Development of differences in response latencies to right and left visual fields
Brain and Cognition, Jul 1, 1984
Robust lateralization developed in right-handed adults who were asked to judge letter pairs as &a... more Robust lateralization developed in right-handed adults who were asked to judge letter pairs as "same" or "different" during 4608 trials. By the end of the first two blocks (768 trials) "same" responses were favored when presented in the RVF (transmitted directly to the left hemisphere) and "different" responses were favored when presented in the LVF (transmitted direction to the right hemisphere). This gradually reversed over sessions with "same" responses becoming faster for letters presented in the LVF, and "different" responses becoming faster for stimuli presented in the RVF. The laterality acquired under these conditions was cumulative and reproducible, appeared in all 16 subjects, and was preserved between sessions a week apart. The data suggest that laterality is a flexible and reversible characteristic of the human brain even when stimulus and task remain constant.
An immunogenomic phenotype predicting behavioral treatment response: Toward precision psychiatry for mothers and children with trauma exposure
Brain, Behavior, and Immunity, 2022
Inflammatory pathways predict antidepressant treatment non-response among individuals with major ... more Inflammatory pathways predict antidepressant treatment non-response among individuals with major depression; yet, this phenomenon may have broader transdiagnostic and transtherapeutic relevance. Among trauma-exposed mothers (Mage=32 years) and their young children (M=4 years), we tested whether genomic and proteomic biomarkers of pro-inflammatory imbalance prospectively predicted treatment response (PTSD and depression) to an empirically-supported behavioral treatment. Forty-three mother-child dyads without chronic disease completed Child Parent Psychotherapy (CPP) for roughly 9 months. Maternal blood was drawn pre-treatment, CD14+ monocytes isolated, gene expression derived from RNA sequencing (n=34; Illumina HiSeq 4000;TruSeqcDNA library), and serum assayed (n=43) for C-Reactive Protein (CRP) and interleukin-1ß (IL-1ß). Symptoms of PTSD and depression decreased significantly from pre- to post-treatment for both mothers and children (all p's<.01). Nonetheless, a higher pre-treatment maternal pro-inflammatory imbalance of M1-like versus M2-like macrophage-associated RNA expression (M1/M2)(ß=.476, p=.004) and IL-1ß (ß=.333, p=.029), but not CRP, predicted lesser improvements in maternal PTSD symptoms, unadjusted and adjusting for maternal age, BMI, ethnicity, antidepressant use, income, education, and US birth. Only higher pre-treatment M1/M2 predicted a clinically-relevant threshold of PTSD non-response among mothers (OR=3.364, p=.015; ROC-AUC=.78). Additionally, higher M1/M2 predicted lesser decline in maternal depressive symptoms (ß=.556, p=.001), though not independent of PTSD symptoms. For child outcomes, higher maternal IL-1ß significantly predicted poorer PTSD and depression symptom trajectories (ß's=.318-.429, p's<.01), while M1/M2 and CRP were marginally associated with poorer PTSD symptom improvement (ß's=.295-.333, p's<.056). Pre-treatment pro-inflammatory imbalance prospectively predicts poorer transdiagnostic symptom response to an empirically-supported behavioral treatment for trauma-exposed women and their young children.
Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications ... more Glucocorticoids are the most commonly prescribed anti-inflammatory/immunosuppressant medications worldwide. This article highlights the risk of clinically significant and sometimes severe psychological, cognitive, and behavioral disturbances that may be associated with glucocorticoid use, as well as ways to prevent and treat these disturbances. An illustrative case vignette is presented describing a patient's experience of cycles of manic-like behavior and depression while on high-dosage prednisone, with long-term cognitive disorganization, vulnerability to stress, and personality changes. Severe neuropsychiatric consequences (including suicide, suicide attempt, psychosis, mania, depression, panic disorder, and delirium, confusion, or disorientation)…
Posttraumatic stress disorder (PTSD) is defined by classic psychological manifestations, although... more Posttraumatic stress disorder (PTSD) is defined by classic psychological manifestations, although among the characteristics are significantly increased rates of serious somatic comorbidities, such as cardiovascular disease, immune dysfunction, and metabolic syndrome. In this review, we assess the evidence for disturbances that may contribute to somatic pathology in inflammation, metabolic syndrome, and circulating metabolites (implicating mitochondrial dysfunction) in individuals with PTSD and in animal models simulating features of PTSD. The clinical and preclinical data highlight probable interrelated features of PTSD pathophysiology, including a proinflammatory milieu, metabolomic changes (implicating mitochondrial and other processes), and metabolic dysregulation. These data suggest that PTSD may be a systemic illness, or that it at least has systemic manifestations, and the behavioral manifestations are those most easily discerned. Whether somatic pathology precedes the development of PTSD (and thus may be a risk factor) or follows the development of PTSD (as a result of either shared pathophysiologies or lifestyle adaptations), comorbid PTSD and somatic illness is a potent combination placing affected individuals at increased physical as well as mental health risk. We conclude with directions for future research and novel treatment approaches based on these abnormalities.
