Brian D. Kangas

• Ph.D.
• Professor (Assistant) at Harvard Medical School

Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing condit...

Exposure to early-life adversity (ELA) is associated with several neuropsychiatric conditions, including major depressive disorder, yet causality is difficult to establish in humans. Recent work in rodents has implicated impaired reward circuit signaling in anhedonic-like behavior after ELA exposure. Anhedonia, the lack of reactivity to previously...

Behavioral pharmacology has been aided significantly by the development of innovative cognitive tasks designed to examine complex behavioral processes in laboratory animals. Performance outcomes under these conditions have provided key metrics of drug action which serve to supplement traditional in vivo assays of physiologic and behavioral effects...

Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in...

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, count...

Background Ketamine is increasingly used as a therapeutic option for treatment-resistant depression (TRD) due to its rapid antidepressant properties, yet the mechanisms underlying these effects remain elusive. Preclinical evidence suggests ketamine acts on neural pathways implicated in reward processing, but translational efforts have proven challe...

Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depr...

Early-life stress (ELS) can produce long-lasting effects that increase the risk for mood and anxiety disorders. Transdiagnostic symptoms include anhedonia (reduced reward sensitivity) and sleep disruption, both of which are quantifiable via objective endpoints that can be utilized across species. Here we used a mouse model for ELS—exposure to juven...

Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family hi...

Ketamine, a dissociative anesthetic with well-documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of...

Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default m...

Although chronic cannabis use during adolescence can alter brain function and impair complex behavioral processes, it is unclear whether such deficits persist into adulthood. Using a coordinated awake neuroimaging and behavioral approach in nonhuman primates, we addressed this issue by examining the impact of chronic adolescent exposure to Δ9-tetra...

Background Deficits in cognitive control are implicated in numerous neuropsychiatric disorders. However, relevant pharmacological treatments are limited, likely due to weak translational validity of applicable preclinical models used. Neural indices derived from electroencephalography may prove useful in comparing and translating the effects of cog...

Background Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by e...

Stagnation in the development of novel therapeutic strategies for treatment‐resistant depression has encouraged continued interest in improving preclinical methods. One tactic prioritizes the reverse translation of behavioral tasks developed to objectively quantify depressive phenotypes in patient populations for their use in laboratory animals via...

Resting-state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and...

Background: Frontline antidepressants such as selective serotonin reuptake inhibitors (SSRIs) leave many patients with unmet treatment needs. Moreover, even when SSRIs reduce depressive symptoms, anhedonia, the loss of pleasure to previously rewarding activities, often remains unabated. This state of affairs is disheartening and calls for the devel...

The Probabilistic Reward Task (PRT) is a laboratory-based technique used to objectively quantify responsivity to reward. The PRT was initially designed to identify reinforcement learning deficits in clinical populations and subsequently was reverse-translated for use in preclinical studies with rats and monkeys. In this task, subjects make visual d...

Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS—including childhood abuse, bullying, poverty, and trauma—are increasingly prevalent. Understanding the signs of ELS, including those associa...

Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS-including childhood abuse, bullying, poverty, and trauma-are increasingly prevalent. Understanding the signs of ELS, including those associa...

Blunted reward learning and reward-related activation within the corticostriatal-midbrain circuitry have been implicated in the pathophysiology of anhedonia and depression. Unfortunately, the search for more efficacious interventions for anhedonic behaviors has been hampered by the use of vastly different preclinical and clinical assays. In a first...

Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and...

Aim There is increasing concern that cannabinoid exposure during adolescence may disturb brain maturation and produce long-term cognitive deficits. However, studies in human subjects have provided limited evidence for such causality. The present study utilized behavioral and neuroimaging endpoints in female non-human primates to examine the effects...

Rationale Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood. Objectives To address this gap, we examined the effects of modafinil on re...

