Randy Bruno - The Cerebral Cortex Is Wired with Two Separate Circuits that Do Separate Things

A new study out of Columbia University, by neuroscientist Randy Bruno, offers what the authors claim is a new model for how the brain is wired. In a study on rat brains, Bruno found that sensory stimuli are processed in two areas of the cortex simultaneously - what previously has been theorized as parallel processing (see Borst, Thompson, and Kosslyn, 2011, American Psychologist, who also proposed an upper and lower pathway in the cortex).

“The upper and lower layers form separate circuits that do separate things.” The discovery, he says, “opens up a different way of thinking about how the cerebral cortex does what it does, which includes not only processing sight, sound, and touch but higher functions such as speech, decision-making, and abstract thought.”

This is not a new idea - it has been assumed that the brain is capable of parallel processing for more than two decades (research looked at the parallel processing of pain in 1991). Here are a couple of older examples (from the Borst, Thompson, and Kosslyn article):

Wilson, Scalaidhe, and Goldman-Rakic (1993) showed that the ventral pathway projects to the ventrolateral prefrontal cortex, whereas the dorsal pathway projects to the dorsolateral prefrontal cortex, mediating, respectively, object working memory and spatial working memory.

And

Goodale and Milner (1992) proposed an alternative account of the functions carried out by the two cortical pathways. Within their framework, the dorsal pathway mediates the control of action by transforming spatial information about objects (locations and spatial configurations) to guide actions. In contrast, the ventral pathway identifies objects, actions, and causal relations between them (see also Milner & Goodale, 1995; Goodale, 2008). This characterization led Goodale and Milner to dub the dorsal and ventral pathways the how and what systems, respectively.

 Anyway, it's not a new idea, but it is another solid piece of the puzzle.

Study Advances New Theory of How the Brain Is Wired

A nerve cell in the thalamus (blue) sends its axon (red) into the cerebral cortex, where it makes synaptic connections with thousands of neurons. While most of these connections are in a middle layer of the cortex (gray rings), some sparse branches connect to deeper layers.

Speaking. Seeing. Hearing. Thinking. Remembering. Understanding this sentence and making a decision about whether or not to read on. All of this work is handled in the cerebral cortex, the deeply creased, outermost portion of the brain that is the center of all the higher brain functions that make us human. Humans have the thickest cortex of any species but, even so, it measures no more than 4 millimeters (.16 inches) thick.

For decades, scientists thought they had a pretty clear understanding of how signals move through the cerebral cortex. By studying the anatomy of nerve axons—the wires that connect nerve cells—they had concluded that information is relayed through a “column” of six layers of specialized nerve cells in a series of hand-offs that begins in the mid-layer of the cortex, then moves to other layers before triggering a behavioral response.

Now a study by Columbia neuroscientist Dr. Randy Bruno indicates this longstanding view is incorrect. Looking at how sensory information is processed in rats, Bruno found that signals are processed in two parts of the cortex simultaneously rather than in series—almost as if there are two brains.


Dr. Randy Bruno. Photo by Amelia Panico.

"Our findings challenge dogma,” says Bruno, assistant professor of neuroscience and a faculty member at Columbia’s new Mortimer B. Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science. “The upper and lower layers form separate circuits that do separate things.” The discovery, he says, “opens up a different way of thinking about how the cerebral cortex does what it does, which includes not only processing sight, sound and touch but higher functions such as speech, decision-making and abstract thought.”

The study, co-authored with Christine Constantinople, who earned a Ph.D. at Columbia and is now a post-doctoral researcher at the Princeton Neuroscience Institute, appears in the June 28 edition of the journal Science.

The research was conducted in the well-understood sensory system of rat whiskers, which operate much like human fingers, providing tactile information about shape and texture. This information travels from nerve fibers at the base of the whiskers to the thalamus in the midbrain and then is processed in the cerebral cortex. Past research has mapped each whisker to a specific barrel-shaped cluster of neurons in the brain. “The wiring of these circuits is similar to those that process senses in other mammals, including humans,” Bruno notes.

