Robert E. Hicks

An immunoreactive theory of selective male affliction

Males are selectively afflicted with the neurodevelopmental and psychiatric disorders of childhood, a broad and virtually ubiquitous phenomenon that has not received proper attention in the biological study of sex differences. The previous literature has alluded to psychosocial differences, genetic factors and elements pertaining to male “complexity” and relative immaturity, but these are not deemed an adequate explanation for selective male affliction. The structure of sex differences in neurodevelopmental disorders is hypothesized to contain these elements: (1) Males are more frequently afflicted, females more severely; (2) disorders arising in females are largely mediated by the genotype; in males, by a genotype by environment interaction; (3) complications of pregnancy and delivery occur more frequently with male births; such complications are decisive and influence subsequent development. We hypothesize that there is something about the male fetus that evokes an inhospitable uterine environment. This “evocative principle” is hypothesized to relate to the relative antigenicity of the male fetus, which may induce a state of maternal immunoreactivity, leading either directly or indirectly to fetal damage. The immunoreactive theory (IMRT) thus constructed is borrowed from studies of sex ratios and is the only explanation consistent with negative parity effects in the occurrence of pregnancy complications and certain neurodevelopmental disorders. Although the theory is necessarily speculative, it is heuristic and hypotheses derived from it are proposed; some are confirmed in the existing literature and by the authors research.

Separating the effects of lead and social factors on IQ.

Initial evaluations of 104 low-socioeconomic status black children screened by the local community health departments in North Carolina showed significant effects of lead in the range 6-59 micrograms/dl on IQ after controlling for concomitant social factors, such as socioeconomic status, home environment, and maternal IQ. The main concomitant variable was socioeconomic status, which was multicolinear with other social factors. Five years later, when all blood lead levels were 30 micrograms/dl or less, lead effects on IQ were no longer significant. The correlation between maternal and child IQ, which had been suppressed initially in children with higher lead levels, returned to expected levels when decreases in blood lead level occurred, while concomitant variables remained stable over the 5-year period.

Clinical correlates of methylphenidate blood levels.

The clinical correlates of methylphenidate blood levels in hyperactive children and normal adults were examined in five studies. Although occasional correlations between blood levels and neuroendocrine response were noted within subjects along the pharmacokinetic time profile of the drug, no significant associations were found between blood levels and clinical response in behavioral measures or laboratory tests of attention or activity. It is unlikely that routine methylphenidate blood level determinations will become a part of the routine clinical management of hyperactive children.

Antagonism of marihuana effects by indomethacin in humans

To investigate whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin antagonized the effects of marihuana, an exploratory single-blind, placebo-controlled study was conducted. Subjects (n = 4) smoked marihuana after pre-treatment with placebo and indomethacin. The subjective rating of marihuana high, heart rate, word recall, time estimation/production, and plasma concentrations of THC and PGE2 were measured. It was found that: 1) indomethacin pre-treatment decreased the elevation of prostaglandins induced by THC; 2) indomethacin significantly attenuated the subjective high and the heart rate accelerating effects of THC, although the magnitude of this effect was modest; 3) indomethacin abolished the profound effect of THC on time estimation and production; and 4) indomethacin pretreatment did not affect the decremental effects of THC on word recall. We conclude that prostaglandins are involved in the neurophysiologic mechanisms that mediate some of the typical clinical effects of THC, particularly the distortion of time perception.

Cannabis, Atropine, and Temporal Information Processing

In experiment 1, subjects judged time by duration production under no-counting instructions. The productions were made following intravenous injection of atropine sulfate or saline, and after smoking cigarettes with and without (-)-delta 9-tetrahydrocannabinol (THC). THC increased the subjective time rate (STR); i.e., the rate at which subjective time passes relative to clock time, whereas atropine had no effect on STR. Thus, reduction in central acetylcholine activity is not a sufficient explanation of THCs effect on STR. Experiment 2 replicated the THC effect on STR when subjects were counting subjective seconds. This result indicates that THC affects the experience of time as it is passing, and not solely the memory for duration experience after a time period.

Influence of sex of antecedent siblings on the human sex ratio

Analysis of family configurations in a population of 649,366 American secondary school students confirmed that sex of later-born children is influenced by the sex of antecedent siblings. Antecedent brothers decrease the probability of subsequent male births. This observation, a confirmation of an earlier report in a substantially smaller sample, is consistent with an immunologic influence on human sex determination.

Abnormal neuroendocrine responsivity to acute I.V. clomipramine challenge in depressed patients

The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.

The pharmacologic effects of daily marijuana smoking in humans.

Six healthy male, paid volunteers smoked one NIDA cigarette containing 1.0% THC each day for 13 consecutive days. They were tested before and after the period of drug administration by the following procedure: the subjects smoked one NIDA marijuana cigarette containing 1.0% THC followed 15 minutes later by the intravenous infusion of 52 micrograms/min of deuterated THC for 50 minutes. The THC plasma concentrations, ratings of high and heart rate effects produced by the combined drug administration were measured, and absolute bioavailability of smoked THC was calculated on Days 1 and 22. Statistical analyses indicate that the only significant changes induced by daily marijuana exposure were in cardioacceleration.

The Locus of Bimanual Skill Transfer

Subjects (N = 128) practiced a typing task with one hand while the other hand either grasped the table leg (experimental condition) or was free (control condition). Subsequently, the other hand showed savings in training in the control but not in the experimental condition. The abolition of transfer of training by engaging the fingers of the test hand in unrelated activity during training suggests that transfer is mediated by irradiation of the emerging motor program from the control center of the training limb to that of the test limb during and not after acquisition.

Differential Psychopharmacology of Methylphenidate and the Neuropsychology of Childhood Hyperactivity

The principle of rate-dependency has been proposed to explain the therapeutic effects of stimulant drugs in hyperactive children (HAC). This paper is a critical discussion of the salience of rate-dependency to childhood hyperactivity, on mathematical, theoretical and clinical levels. The results of a stimulant drug trial in 55 HAC are presented; the data are analyzed using analysis of variance to describe main drug effects, and these are compared to results derived from a traditional rate dependency analysis. The latter are found to have little salience to the actual clinical effects of stimulant drugs on a wide variety of behavioral, physiological and laboratory measures. The weakness of the rate dependency hypothesis, however, is not necessarily fatal to the idea that the state of the organism prior to drug administration influences the response profile of the drug. The heterogeneity of stimulant effects, and the relationship between stimulant effects and the predrug state of the organism, especially in electrophysiological paradigms, are clear. A hypothesis is presented to suggest that HAC may be characterized by a trait of excessive variability. Homeostatic stimulant effects in reducing response variability may be central to the therapeutic action of the drug. A neural substrate for the abnormal oscillations which characterize HAC, the correction of which is germane to therapeutic stimulant effects, is presented in terms of the regulatory functions of the frontal lobe. A neuroanatomic locus of childhood hyperactivity is proposed in terms of disorder or dysmaturation of frontal striatal systems.