain death without affecting psychological distress.\ud \ud Design: Randomized controlled trial.\ud \ud Setting: Four ICUs at an academic tertiary care center.\ud \ud Subjects: Immediate family members of patients suspected to have suffered brain death.\ud \ud Interventions: Subjects were group randomized to presence or absence at bedside throughout the brain death evaluation with a trained chaperone. All randomized subjects were administered a validated understanding brain death survey before and after the intervention. Subjects were assessed for psychological well-being between 30 and 90 days after the intervention.\ud \ud Measurements and Main Results: Follow-up assessment of psychological well-being was performed using the Impact of Event Scale and General Health Questionnaire. Brain death understanding, Impact of Event Scale, and General Health Questionnaire scores were analyzed using Wilcoxon nonparametric tests. Analyses were adjusted for within family correlation. Fifty-eight family members of 17 patients undergoing brain death evaluation were enrolled: 38 family members were present for 11 brain death evaluations and 20 family members were absent for six brain death evaluations. Baseline understanding scores were similar between groups (median 3.0 [presence group] vs 2.5 [control], p = 0.482). Scores increased by a median of 2 (interquartile range, 1-2) if present versus 0 (interquartile range, 0-0) if absent (p < 0.001). Sixty-six percent of those in the intervention group achieved perfect postintervention understanding scores, compared with 20% of subjects who were not present (p = 0.02). Median Impact of Event Scale and General Health Questionnaire scores were similar between groups at follow-up (Impact of Event Scale: present = 20.5, absent = 23.5, p = 0.211; General Health Questionnaire: present = 13.5, absent = 13.0, p = 0.250).\ud \ud Conclusions: Family presence during brain death evaluation improves understanding of brain death with no apparent adverse impact on psychological well-being. Family presence during brain death evaluation is feasible and safe