The new study relies on a sensitive technique that allows researchers to record how signals move across synapses from one neuron to the next in a live animal by using micropipettes whose tips are just 1 micron wide—one-thousandth of a millimeter. The recordings showed that signals are relayed from the thalamus to the mid- and deeper layers of the cortex simultaneously with surprisingly robust signaling to the deeper layer.

A microscope image of a nerve cell and its many branches (or dendrites) 

in a deep layer of a rat's cerebral cortex.

To confirm that the deeper layer receives sensory information directly from the thalamus, the researchers blocked all signals from the mid-layer using a local anesthetic. Sure enough, activity in the deeper layer remained unchanged.

“This was very surprising,” says Constantinople. “We expected activity in the lower layers to be turned off or very much diminished.”

The study suggests that the upper and lower layers of the cerebral cortex form separate circuits that play separate roles in processing sensory information. Researchers believe that the deeper layers are evolutionarily older—they are found in reptiles, for example, while the upper and middle layers appear in more evolved species and are thickest in humans.

One possibility, suggests Bruno, is that basic sensory processing occurs in the lower layers: for example, visually tracking a tennis ball. Processing that involves integrating context or experience might be done in the upper layers – for example, watching where an opponent is hitting the ball and planning where to return the shot.

German neurobiologist Bert Sakmann, who won a 1991 Nobel Prize for developing the micropipette system of mapping nerve impulses, describes the study as a game changer. “Dr. Bruno has produced a technical masterpiece that now firmly establishes two separate input streams to the cortex,” he says.

Bruno’s lab is now focused on exploring how the various layers of cortex relate to specific behaviors, such as memory and learning. “Developing a more refined understanding of cortical processing will take the combined efforts of anatomists, cell and molecular biologists, and animal behaviorists,” says Dr. Thomas Jessell, Claire Tow Professor of Motor Neuron Disorders in Neuroscience and a director of both the Zuckerman Institute and the Kavli Institute. “The Zuckerman Institute, with its multidisciplinary faculty and broad mission, is ideally suited to building on Bruno’s fascinating new insight.”

—by Claudia Wallis

* * * * * * *

Here is the abstract from Science, which is not an open access journal.

DEEP CORTICAL LAYERS ARE ACTIVATED DIRECTLY BY THALAMUS

The thalamocortical (TC) projection to layer 4 (L4) is thought to be the main route by which sensory organs communicate with cortex. Sensory information is believed to then propagate through the cortical column along the L4→L2/3→L5/6 pathway. Here, we show that sensory-evoked responses of L5/6 neurons in rats derive instead from direct TC synapses. Many L5/6 neurons exhibited sensory-evoked postsynaptic potentials with the same latencies as L4. Paired in vivo recordings from L5/6 neurons and thalamic neurons revealed substantial convergence of direct TC synapses onto diverse types of infragranular neurons, particularly in L5B. Pharmacological inactivation of L4 had no effect on sensory-evoked synaptic input to L5/6 neurons. L4 is thus not an obligatory distribution hub for cortical activity, and thalamus activates two separate, independent “strata” of cortex in parallel.

Full Citation:
Constantinople, CM, and Bruno, RM. (2013, Jun 28). Deep Cortical Layers Are Activated Directly by Thalamus. Science: Vol. 340 no. 6140 pp. 1591-1594. DOI:10.1126/science.1236425

On Vacation . . . Normal Posting Returns Next Week

Just a quick note. I have scheduled one post each day while I am out of town. I'm taking a much needed vacation with my partner in beautiful, humid Sedona, AZ. Pics below (because without pics, it didn't happen).

Degree of Early Life Stress Predicts Decreased Medial Prefrontal Cortex Activity and Shift from Internal to External Decision-Making

Another piece of research in the continuing saga of the prefrontal cortex - this time a look at how early life stress (ELS) predicts decreased prefrontal medial cortex activity, as well as a shift from internally-focused decision-making to externally-focused decision making.

This study is expected to be of great interest in the field of ELS itself in that it provides evidence about the relations among ELS, resting-state brain activity, task induced brain activity, and behavioral tendencies. Beyond elucidating the phenomena associated with ELS, this line of investigation is expected to contribute to improvement of our understanding of resting-state brain activity and self-oriented processes.

Interesting stuff - this is another piece of support for the developmental trauma diagnosis that should have been in the DSM-5.

