Sunday, December 16, 2007

Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude

Iacono, W.G., Malone, S.M., & McGue, M. (2002). Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude, International Journal of Psychophsiology, 147-178.

This article hypothesizes the existence of an inherited predisposition for a variety of externalizing disorders characterized by behavioral disinhibition, or behavioral undercontrol. This study names as examples childhood disruptive disorders, antisocial behavior, and substance use disorders. Support for genetically-influenced nervous system dysfunction comes from a reduced P300 amplitude (abbreviated as P3-AR), a positive deflection signal recorded via EEG, witnessed in visual oddball tasks. Several findings support using the P3-AR as an endophenotype, or index of vulnerability for these externalizing disorders, all coming from the Minnesota Twin Family Study. Namely, (i) the P3-AR is shown to be associated with familial risk for substance use and antisocial personality disorders, (ii) the P3-AR is associated with diagnoses of childhood disruptive disorders and substance abuse disorders, (iii) and the P3-AR is associated with early onset of undersocialized behavior, among others.

Tuesday, December 4, 2007

Affect Regulation

Schore, A.N. (2002). Dysregulation of the Right Brain: A Fundamental Mechanism of Traumatic Attachment and the Psychopathogenesis of Posttraumatic Stress Disorder, Australian and New Zealand Journal of Psychiatry, 36, 9-30.

This article is by Allan Schore, a doctor in UCLA’s department of Psychiatry and an impressively well-published author. Schore’s style is to assimilate interdisciplinary literature into unified theories of brain function. This review article does well to illustrate his approach by integrating the latest thinking from attachment theory, affective neuroscience, developmental stress research, and infant psychiatry into a theory on post-traumatic stress disorder (PTSD). The article drives home several key points:

(1) The individual response to stressful stimuli may or may not be adaptive.

(2) Current evidence shows that the neural circuitry of the stress system is located in the early developing right brain, the hemisphere that is dominant for affect regulation and inhibitory control.

(3) The development of the right brain is highly experience-dependent, and this experience is primarily mediated by the dyadic attachment relationship that develops between caregiver and infant. Simply put, the mother plays a key role in co-regulating the infant’s postnatally developing nervous system, particularly its stress responses. At a very early age, we thereby rely on and learn strategies from our mothers on self-regulation of emotion. As such, if either the mother or the child is improperly psychobiologically attuned to the body-based states of the self or the other (for whatever reason), this can have detrimental effects on the child’s autoregulatory mechanisms which are still under construction.

(4) This point I will offer more parenthetically. Social stressors are far more detrimental than non-social aversive stimuli. As an example, abuse or neglect would be likely to have a much more deleterious effect on the infant brain than assaults from the nonhuman or inanimate, physical environment. From this, I think one can conclude our brains are more specially honed to social cues than to other types of input.

(5) Due to the shape of the human developmental arc, early experiences in life may be particularly important in shaping an individual’s responsiveness later in life. As developmental effects are almost always cumulative, building on the brick and mortar that has already been laid by previous developmental processes, later growth is “limited by the adequacy of already-formed, underlying networks, and therefore maturation is optimal only if the preceding stages were installed optimally”.

(6) Stress effects are also shown to be cumulative. Whereas acute stress produces short-term and reversible deficits, repeated, prolonged, chronic stress can lead to irreversible or only partially reversible enduring effects.

Add it all up and essentially Shore has conceived of a vignette in which the experiences of the maturing infant can establish inefficient coping mechanisms and individual “dissociation” in times of stress, seen behaviorally even many years later in adulthood. The crux of it… “Optimal attachment experiences allow for the emergence of self-awareness, the ability to sense, attend to, and reflect upon the dynamic changes of one’s subjective self states, but traumatic attachments in childhood lead to self-modulation of painful affect by directing attention away from internal emotional states.” More impressive yet are the 246 citations he makes in an 18-page article!

What is personally interesting to me is the take-away that our development – and in this case, our emotional development – is so unambiguously externally mediated, especially by close parental and familial relationships. (We actually see a reasonable case for the intergenerational transmission of regulation and coping strategies.)

But more importantly, we are essentially “propped” or “wired up” to learn via social mechanisms from people with whom we have intimacy. Said another way, certain parts of the brain may be more receptive to reprogramming by social “interfacing” than by other mechanisms, perhaps even in adulthood. This idea is central to Schore’s thinking on the therapist-patient relationship, which he expounds upon in his three-book-set on Affect Regulation.

