Noradrenergic ß-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine.

Cocaine has been shown to produce both initial rewarding and delayed anxiogenic effects. Although the neurobiology of cocaine's rewarding effects has been well studied, the mechanisms underlying its anxiogenic effects remain unclear. We used two behavioral assays to study these opposing actions of cocaine: a runway self-administration test and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine, but avoid environments paired with the drug's delayed/anxiogenic actions. In the present study, these two behavioral assays were used to examine the role of norepinephrine (NE) transmission within the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), each of which has been implicated in drug-withdrawal-induced anxiety and stress-induced response reinstatement. Rats experienced 15 single daily cocaine-reinforced (1.0 mg/kg, i.v.) runway trials 10 min after intracranial injection of the ß1 and ß2 NE receptor antagonists betaxolol and ICI 118551 or vehicle into the CeA or BNST. NE antagonism of either region dose dependently reduced approach-avoidance conflict behavior compared with that observed in vehicle-treated controls. In addition, NE antagonism selectively interfered with the expression of conditioned place aversions while leaving intact cocaine-induced place preferences. These data suggest a role for NE signaling within the BNST and the CeA in the anxiogenic actions of cocaine.

Decreasing neuroscience anxiety in an introductory neuroscience course: an analysis using data from a modified science anxiety scale.

To determine whether participation in a neuroscience course reduced neuroscience anxiety, a modified version of the Science Anxiety Scale was administered to students at the beginning and end of an introductory course. Neuroscience anxiety scores were significantly reduced at the end of the course and correlated with higher final grades. Reduced neuroscience anxiety did not correlate with reduced science anxiety, suggesting that neuroscience anxiety is a distinct subtype of anxiety.

Early detection and tracking of bulbar changes in ALS via frequent and remote speech analysis.

Bulbar deterioration in amyotrophic lateral sclerosis (ALS) is a devastating characteristic that impairs patients' ability to communicate, and is linked to shorter survival. The existing clinical instruments for assessing bulbar function lack sensitivity to early changes. In this paper, using a cohort of N = 65 ALS patients who provided regular speech samples for 3-9 months, we demonstrated that it is possible to remotely detect early speech changes and track speech progression in ALS via automated algorithmic assessment of speech collected digitally.

Improved ALS clinical trials through frequent at-home self-assessment: a proof of concept study.

OBJECTIVE: To determine the potential for improving amyotrophic lateral sclerosis (ALS) clinical trials by having patients or caregivers perform frequent self-assessments at home. METHODS AND PARTICIPANTS: We enrolled ALS patients into a nonblinded, longitudinal 9-month study in which patients and caregivers obtained daily data using several different instruments, including a slow-vital capacity device, a hand grip dynamometer, an electrical impedance myography-based fitness device, an activity tracker, a speech app, and the ALS functional rating scale-revised. Questions as to acceptability were asked at two time points. RESULTS: A total of 113 individuals enrolled, with 61 (43 men, 18 women, mean age 60.1 ± 9.9 years) collecting a minimum of 7 days data and being included in the analysis. Daily measurements resulted in more accurate assessments of the slope of progression of the disease, resulting in smaller sample size estimates for a hypothetical clinical trial. For example, by performing daily slow-vital capacity measurements, calculated sample size was reduced to 182 subjects/study arm from 882/arm for monthly measurements. Similarly, performing the ALS functional rating scale weekly rather than monthly led to a calculated sample size of 73/arm as compared to 274/arm. Participants generally found the procedures acceptable and, for many, improved their sense of control of their disease. INTERPRETATION: Frequent at-home measurements using standard tools holds the prospect of tracking progression and reducing sample size requirements for clinical trials in ALS while also being acceptable to the patients. Future studies in this and other neurological disorders should consider adopting this approach to data collection.

Repeatability of Commonly Used Speech and Language Features for Clinical Applications.