Annals of the New York Academy of Sciences, Oct 1, 2009
Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across se... more Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across several different conditions. It remains unknown if this hormonal abnormality is a cause or an effect of the psychiatric conditions. For example, the hypercortisolemia observed in a subset of patients with depression may have a direct impact on the symptoms of depression, but it is also possible that the hypercortisolemia merely reflects the stress associated with depression. Further, rather than causing depression, hypercortisolemia could represent a homeostatic attempt to overcome glucocorticoid resistance. Each of these possibilities will be considered, and correlational and causal evidence will be reviewed. This article will focus on the relationships between glucocorticoids and psychiatric symptoms in Cushing's syndrome, major depression, and steroid psychosis/steroid dementia, as well as the effects of exogenously administered glucocorticoids in normal volunteers. Similarities and differences in the relationship of glucocorticoid hormones to psychiatric symptoms in these conditions will be reviewed. Possible mediators of glucocorticoid effects on the brain and behavior, as well as possible “pro‐aging” effects of glucocorticoids in certain cells of the body, will be reviewed. The article concludes with a conceptual model of glucocorticoid actions in the brain that may lead to novel therapeutic opportunities.
Controllable and uncontrollable stress in humans: alterations in mood and neuroendocrine and psychophysiological function
American Journal of Psychiatry, Nov 1, 1987
The authors exposed 10 healthy human volunteers to the stress of loud (100 dB) noise under contro... more The authors exposed 10 healthy human volunteers to the stress of loud (100 dB) noise under controllable and uncontrollable conditions on two separate days. Subjects reported higher self-ratings of helplessness, lack of control, tension, stress, unhappiness, anxiety, and depression; had greater hypothalamic-pituitary-adrenal axis function as measured by elevations in plasma adrenocorticotropic hormone; and had higher levels of sympathetic nervous system and electrodermal activity after the uncontrollable stress condition than after exposure to controllable stress. Thus, lack of control over even a mildly aversive stimulus can produce alterations in mood as well as neuroendocrine and autonomic nervous system changes in healthy subjects.
Dr. Wolkowitz and Associates Reply
American Journal of Psychiatry, Oct 1, 1986
Diazepam-induced amnesia: a neuropharmacological model of an "organic amnestic syndrome
American Journal of Psychiatry, 1987
Diazepam has well-known amnestic properties. These effects, however, are selective for certain ps... more Diazepam has well-known amnestic properties. These effects, however, are selective for certain psychobiologically distinct memory functions. In this study, incremental doses of diazepam administered to 10 normal volunteers selectively impaired anterograde episodic memory and attention while totally sparing access to information in long-term memory (semantic or knowledge memory). This pattern of disruption mimics that seen in patients with organic amnesias and is in sharp contrast to the pattern seen in patients with dementia. These findings provide a framework for defining specific psychobiological determinants of cognitive failure.
Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA)
De Gruyter eBooks, Jul 1, 2011
510. Major Depression, Childhood Trauma, Parenting Styles and Oxidative Stress: A Well-controlled Study in Unmedicated Individuals
Biological Psychiatry, May 1, 2017
Dehydroepiandrosterone (DHEA) and memory in depressed patients
Biological Psychiatry, May 1, 1994
Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), major circulating steroids in humans whic... more Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), major circulating steroids in humans which serve as precursors for both androgenic and estrogenic steroids, are pleiotropic facilitators of coordinating processes in immune, neural, and metabolic systems, and have been shown to enhance memory in young mice and improve defective recall in old mice. Both substances are diminished with aging and as a result of prolonged s~ss. As a first step in study of possible linkage between impaired memory function and steroid metabolism in patients with major depression, measurements were made of blood levels of cortisol, DHEA, DHEA-S, and of performance in the Weingartuer Memory Task in 57 depressives and 23 age and sex.matched normal controls. No significant differences between depressives and controls were found in levels of DHEA, DHEAS, or cortisol/DHEA and eortisol/DHEA-S ratios. Both groups showed a significant positive correlation of the above ratios with age, reflecting the relative constancy of cortisol and prog.'essive decrements of DHEA and DHEA-S. In the controls, cortisol/DEIEA-S ratios were negatively correlated with components of automatic (p .0009) and semantic (p .04) memory processes. Because of greater variability in cognitive and biochemical measures, correlations did not attain statistical significance in the patients. The results cited above and preliminary data in cognitively impaired individuals support the supposition that circulating androgenic steroids may interact intimately with cognitive processes, and suggest that therapeutic trials are warranted.
Measurement and interpretation of changes in memory in response to drug treatments
PubMed, 1992
Drug-induced changes in cognitive functions such as memory are generally domain specific rather t... more Drug-induced changes in cognitive functions such as memory are generally domain specific rather than general effects, that is, only some components of memory are altered. Changes in memory can be secondary to alterations in other cognitive domains such as attention, or non-cognitive domains (mood and arousal), or the direct result of alterations on those neurobiological systems that determine memory functions. The selective memory impairing effects of benzodiazepines are used to illustrate how cognitive neuroscience methods and theory can be useful in assessing the memory changes produced by psychoactive drugs.
Hormonal changes with cholesterol reduction: a double-blind pilot study
Journal of Clinical Pharmacy and Therapeutics, Feb 1, 2004
The lowering of high serum cholesterol levels may be associated with increased non-cardiac mortal... more The lowering of high serum cholesterol levels may be associated with increased non-cardiac mortality due to behavioral changes, although such endpoints are likely rare. This current study sought to determine if hormonal changes accompany pharmacologically induced decreases in serum cholesterol levels. Cholesterol, dopamine, homovanillic acid (HVA), serotonin, 5-HIAA, testosterone, cortisol and pregnenolone were measured at baseline and after 4 weeks of treatment. Subjects&#39; cholesterol levels significantly declined within 4 weeks. Concomitant significant increase in dopamine and HVA were noted. Although this study is limited in size, it raises the possibility that cholesterol-lowering drug treatment is associated with hormonal perturbations.
Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression
Journal of Psychiatric Research, Jul 1, 2009
Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and d... more Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 (p=0.03, Cohen&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s d=-0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios (p=0.05, Cohen&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s d=0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 (r(21)=-0.57, p=0.005) and non-significantly higher IL-6/IL-10 ratios (r(21)=0.38, p=0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls (r(9)=0.81, p=0.003), but were completely dissociated in depressed subjects (r(10)=0.01, p=0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.
Post-traumatic stress disorder (PTSD) is a highly debilitating psychiatric disorder that can be t... more Post-traumatic stress disorder (PTSD) is a highly debilitating psychiatric disorder that can be triggered by exposure to extreme trauma. Even if PTSD is primarily a psychiatric condition, it is also characterized by adverse somatic comorbidities. One illness commonly co-occurring with PTSD is Metabolic syndrome (MetS), which is defined by a set of health risk/resilience factors including obesity, elevated blood pressure, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, higher triglycerides, higher fasting blood glucose and insulin resistance. Here, phenotypic association between PTSD and components of MetS are tested on a military veteran cohort comprising chronic PTSD presentation (n = 310, 47% cases, 83% male). Consistent with previous observations, we found significant phenotypic correlation between the various components of MetS and PTSD severity scores. To examine if this observed symptom correlations stem from a shared genetic background,...
Uploads
Papers by Owen Wolkowitz