Saturday, December 1, 2007

The Neural Basis of Human Error Processing

Holroyd, C.B. and Coles, M.G.H. (2002). The Neural Basis of Human Error Processing: Reinforcement Learning, Dopamine, and the Error-Related Negativity, Psychological Review, Vol. 109, No. 4, 679-709.

It is clear that our superior ability to learn from consequences makes us quite exceptional animals. But what are the neural substrates for reinforcement learning? This article takes a stab at that question.

Researchers have inferred the existence of a generic, high-level error-processing system in the brain for some time. When human participants commit errors in a wide variety of psychological tasks, a negative deflection is witnessed in EEG data, deemed the error-related negativity (ERN), which appears to be generated from anterior cingulate cortex (ACC). On the other hand, researchers have argued that the mesencephalic dopamine system conveys reinforcement learning signals to the basal ganglia and frontal cortex, where they are used to facilitate development of adaptive behavioral programs. This article proposes a hypothesis which unifies the two – specifically, when human subjects commit errors the dopamine system conveys a negative reinforcement learning signal to the frontal cortex where it generates an ERN by disinhibiting the dendrites of motor neurons in the ACC (hence the negative potential seen).

To dig a bit deeper... first the mesencephalic dopamine system. This is a small collection of nuclei including the substantia nigra pars compacta and the ventral tegmental area (VTA) that project diffusely to the basal ganglia and frontal cortex. The consequence of stimulation from this area appears to reinforce learning, solidifying behavior. After learning how to complete a task properly, presentation of a reward elicits a phasic response in dopamine neurons. When a reward is better than predicted, a positive dopamine signal is elicited. And, as expected, when (i) an expected reward is not delivered, (ii) a reward is worse than predicted, or (iii) punishment is administered instead, mesencephalic dopamine neurons decrease their firing rate, falling below baseline. Interestingly, over time and practice on a task, the presentation of the reward no longer elicits the phasic dopaminergic response; instead, the conditioned stimulus predicting delivery of the reward elicits the phasic activity. As such, the phasic dopaminergic activity is said to propagate “back in time” from the reward to the conditioned stimulus with learning. Thus, the mesencephalic dopamine system can be understood to produce predictive and critical error signals which can be used by other parts of the brain for reinforcement learning.

Now the ERN. The ERN is a negative wave pattern witnessed during commission of an error, essentially the brain’s “Oh shit!” signal. The amplitude of the ERN increases with incentive (e.g. financial reward) and with the degree of error (i.e. very wrong errors as opposed to only slightly incorrect). The ERN can be elicited (i) by presentation of negative feedback to the participant, or (ii) by detection of error commission itself.

The theory that this paper offers is that the ACC, which generates the ERN and receives input from numerous semi-independent command structures, is responsible for conflict monitoring in the brain – detecting competing choices from these multiple motor controllers and resolving the response conflict. Its job is therefore to identify which of its input are best suited for carrying out the task – serving as a motor control filter – and finally transforming multiple intentions into a unitary action. They contend that the ACC is “trained” into choosing the correct controller by the mesencephalic dopamine system’s reinforcement learning signals, and that the ERN essentially reflects transmission of this reinforcement learning signal to the ACC. The mesencephalic dopamine system, then, plays the role of an adaptive critic, assigning a “goodness” or “badness” to witnessed response outcomes, and communicates its opinion to the ACC to bias future decision-making.

The article used behavioral data (a probabilistic learning task) to support this hypothesis, as well as computer simulation modeling which predicted the observed behavioral results.

Selective Effects of Ritalin in ADHD

Vaidya, C.J., Austin, G., Kirkorian, G., Ridlehuber, H.W., Desmond, J.E., Glover, G.H., & Gabrieli, J.D.E. (November 1998). Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study, Neurobiology, 95, 14494-14499.