The degree of early life stress predicts decreased medial prefrontal activations and the shift from internally to externally guided decision making: an exploratory NIRS study during resting state and self-oriented task

Takashi Nakao 1, Tomoya Matsumoto 2, Machiko Morita 3, Daisuke Shimizu 3, Shinpei Yoshimura 4, Georg Northoff 5, Shigeru Morinobu 2, Yasumasa Okamoto 2 and Shigeto Yamawaki 2

1. Department of Psychology, Graduate School of Education, Hiroshima University, Hiroshima, Japan2. Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan3. Faculty of Medicine, Hiroshima University, Hiroshima, Japan4. Faculty of Psychology, Otemon Gakuin University, Osaka, Japan5. Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

Early life stress (ELS), an important risk factor for psychopathology in mental disorders, is associated neuronally with decreased functional connectivity within the default mode network (DMN) in the resting state. Moreover, it is linked with greater deactivation in DMN during a working memory task. Although DMN shows large amplitudes of very low-frequency oscillations (VLFO) and strong involvement during self-oriented tasks, these features’ relation to ELS remains unclear. Therefore, our preliminary study investigated the relationship between ELS and the degree of frontal activations during a resting state and self-oriented task using near-infrared spectroscopy (NIRS). From 22 healthy participants, regional hemodynamic changes in 43 front-temporal channels were recorded during 5 min resting states, and execution of a self-oriented task (color-preference judgment) and a control task (color-similarity judgment). Using a child abuse and trauma scale, ELS was quantified. We observed that ELS showed a negative correlation with medial prefrontal cortex (MPFC) activation during both resting state and color-preference judgment. In contrast, no significant correlation was found between ELS and MPFC activation during color-similarity judgment. Additionally, we observed that ELS and the MPFC activation during color-preference judgment were associated behaviorally with the rate of similar color choice in preference judgment, which suggests that, for participants with higher ELS, decisions in the color-preference judgment were based on an external criterion (color similarity) rather than an internal criterion (subjective preference). Taken together, our neuronal and behavioral findings show that high ELS is related to lower MPFC activation during both rest and self-oriented tasks. This is behaviorally manifest in an abnormal shift from internally to externally guided decision making, even under circumstances where internal guidance is required.

Full Citation: 

Nakao T, Matsumoto T, Morita M, Shimizu D, Yoshimura S, Northoff G, Morinobu S, Okamoto Y, and Yamawaki S. (2013, Jul 3). The degree of early life stress predicts decreased medial prefrontal activations and the shift from internally to externally guided decision making: an exploratory NIRS study during resting state and self-oriented task. Frontiers in Human Neuroscience; 7:339. doi: 10.3389/fnhum.2013.00339

Introduction

By definition, early life stress (ELS) derives from adverse experiences during childhood and adolescence including physical, sexual, and maltreatment abuse (Brown et al., 2009). Demonstrably, ELS is associated with deficits in cognitive and affective function (Pechtel and Pizzagalli, 2011) and is a significant risk factor for mood and anxiety disorders later in life (Heim and Nemeroff, 2001; Heim et al., 2010; Schmidt et al., 2011). Several lines of evidence have indicated that ELS elicits structural changes in the brain. For example, reports of some animal studies have described that ELS results in abnormally increased synaptic density in the infralimbic cortex (Ovtscharoff and Braun, 2001), and decreased dendritic spine density in the prefrontal cortex (PFC) (Murmu et al., 2006). Reports of human neuroimaging studies have described that ELS is associated with reduced gray matter volume including that of the PFC (De Bellis et al., 2002; Andersen et al., 2008; Paus et al., 2008; Hanson et al., 2010).