Despite the prominence of anhedonic symptoms associated with diverse neuropsychiatric conditions, there are currently no approved therapeutics designed to attenuate the loss of responsivity to previously rewarding stimuli. However, the search for improved treatment options for anhedonia has been reinvigorated by a recent reconceptualization of the...

Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)—which refers to decreased power in the alpha frequency band after an incorrect response—is thought to reflect cognitive arousal after errors. Much of this work has been correlational, ho...

There is substantial evidence that cholinergic system function impairment plays a significant role in many central nervous system (CNS) disorders. During the past three decades, muscarinic receptors (mAChRs) have been implicated in various pathologies and have been prominent targets of drug-design efforts. However, due to the high sequence homology...

Anhedonia, the loss of pleasure from previously rewarding activities, is a core symptom of several neuropsychiatric conditions, including major depressive disorder (MDD). Despite its transdiagnostic relevance, no effective therapeutics exist to treat anhedonia. This is due, in part, to inconsistent assays across clinical populations and laboratory...

Background: Clinical research shows that regular use of 9-tetrahydrocannabinol (THC), a CB1 receptor partial agonist, during adolescence increases the propensity for developing psychosis in adulthood. CB1 receptor expression is abundant in the hippocampus, and its alteration might be behind the structural and functional hippocampal changes reporte...

Studies in rodents suggest that exposure to distinct spaceflight stressors (e.g., space radiation, isolation/confinement, microgravity) may have a profound impact on an astronaut's ability to perform both simple and complex tasks related to neurocognitive performance, central nervous system (CNS) and vestibular/sensorimotor function. However, limit...

The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage to the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggr...

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and labor...

Background: Daily use of marijuana is rising in adolescents, along with consumption of high potency marijuana products (high % Δ-9-tetrahydrocannabinol or THC). These dual, related trends have opened gaps in understanding the long-term effects of daily consumption of a high dose of THC in adolescents and whether a therapeutic dose of cannabidiol (...

Background: Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder (MDD) and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the developme...

Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen—two brain regions involved in cognitive function and moto...

Anhedonia, the loss of pleasure from previously rewarding activities, is implicated in several neuropsychiatric conditions, including major depressive disorder (MDD). In order to accelerate drug development for mood disorders, quantitative approaches are needed to objectively measure responsiveness to reward as a means to identify deficits. One suc...

Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, FDA-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their pr...

Anhedonia, the loss of pleasure derived from previously rewarding activities, is a behavioral phenotype that is implicated in several neuropsychiatric conditions, including major depressive disorder (MDD), schizophrenia, bipolar disorder, and drug dependence. Assessment of anhedonia in clinical populations has historically been derived from questio...

The marijuana plant produces over 100 different cannabinoids, including Δ ⁹⁻ tetrahydrocannabinol (THC) and cannabidiol (CBD). THC concentrations in retail marijuana have risen dramatically, while CBD levels have declined. High concentrations of THC and high ratios of THC:CBD in marijuana are thought to be associated with more robust psychoactive e...

Developing effective analgesics with fewer unwanted side effects is a pressing concern. Due to a lack of effective nonopioid options currently available, an alternative approach termed opioid-sparing evaluates the ability of a coadministered drug to reduce the amount of opioid needed to produce an antinociceptive effect. Opioids and benzodiazepines...

The effective management of pain is a longstanding public health concern. Although opioids have been frontline analgesics for decades, they also have well-known undesirable effects that limit their clinical utility, such as abuse liability and respiratory depression. The failure to develop better analgesics has, in some ways, contributed to the esc...

Background: Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has been little systematic research regarding the effects of opioid dependence and withdrawal on aspects of cognition-related behavior in laboratory animals. The present studi...

Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high intake chronic users, there are no FDA-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective...

Background: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a shortage of animal models. Methods: The pr...

Rationale: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamat...