ADHD is the most common developmental disorder of childhood and has been associated with such adverse life outcomes as lower educational and occupational achievement, as well as increased risk for various disorders in adulthood. Evidence suggests that ADHD is characterized by dysfunction in transmission of dopamine to the frontal lobes and striatal (basal ganglia) structures of the brain since ADHD symptoms typically respond favorably to stimulant medications (e.g. methylphenidate) that release and inhibit reuptake of dopamine in these regions. However, prior to this study, there was no direct evidence to indicate differences in dopaminergic modulation between ADHD and normal children. Therefore, the purpose of this study was to see: (a) how performance in response inhibition tasks differs between ADHD children and normal children, (b) how administration of methylphenidate improved performance in response inhibition tasks in ADHD children in comparison with normal children, (c) how baseline frontal-striatal function differ in ADHD and control children, and (d) how methylphenidate modulates frontal-striatal function differently in ADHD and control children. Since inhibition of motor responses is known to depend on the integrity of both frontal and striatal structures, functional magnetic resonance imaging (fMRI) was used to image the frontal lobes, as well as the head of the caudate nucleus and the anterior portion of the putamen during response inhibition tasks to assess the four aforementioned points.

Each subject in the study was presented with various computer-generated stimuli and instructed to respond with a button-press on a hand-held joystick. In one block, they were told to respond to all stimuli presented. In another block, they were told to respond to all stimuli except for one (inhibition). Their behavioral performance was measured by the percentage of errors committed during the task. At the same time, activation of certain brain regions was gathered during the trials via fMRI. With the different independent variables and levels, the overall design looks something like the following table for the "stimulus-controlled" task (for brevity, I will neglect to mention the "response-controlled" task and results):

The results can be condensed as follows: (a) The ADHD group made more errors than the control group on the response inhibition task. (b) Both the ADHD and the control groups showed significant improvements on the task with the administration of MPH. (c) Baseline striatal activation was shown to be lower in ADHD subjects than in the control group. (d) Administration of MPH increased striatal activation in ADHD subjects but decreased striatal activation in control subjects.

The results support the hypothesis that there are indeed differences between ADHD children and normal children, both in performance on response inhibition tasks and in their striatal activation in the absence of stimulant medication. And further, when administered stimulant medication, ADHD children showed different functional reactions to the medication in the striatum than their control group counterparts. These are important findings, especially given the neural specificity of the results.

Neuroscience of ADHD

Castellanos, F. X. (August 2002). Neuroscience of Attention-Deficit/Hyperactivity Disorder: The Search for Endophenotypes, Nature Reviews. Volume 3.

An endophenotype is an heritable quantitative trait that can be used to index and predict a person's risk of developing a given disease. Research into ADHD has traditionally been hampered by confusion over fuzzy operational definitions and diagnostic criteria. Towards development of an objective diagnostic test, the authors of this article propose three categories of endophenotypes, each grounded in neuroscience.

Abnormality in the reward-related circuitry that leads to shortened delay gradients. Delay aversion tasks can assess a person's intolerance for waiting that can lead to selection of an immediate reward over a larger, delayed reward. Sonuga-Barke argues that fundamental abnormalities in the reward mechanisms of ADHD subjects translate into a faster decline in the effectiveness of reinforcement as the delay between behavior and reward increases.

Deficits in temporal processing. People with ADHD appear to exhibit deficits in time-estimation and time-production, especially time estimation tasks between 2-60 seconds which require cortical mediation and rehearsal in working memory (as opposed to smaller durations which are dependent on the basal ganglia and cerebellum), but not wholesale -- instead, they exhibit variability in performance. This article suggests that this variability itself is a characteristic of the disorder and can be used as a rating.

Deficits in working memory. Working memory controls attention and guides decision-making and behavior. It is mediated by the prefrontal cortex and modulated by the catecholamines dopamine and noradrenaline. Catecholaminergic dysregulation and prefrontal dysfunction are central to the pathophysiology of ADHD. A P300 Component, derived from EEG analysis, provides an index of the attentional and working memory demands of a task and may be fitting for use as an endophenotype. (See also Coherence wave patterns.)

Other candidate endophenotypes were ruled out due to incompleteness of data, potential confounds, or the multiplicity of operational definitions. These include genetic factors, locomotor hyperactivity, and general response inhibition.

Sex Differences in Jealousy

Buunk, B.P., Angleitner, A., Oubaid, V., & Buss, D.M. (1996). Sex Differences in Jealousy in Evolutionary and Cultural Perspective: Tests From the Netherlands, Germany, and the United States, Psychological Science, 7, 359-363.