INTRODUCTION: Changes in speech have the potential to provide important information on the diagnosis and progression of various neurological diseases. Many researchers have relied on open-source speech features to develop algorithms for measuring speech changes in clinical populations as they are convenient and easy to use. However, the repeatability of open-source features in the context of neurological diseases has not been studied. METHODS: We used a longitudinal sample of healthy controls, individuals with amyotrophic lateral sclerosis, and individuals with suspected frontotemporal dementia, and we evaluated the repeatability of acoustic and language features separately on these 3 data sets. RESULTS: Repeatability was evaluated using intraclass correlation (ICC) and the within-subjects coefficient of variation (WSCV). In 3 sets of tasks, the median ICC were between 0.02 and 0.55, and the median WSCV were between 29 and 79%. CONCLUSION: Our results demonstrate that the repeatability of speech features extracted using open-source tool kits is low. Researchers should exercise caution when developing digital health models with open-source speech features. We provide a detailed summary of feature-by-feature repeatability results (ICC, WSCV, SE of measurement, limits of agreement for WSCV, and minimal detectable change) in the online supplementary material so that researchers may incorporate repeatability information into the models they develop.

ALS longitudinal studies with frequent data collection at home: study design and baseline data.

OBJECTIVE: To design an ALS clinical study in which patients are remotely recruited, screened, enrolled and then assessed via daily data collection at home by themselves or caregivers. METHODS: This observational, natural-history study included two academic medical centers, one providing overall clinical management and the other overseeing computing and web-services design and management. Both healthy and ALS subjects were recruited on the Internet via advertisement on governmental and foundation websites as well as through Facebook and Google paid advertisements. Individuals underwent screening and enrollment remotely, including signing an electronic informed consent form. Participants were then provided self-measurement equipment and instructed on their use through a series of web-based videos. The equipment included a handgrip dynamometer, spirometer with smartphone connection, electrical impedance myography device, and an activity tracker. ALS Functional Rating Scale-Revised data were also collected. Subjects were asked to collect data daily for three months and twice-weekly for the subsequent six months. RESULTS: One hundred and eleven ALS patients and 30 healthy individuals enrolled in the study from across 41 states (74 men, 62 women). Baseline median ALSFRS-R score was 33. Seventy two percent of the ALS patients sent equipment and 88% of the healthy subjects sent equipment were able to complete a first set of measurements. Expected baseline differences between the ALS patients and healthy participants were identified for all measures. CONCLUSIONS: It is possible to design and institute an at-home based study in ALS patients, using a number of state-of-the-art approaches, including web-based consenting and training and Internet-connected measurement devices.

OBJECTIVE ASSESSMENT OF VOCAL TREMOR.

Detecting early signs of neurodegeneration is vital for planning treatments for neurological diseases. Speech plays an important role in this context because it has been shown to be a promising early indicator of neurological decline, and because it can be acquired remotely without the need for specialized hardware. Typically, symptoms are characterized by clinicians using subjective and discrete scales. The poor resolution and subjectivity of these scales can make the earliest speech changes hard to detect. In this paper, we propose an algorithm for the objective assessment of vocal tremor, a phenomenon associated with many neurological disorders. The algorithm extracts and aggregates a feature set from the average spectra of the energy and fundamental frequency profiles of a sustained phonation. We show that the resultant low-dimensional feature set reliably classifies healthy controls and patients with amyotrophic lateral sclerosis perceptually rated for tremor by speech language pathologists.

Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration.

Cocaine has long been known to produce an initial "high" followed by an aversive/anxiogenic "crash". While much is known about the neurobiology of cocaine's positive/rewarding effects, the mechanisms that give rise to the drug's negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15µg/side) or the D2 agonist, sumanirole (0, 5 or 10µg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.

On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats.

RATIONALE: Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic "crash." OBJECTIVE: The objective of this study was to determine whether individual differences in the relative value of cocaine's positive and negative effects would account for variations in subsequent drug self-administration. METHODS: The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance "retreat" behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration. RESULTS: Larger place preferences were associated with faster runway start latencies (r s = -0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = -0.60). CONCLUSIONS: Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.

The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats.

Human cocaine users report that the initial "high" produced by cocaine administration is followed by an anxiogenic "crash". Given that cocaine has such robust and opposing properties, it is likely that both positive and negative effects of cocaine contribute to an individual's motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine's dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug's negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine's opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1mg/kg/0.1ml) 3h after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine's immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug's negative/anxiogenic properties.