Anhedonia, the loss of pleasure derived from previously rewarding activities, is a behavioral phenotype that is implicated in several neuropsychiatric conditions, including major depressive disorder (MDD), schizophrenia, bipolar disorder, and drug dependence. Assessment of anhedonia in clinical populations has historically been derived from questio...

Over the past decade, prescription opioid abuse has become a major public health concern. Despite increased prevalence, however, the effects of chronic opioid abuse on cognition‐related behavior remains poorly understood. Previous studies in our laboratory have shown that self‐administration of other abused drugs can have adverse effects on cogniti...

There is a growing need for new translational animal models designed to capture complex behavioral phenotypes implicated in addiction and other neuropsychiatric conditions. For example, a complete understanding of the effects of commonly abused drugs, as well as candidate medications, requires assessments of their effects on learning, memory, atten...

An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type-1 (CB1) receptor agonists such as Δ9-tetrahydrocannabinol are increasingly utilized for their medicinal actions; however, their utility is constrai...

A defining feature of radical behaviorism is the explicit inclusion of private events as material phenomena within a science of behavior. Surprisingly, however, despite much theorizing, there is a notable paucity within behavior analysis of controlled experimentation and analysis of private events, especially in nonhuman animals. One technique that...

Recent developments in precision gene editing have led to the emergence of the marmoset as an experimental subject of considerable interest and translational value. A better understanding of behavioral phenotypes of the common marmoset will inform the extent to which forthcoming transgenic mutants are cognitively intact. Therefore, additional infor...

Rationale Frequent exposure to methamphetamine has been reported to adversely influence cognitive behavior and, in particular, inhibitory control processes. Objective The present studies were conducted in squirrel monkeys to assess the effects of daily intravenous methamphetamine self-administration on touch screen-based repeated acquisition and di...

The primary psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of differe...

The discriminative‐stimulus (SD) effects of CB1 ligands can be reproduced in mice by non‐selective inhibition of the anandamide‐(AEA‐) and 2‐arachidinoyl glycerol‐(2‐AG‐) inactivating enzymes, respectively, fatty‐acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGL). Additionally, we have shown that nonselective FAAH/MGL inhibitors produce...

The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative tr...

The discriminative‐stimulus (S d ) and other behavioral effects of CB1 ligands can be reproduced in mice by combined inhibition of the anandamide‐ (AEA‐) and 2‐arachidinoyl glycerol‐ (2‐AG‐) inactivating enzymes fatty‐acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL; Long et al. 2009). The present studies using selective and non‐selecti...

Long‐term chronic exposure to methamphetamine (MA) has been related to profound neural impact including, but not limited to, damage to monoamine nerve terminals. In turn, neural changes following repeated MA administration may be related to adverse effects on learning and other cognitive performance. However, the characterization of such neurobehav...

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increase...

Repeated acquisition and discrimination reversal tasks are often used to examine behavioral relations of, respectively, learning and cognitive flexibility. Surprisingly, despite their frequent use in cognitive neuroscience and behavioral pharmacology, variables that control performance under these two tasks have not been widely studied. The present...

The primary psychoactive ingredient of marijuana, Δ ⁹ ‐ tetrahydrocannabinol (THC), has medicinal effects that promote continued development of CB 1 agonists as therapeutics but also produces well‐documented deleterious effects on cognitive endpoints. In the present study, CB 1 agonists—THC (0.03–1.8 mg/kg), WIN 55,212 (0.3–1.8 mg/kg), AM4054 (0.00...

The enzyme that degrades the endocannabinoid anandamide (fatty acid amide hydrolase; FAAH) has been forwarded as a therapeutic target for metabolic and other disorders. The recently developed ligand, AM3506, inhibits FAAH selectively and with high potency (IC50: 2.8nM) and, as well, shows moderate CB1 receptor affinity (Ki: 192nM). The present work...

CB(1) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. Howe...