In the 1992 article “Sex differences in jealousy in evolutionary and cultural perspective”, Buunk et al. suggested that women typically find emotional infidelity to be more distressing than sexual infidelity, whereas men are bothered more than women by sexual infidelity. The article leapt to the conclusion that these results supported hypotheses of jealousy offered by evolutionary psychology, a field which believes behavior evolves in a species if it is (or was) somehow adaptive. C.R. Harris & N. Christenfeld (HC) reacted to the article with “Gender, Jealousy, and Reason” which provided an alternate explanation for how such data might appear.

The experiment of the 1992 Buunk et al. article was replicated by HC during their subsequent study, reaching similar results. Both studies revealed that men demonstrate greater anguish to sexual than to emotional infidelity of their partner, whereas women grow more upset to emotional infidelity. However, HC were skeptical of the conclusions drawn by Buunk et al. – namely that the gender differences in sexual jealousy shown across geography and cultures was necessarily in support of an evolutionary psychology explanation.

In order to combat such conclusions, HC posed some additional questions to their respondents. First, they explicitly asked if they discovered that their partner was engaging in sexual intercourse with someone else, how likely did they think that their mate would be in love with this person. Conversely, they also asked respondents to imagine they discovered their mate was in love with someone else and to indicate how likely they believed their partner would also be engaging in sex with this other person.

The results concluded that men think that sex implies love for their partners more so than women, whereas women think that love implies sex more so than men. Given this extra data, one would find it reasonable to conclude, as a woman, that emotional infidelity also implies sexual infidelity. Essentially a double whammy, likely signifying both emotional and sexual infidelity, emotional infidelity is thus logically more troubling to a woman and might account for the uniqueness of results across genders.

Suggesting that men and women may instead show differences in their interpretations of the evidence of infidelity, HC challenged the foundational conclusions of Buunk et al. Although applying evolutionary psychology models may be provocative and convincing, HC showed that cognitive explanations may be equally plausible. Thus, one should exercise caution when interpreting the results of such a study of jealousy.

The Neurobiology of Depression

Nemeroff, C.B. (June 1998). The neurobiology of depression. Scientific American, vol. 278, no. 6, 42(7).

This article by Nemeroff is about depression and the search for its biological underpinnings. Depression is a psychiatric disorder characterized by an inability to concentrate, insomnia, loss of appetite, general absence of pleasure, feelings of extreme sadness, guilt, helplessness and hopelessness, and perseverant thoughts of death. However, understanding the neurobiology of depression is a daunting task and still ongoing, as is the goal of identifying simple biological markers (endophenotypes) for the disorder.

The prevalence of depression is surprisingly high, and should get more publicity in my opinion. 5-12% of men and 10-20% of women in the US will experience a major depressive episode at least once in their life, with half of these individuals becoming depressed more than once. As many as 15% of those who suffer from depression will commit suicide each year; in fact, the CDC has ranked depression as the 9th leading cause of death in the US. Further, depression takes its toll economically as well, with an estimated productivity hit of $43 billion each year. Clearly, the need for improved methods of diagnosing, treating, and preventing the disease is becoming more and more critical.

Several neurobiological theories of depression were mentioned in this article. Neurotransmitter hypotheses focus on disturbances in brain circuits that convey signals through monoamine neurotransmitters. For example, Joseph Schildkraut proposed that depression stems from a deficiency in norepinephrine whose circuits originate in the brain stem’s pigmented locus coeruleus and project to many cortical and subcortical regions throughout the brain. Arthur J. Prange, Jr. implicated serotonin-producing neurons which project from the brain stem’s raphe nuclei. Still others point to the dysregulation of the hypothalamicpituitary-adrenal (HPA) axis, which mediates the body’s response to stress. Studies have revealed that chronic hyperactivity in this region is well correlated with depressive symptomatology. In particular, studies show an increased number of corticotrophin releasing factor (CRF) producing neurons in the hypothalamus as well as increased synthesis of CRF in depressed patients as compared with controls, increasing the likelihood of these patients to enter states of hyperarousal (i.e. low stress tolerance) and inevitably lowering their threshold for depression.

Vision: A Window on Consciousness

Logothetis, N.K. (November 1999). Vision: A Window on Consciousness, Scientific American.

In this article, Nikos k. Logothetis, Director of the physiology of cognitive processes division at the Max Planck Institute in Germany, summarizes some recent research attempting to grope at the problem of consciousness.

