Tara L. White

Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (Delta Glu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (Delta PA). MRS indicated drug-induced Delta Glu related positively to Delta PA (Delta Glu(MA) r = +0.44, p < 0.05, N = 21), with large effects in females (Delta Glu(MA) r = +0.52, p < 0.05; Delta Glu(AMP) r = +0.61, p < 0.05, N = 11). Subjective states related to Delta Glu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = -0.61, p < 0.05, N = 11). These self-reports correlated with Delta Glu to the extent they loaded on Delta PA (r = 0.95 AMP, p = 5 x 10(-10); r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of Delta Glu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (Delta Glu(AMP) r = +0.59 to +0.65, p's < 0.05; Delta Glu(MA) r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30–45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.

Contributions of brain glutamate to conscious emotion are not well understood. Here we evaluate the relationship of experimentally-induced change in neocortical glutamate (△Glu) and subjective states in well individuals. Drug challenge with d-amphetamine (AMP; 20 mg oral), methamphetamine (MA; Desoxyn®, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton magnetic resonance spectroscopy (MRS) quantified neurometabolites in the right dorsal anterior cingulate cortex (dACC) 140-150 m post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5-hours on each session, yielding 3,792 responses per participant (91,008 responses overall, N=24 participants). Self-reports were reduced by principal components analysis to a single factor score of AMP- and MA-induced Positive Agency (△PA) in each participant. We found drug-induced △Glu related positively with △PA (△Glu_MA r=+.44, p<.05, N=21), with large effects in females (△Glu_MA r=+.52, p<.05; △Glu_AMP r=+.61, p<.05, N=11). States related to △Glu in females included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r’s=+.51 to +.74, p<.05), and alleviation of anxiety (r=-.61, p<.05, N=11). Self-reports correlated with DGlu to the extent they loaded on △PA (r=.95 AMP, p=5x10^-10; r=.63 MA, p=.0015, N=11), indicating coherence of △Glu effects. Timing data indicated Glu shaped emotion both concurrently and prospectively, with no relationship to pre-MRS emotion (△Glu_AMP r=+.59 to +.65, p’s<.05; △Glu_MA r=+.53, p<.05, N=11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, most readily observed in women.

Contributions of brain glutamate to conscious emotion are not well understood. Here we evaluate the relationship of experimentally-induced change in neocortical glutamate (Delta Glu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP; 20 mg oral), methamphetamine (MA; Desoxyn®, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex (dACC) 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5-hours on each session, yielding 3,792 responses per participant (91,008 responses overall, N=24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced Positive Agency (Delta PA). MRS indicated drug-induced Glu related positively to PA (Delta GluMA r=+.44, p<0.05, N=21), with large effects in females (Delta GluMA r=+.52, p<0.05; Delta GluAMP r=+.61, p<0.05, N=11). Subjective states related to Delta Glu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r’s=+.51 to +.74, p<0.05), and alleviation of anxiety in females (r=-.61, p<0.05, N=11). These self-reports correlated with Delta Glu to the extent they loaded on Delta PA (r=0.95 AMP, p=5x10-10; r=0.63 MA, p=0.0015, N=11), indicating coherence of Glu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (Delta GluAMP r=+0.59 to +0.65, p’s<0.05; Delta GluMA r=+0.53, p<0.05, N=11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Anger can engender action by individuals and groups. It is thus important to understand anger’s behavioral phenotypes and their underlying neural substrates. Here we introduce a construct we term agentic anger, a state that motivates action to achieve risky goals. We test predictions of our neurobehavioral model in two proof-of-concept studies. Study 1 used the Incentive Balloon Analogue Risk Task (iBART) in a within-subjects, repeated measures design in 39 healthy volunteers to evaluate: a) impact of frustrative non-reward on agentic anger, assessed by self-reports of negative activation (NA), b) impact of achieved reward on exuberance, assessed by self-reports of positive activation (PA), c) their interrelationship, and d) their relationship with traits of positive emotion, negative emotion, immersive emotion and impulsivity. Task-induced NA was positively correlated with task-induced PA (r=0.56, p<.001), risk-taking on the task (r=0.27 to 0.36, p≤.05, .01) and trait Social Potency (SP, r=0.34 to 0.35, p<.05), a measure of reward sensitivity on the Multidimensional Personality Questionnaire Brief-Form (MPQ-BF). Study 2 assessed functional MRI response to stakes for risk-taking in healthy volunteers receiving 20 mg d-amphetamine (AMP) in a double-blinded, placebo-controlled crossover design (N = 10 males; 20 MRI scans), providing preliminary information on ventral striatal response to risky rewards during catecholamine (CA) activation. Trait SP and task-induced PA were strongly positively related to AMP-facilitated BOLD response in the right nucleus accumbens, a brain region in which DA prediction error signal shapes action value and selection (SP r=+.60, p=.03; PA r=+.72, p=.02, respectively). Participants’ task-induced NA was also strongly positively related with trait SP (r=0.51; d=1.2) and task-induced PA (r=0.68; d=1.9), replicating the findings of Study 1. Together these results inform the phenomenology and neurobiology of agentic anger, which recruits incentive motivational circuitry and motivates personal action in response to goals that entail risk (defined as exposure to uncertainty, obstacles, potential harm, loss and/or financial, emotional, bodily or moral peril). Neural mechanisms of agency, anger, exuberance and risk-taking are discussed, with implications for personal and group action, decision-making, social justice, and behavior change.

Universal human rights are defined by international agreements, law, foreign policy, and the concept of inherent human dignity. However, rights defined on this basis can be readily subverted by overt and covert disagreements and can be treated as distant geopolitical events rather than bearing on individuals’ everyday lives. A robust case for universal human rights is urgently needed and must meet several disparate requirements: (1) a framework that resolves tautological definitions reached solely by mutual, revocable agreement; (2) a rationale that transcends differences in beliefs, creed, and culture; and (3) a personalization that empowers both individuals and governments to further human rights protections. We propose that human rights in existing agreements comprise five elemental types: (1) agency, autonomy, and self‐determination; (2) freedom from want; (3) freedom from fear; (4) uniqueness; and (5) unconditionality, including protections for vulnerable populations. We further propose these rights and protections are rooted in fundamental properties of the human brain. We provide a robust, empirical foundation for universal rights based on emerging work in human brain science that we term dignity neuroscience. Dignity neuroscience provides an empirical foundation to support and foster human dignity, universal rights, and their active furtherance by individuals, nations, and international law.