Emerging evidence suggests that nicotine may enhance short-term memory. Some of this evidence comes from nonhuman primate research using a procedure called delayed matching-to-sample, wherein the monkey is trained to select a comparison stimulus that matches some physical property of a previously presented sample stimulus. Delays between sample sti...

Six pigeons key-pecked under a fixed-interval (FI) 3-min schedule of food presentation. Each pigeon was studied for 200 daily sessions with 15 intervals per session (3,000 total food presentations). Analyses included the examination of latency to first peck (pause), mean rate of key pecking, and ambulation. Characterizations of stable performance w...

CB1 inverse‐agonist antagonists (e.g., rimonabant) have behavioral effects that limit their clinical utility. Recent data suggest that CB1 neutral antagonists may not have rimonabant‐like effects, raising the possibility of improved clinical utility. The present studies were conducted to compare how inverse‐agonist antagonists (SR141716A, AM 6538)...

The effects of cocaine were examined under a titrating-delay matching-to-sample procedure. In this procedure, the delay between sample stimulus offset and comparison stimuli onset adjusts as a function of the subject's performance. Specifically, matches increase the delay and mismatches decrease the delay. Titrated delay values served as the primar...

The Cognitive Style of PowerPoint: Pitching Out Corrupts Within by Edward Tufte (2006) condemns the software for failing to help users achieve many of the goals of an effective presentation and instead offers a low resolution platform with a deeply hierarchical single-path structure capable of convening a trivial amount of information even over ext...

Thirty-five years ago, B.F. Skinner (1976) lamented a decreasing trend in the prevalence of cumulative records in the Journal of the Experimental Analysis of Behavior (JEAB). The editorial began with the two memorable lines, “Evidently we have not long to wait for an issue of JEAB without a single cumulative record! I shall not miss the records so...

Despite its frequent use to assess effects of environmental and pharmacological variables on short-term memory, little is known about the development of delayed matching-to-sample (DMTS) performance. This study was designed to examine the dimensions and dynamics of DMTS performance development over a long period of exposure to provide a more secure...

The titrating-delay matching-to-sample (TDMTS) procedure offers researchers an additional behavioral task thought to capture some important features of remembering. In this procedure, the delay between sample offset and comparison onset adjusts as a function of the subject's performance. Specifically, correct matches increase the delay and incorrec...

Adult human subjects engaged in a simulated Rock/Paper/Scissors game against a computer opponent. The computer opponent's responses were determined by programmed probabilities that differed across 10 blocks of 100 trials each. Response allocation in Experiment 1 was well described by a modified version of the generalized matching equation, with und...

Despite continued abuse, there is a paucity of empirical investigations on inhalants as reinforcers. The present study attempted to derive a method for studying the reinforcing effects of nitrous oxide (N2O) with human participants. An adjusting-dose procedure was employed to assess choice allocation for inhalation periods of varying doses of N2O....

The development of position and stimulus biases often occurs during initial training on matching-to-sample tasks. Furthermore, without intervention, these biases can be maintained via intermittent reinforcement provided by matching-to-sample contingencies. The present study evaluated the effectiveness of a correction procedure designed to eliminate...

The present report analyzes trends in attendance and presentations at the annual conference of the Association for Behavior Analysis (ABA). Numbers of registered attendees were plotted over time. The trends show that the number of registered attendees has grown considerably over the last three decades, with the largest proportion of the growth occu...

The year 2007 marks the 80th anniversary of the birth of Marvin Harris (1927-2001). Although relations between Harris' cultural materialism and Skinner's radical behaviorism have been promulgated by several in the behavior-analytic community (e.g., Glenn, 1988; Malagodi & Jackson, 1989; Vargas, 1985), Harris himself never published an exclusive and...

Increases in regulatory oversight of animal research require verification of effects of standard practices. There are no formal guidelines for establishing free-feeding weights in adult pigeons. In the present study, pigeons were obtained from a commercial supplier, weighed upon arrival, and then held in quarantine for 7 days with free access to fo...