What is consciousness? What are we actually conscious of? Is there a consciousness cortex? Or shy of that, are there certain pockets of neurons well correlated with subjective awareness? Neuroscience has grown increasingly concerned with these questions as it has grown increasingly more equipped to answer them. Logothetis scopes the article to a discussion of experiments related to visual awareness. As our visual processing is far and away the most adept sensory system, it is an important place to begin study.

Inspired by ambiguous stimuli (such as Necker Cubes and Salvador Dali paintings), which can be useful in experiments designed to reach consciousness, Logothetis describes how experiments involving binocular rivalry have show promising initial results. In binocular rivalry, the visual system is exposed to two “opposing” images, one in each eye, which can be difficult to resolve. To the conscious observer, these opposing images appear to alternate in consciousness, the mind becoming aware of one and then the other as the visual system selects one visual stimulus from one eye and then the other. This presents some interesting opportunities for examining the role of consciousness.

Using brain imaging and single cell recording techniques, the researchers reveal that neurons whose behavior reflects perception are distributed throughout the visual pathway. However, earlier stages of the visual pathway do not show behavior related directly to perception as often as later stages of the pathway which more reliably correlate with awareness. As an example, the inferior temporal cortex (ITC), long believed to be important for perceiving form and recognizing objects, appears to be a particularly active region when subjects report seeing faces.Technology has brought us to a place where tools exist in our toolbox for elucidating the mysteries of the mind. However, the sheer complexity of the human brain will ensure that isolating brain structures, pathways, and processes responsible for mediating consciousness will still be a daunting task for future researchers.

The Quest for a Smart Pill

Hall, S. S. (September 2003). The Quest for a Smart Pill, Scientific American, Vol. 289 (Issue 3).

This article shines light on a relatively new class of drugs that has cognitive enhancement effects such as improved memory, increased alertness, and better overall mental acuity. While this may seem like good news for the many people worldwide who already suffer cognitive impairments as the result of neurodegenerative diseases, aging, stroke, or retardation, others question how these drugs may be “abused” by the normal population for daily performance enhancement. As the science and engineering pushes quickly ahead, bioethicists are left playing catch-up, contemplating and debating the social dangers of the widespread use of these substances as “lifestyle” drugs.

The Neurobiology of Multiple Sclerosis

Hauser, S.L. & Oksenberg, J.R. (October 5, 2006). The Neurobiology of Multiple Sclerosis: Genes, Inflammation, and Neurodegeneration, Neuron.

Multiple sclerosis (MS) is the most common cause of chronic neurological disability in adults. It is estimated to affect two million individuals worldwide. The diagnosis of MS has been aided by MRI technology which reveals multiple, asymmetrically-located white matter lesions throughout the CNS. The PNS, however, appears to be unaffected by the disease. The destruction of this insulating layer of myelin in the brain and spinal cord causes vital electrical signals to be sent more slowly and less efficiently.

Initial symptoms commonly include weakness or diminished dexterity in the limbs, sensory disturbance, monocular visual loss, double vision, and gait instability. As the disease progresses, bladder dysfunction, fatigue, and heat sensitivity are all likely to occur. Cognitive impairments include memory loss, impaired attention, problem-solving difficulties, slowed information processing, and difficulties in shifting between cognitive tasks. Depression is experienced by about 60% of patients during the course of the illness. Onset of symptoms may be either quick or slow depending on the individual.

The genetic component in MS is primarily suggested by aggregated family students and the high incidence of the disease in some ethnic populations (particularly those of northern European origin). Correlational data also suggest a role for environmental factors in MS, and common viruses are thought to be likely infectious agent culprits.

Numerous studies provide the rationale for a disease model driven by the loss of immune homeostasis and uncontrolled immune responses against structural CNS components. Therefore, treatments typically take aim at both inflammation and neurodegeneration. One class of drugs attempts to suppress the auto-immune response, while another aims to promote remyelination in surviving axons as well as more holistic repair. However, mixed therapeutic results in practice leave this an open problem for science to solve.

About this Blog

In the upcoming months and years, I will be doing increasingly more and more reading of articles in the areas of Psychology and Neuroscience. To help myself and others in this process, I will be posting quick, pithy summaries of these articles on this blog.

Please keep me honest... Comments welcome, of course!

As a companion to this blog, I recommend using:
Google Scholar