Although few functional neuroimaging studies have addressed the influence of ELS, activations within the default mode network (DMN) are known to be associated with ELS (Burghy et al., 2012; Philip et al., 2013a,b; van der Werff et al., in press; Cisler et al., 2013; Wang et al., in press). The DMN consists mainly of cortical midline structures (Northoff and Bermpohl, 2004; Raichle and Gusnard, 2005) and comprises the medial prefrontal cortex (MPFC), posterior cingulate cortex, and superior temporal/inferior parietal cortex (Fox et al., 2005; Kim et al., 2010; Qin and Northoff, 2011). The DMN is more active at rest than during goal-directed/externally guided cognitive tasks (Raichle et al., 2001; Buckner et al., 2008). Regions within the DMN show a high degree of functional connectivity during rest (Raichle et al., 2001; Beckmann et al., 2005; Raichle and Snyder, 2007;Buckner et al., 2008). Regarding these features of the DMN, ELS is known to be associated with greater deactivation of DMN during a working memory task (Philip et al., 2013b), and shows decreased functional connectivity within the DMN during a resting state (Burghy et al., 2012;van der Werff et al., in press; Cisler et al., 2013; Wang et al., in press; Philip et al., 2013a).

Neuronally, the DMN can be characterized by large amplitudes of spontaneous slow oscillations during a resting state (Raichle et al., 2001;Fransson, 2005; Zou et al., 2008). Slow oscillations have been observed using measurements of different types, functional magnetic resonance imaging (fMRI; Biswal et al., 1995; Fransson, 2006; Chepenik et al., 2010), electroencephalography (EEG; Horovitz et al., 2008; Helps et al., 2010;Broyd et al., 2011), and near-infrared spectroscopy (NIRS; Obrig et al., 2000; Näsi et al., 2011; Pierro et al., 2012). Slow oscillations from 0.04 to 0.15 Hz are called low-frequency oscillations (LFOs). Even lower frequency oscillations (<0.04 Hz) are designated as very low-frequency oscillations (VLFOs) (Obrig et al., 2000; Näsi et al., 2011). Although the mechanisms underlying the slow oscillations remain unclear, several reports of the literature have described these as neuronal characteristics of psychological personality traits (Kunisato et al., 2011) and psychiatric disorders such as anxiety (Hou et al., 2012) and mood disorders (Chepenik et al., 2010; Wang et al., 2012). Psychiatric disorders have shown high degrees of ELS (Heim and Nemeroff, 2001; Heim et al., 2010; Schmidt et al., 2011). Therefore, one would suspect high ELS to be related to changes in slow oscillations during the resting state. This point, however, remains to be investigated.

In addition to LFOs during the resting state, the DMN shows activation in fMRI during various tasks such as self-reference (Kelley et al., 2002;Northoff et al., 2006), episodic memory retrieval (Buckner et al., 2008), envisioning the future (Szpunar et al., 2007), mentalizing (Gusnard et al., 2001; Amodio and Frith, 2006), and internally guided decision making (Nakao et al., 2012). The DMN is often explained integratively as associated with self-oriented/internally guided psychological processes (Qin and Northoff, 2011; Whitfield-Gabrieli and Ford, 2012). Again, however, no report in the relevant literature has described the association between ELS and DMN activity during self-oriented tasks.

This preliminary study was undertaken to investigate the relations between ELS and the degree of MPFC activations during a resting state and self-oriented task using NIRS. This non-invasive technique uses near-infrared light to evaluate spatiotemporal characteristics of brain function near the brain surface. The use of NIRS enables the detection of spontaneous slow oscillations in oxygenated hemoglobin (oxy-Hb: Obrig et al., 2000). The LFOs and VLFO measured by NIRS are known to be differentiated from other oscillatory phenomena such as heart beat and respiratory cycles (Obrig et al., 2000). The activation of surface regions of MPFC during self-oriented tasks has also been measured using NIRS (Di Domenico et al., 2012).

For the experiment described hereinafter, a child abuse and trauma scale (CATS) (Sanders and Becker-Lausen, 1995) was used to assess ELS. To control the effect of the recent stress level, we used the life event stress scale (LES) (Sarason et al., 1978). Stressful life events are known to affect brain function adversely through elevated cortisol level in the blood which is acutely or chronically caused by the hormonal stress response system: the hypothalamic–pituitary–adrenal (HPA) axis (Numakawa et al., 2013). Therefore, we also measured the blood levels of cortisol to assess whether early and/or recent life stress might elevate cortisol concentrations in the blood, resulting in alteration of PFC activation. We recorded eyes-closed (EC) and eyes-open (EO) resting-state NIRS before conducting cognitive tasks. In self-oriented cognitive and control tasks, color stimulus was used (see Figure 1A for example). The same color stimulus and color stimulus pairs were used in both tasks. As a self-oriented task, color-preference judgment (Johnson et al., 2005; Nakao et al., 2013) was used while the color-similarity judgment served as control (Johnson et al., 2005; Nakao et al., 2013) (see Figure 1A). We used these tasks for the following three reasons. First, using these tasks, we can differentiate between goal-directed/externally guided and self-oriented/internally guided psychological processes (Johnson et al., 2005; Nakao et al., 2013). Although color-similarity judgment requires participants to make a decision based on the external criterion (i.e., color-similarity), color-preference judgments require participants to make a decision based on their own internal criteria. Second, the same color-set is used in both tasks: the effects of stimuli can be well controlled. Third, Johnson et al. (2005) reported that the color-preference judgment activate the DMN including the MPFC [Brodmann area (BA) 9, 10] compared to the color-similarity judgment. The MPFC is the region of interest (ROI) in this study.

FIGURE 1

Figure 1. (A) Design of cognitive tasks. (B)Schematic figure showing how to make color combinations in the color-similarity judgment and color-preference judgment tasks. The left color wheel portrays examples of the color combinations of the similarity-easy set. The right color wheel displays examples of color combinations of the similarity-difficult set. The degrees from target color to choice color signify the color similarity. (C)Approximate location of the NIRS channel positions in MNI space. (D) NIRS probe position.

Prefrontal networks are responsible for forming and holding coherent thoughts (a process that is impaired in schizophrenia), and it has been shown in this study that nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex.

Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha-7 nicotinic receptor.

This is an interesting study - and it demonstrates again the importance of the prefrontal cortex in nearly all forms of higher order cognition.

Tomorrow, I will share an article that suggests that early life stress can predict a decrease in medial prefrontal activation and cause a shift from internally to externally guided decision-making. This study will have real implications for understanding how developmental trauma affects adult cognition and locus of control.

Yale team finds nicotinic receptor essential for cognition — and mental health

By Bill Hathaway

July 1, 2013

Nicotinic alpha-7 receptors (indicated by red arrowheads) are next to a synapse between two brain cells in the prefrontal cortex. Stimulation of the nicotinic alpha-7 receptors allows the cells to communicate and thus generate higher cognition. 

(Image from Dr. C. Paspalas, Yale University)

The ability to maintain mental representations of ourselves and the world — the fundamental building block of human cognition — arises from the firing of highly evolved neuronal circuits, a process that is weakened in schizophrenia. In a new study, researchers at Yale University School of Medicine pinpoint key molecular actions of proteins that allow the creation of mental representations necessary for higher cognition that are genetically altered in schizophrenia. The study was released July 1 in the Proceedings of the National Academy of Sciences.

Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha7 nicotinic receptor.

Acetycholine is released when we are awake — but not in deep sleep. These receptors allow prefrontal circuits to come “online” when we awaken, allowing us to perform complex mental tasks. This process is enhanced by caffeine in coffee, which increases acetylcholine release. As their name suggests, nicotinic alpha-7 receptors are also activated by nicotine, which may may help to explain why smoking can focus attention and calm behavior, functions of the prefrontal cortex.

The results also intrigued researchers because alpha-7 nicotinic receptors are genetically altered in schizophrenia, a disease marked by disorganized thinking. “Prefrontal networks allow us to form and hold coherent thoughts, a process that is impaired in schizophrenia,” said Amy Arnsten, professor of neurobiology, investigator for Kavli Institute, and one of the senior authors of the paper. “A great majority of schizophrenics smoke, which makes sense because stimulation of the nicotinic alpha7 receptors would strengthen mental representations and lessen thought disorder.”

Arnsten said that new medications that stimulate alpha-7 nicotinic receptors may hold promise for treating cognitive disorders.

Publication of the PNAS paper comes on the eve of the 10th anniversary of the death of Yale neurobiologist Patricia Goldman-Rakic, who was hit by a car in Hamden Ct. on July 31, 2003. Goldman-Rakic first identified the central role of prefrontal cortical circuits in working memory.

“Patricia’s work has provided the neural foundation for current studies of molecular influences on cognition and their disruption in cognitive disorders,” said Arnsten. “Our ability to apply a scientific approach to perplexing disorders such as schizophrenia is due to her groundbreaking research.”

Yang Yang and Min Wang of Yale are lead author and co-senior authors, respectively. Constaninos D. Paspalas, Lu E Jin and Marina R. Picciotto are other Yale authors.

Here is the abstract and introduction to the full article, available for free online.

Full Citation:
Yang Yang, Constantinos D. Paspalas, Lu E. Jin, Marina R. Picciotto, Amy F. T. Arnsten, and Min Wang. (2013, Jul 1). Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. PNAS: doi: 10.1073/pnas.1307849110

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

Yang Yanga, Constantinos D. Paspalasa, Lu E. Jina, Marina R. Picciottob, Amy F. T. Arnstena, and Min Wanga

Abstract

The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510–1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477–485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade ofα7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110–1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia.

Acetylcholine (ACh) acts through a variety of nicotinic and muscarinic receptors to modulate wakefulness (1–3) and orchestrate attention-related circuits in the brain (4). It is released during wakefulness and rapid eye movement (REM) sleep (1, 3), exciting the thalamus and cortex (2, 3, 5) and allowing conscious experience (6). Despite the established importance of ACh in cortical function, there is very little known about its effects at the cellular level in cognitively engaged circuits. One study of the primate primary visual cortex [V1 (7)] showed attentional modulation by muscarinic but not nicotinic receptors. However, there have been no physiological studies of cholinergic actions in higher association cortices in primates, even though behavioral data indicate that ACh is essential for the working memory (WM) functions of the dorsolateral prefrontal cortex (dlPFC) (8), a highly evolved brain region that subserves mental representation and executive function as well as the reactivation of long-term memories onto the “mental sketch pad” (9, 10).

Goldman-Rakic and colleagues discovered the cellular basis of the spatial WM functions of primate dlPFC (9). Lesions to the principal sulcal dlPFC in monkeys permanently impair spatial WM performance, whereas physiological recordings from this area have revealed “delay cells” that generate mental representations of visual space even when stimuli were no longer present in the environment (9). These delay cells can maintain information in temporary storage to guide prospective motor acts, thus integrating perception and action (11). These neurons maintain persistent firing throughout the delay period when information is held in WM, firing selectively for a “preferred direction” to create visuospatial representations (Fig. 1 A–C). Goldman-Rakic uncovered the cellular basis of these spatial WM functions and the circuitry underlying visuospatial representation (Fig. S1) (9): Neurons in dlPFC receive highly processed visuospatial information  from the parietal association cortex, and layer III dlPFC pyramidal cell microcircuits excite each other to maintain persistent firing across the delay. Persistent firing also may involve reciprocal excitation with longer-range cortical–cortical circuits, for example, with the parietal association cortex (12). The spatial tuning of dlPFC delay cells is refined by GABAergic lateral inhibition from local basket and chandelier cells (Fig. S1). Recent studies have shown that the persistent firing of delay cells relies on glutamate NMDA receptors (NMDARs), including those with NR2B subunits, which are localized in the postsynaptic densities of glutamatergic synapses on spines in deep layer III (13). These pyramidal cells expand greatly in primate evolution (14), and are especially afflicted in schizophrenia (15, 16) and Alzheimer’s disease [AD (17)].

A variety of higher cognitive disorders are associated with impaired dlPFC function and genetic insults to nicotinic α7 receptors (α7-nAChRs) and/or NMDAR signaling. There is extensive evidence linking genetic alterations of α7-nAChR to schizophrenia and attentional deficits (18, 19), including alterations at the transcription level (20). Recent data have also shown that α7-nAChR expression depends on neuregulin, another molecule linked to schizophrenia (21), and that smoking in schizophrenia may be a form of self-medication, normalizing expression of α7-nAChRs (22). More recent studies have linked α7-nAChRs to autism (23), attention deficit hyperactivity disorder [ADHD (24)], and AD (25), suggesting that a variety of dlPFC disorders are linked to alterations in α7-nAChR signaling. α7-nAChR agonists are currently under development as potential therapeutic treatments for these disorders, based in part on animal studies showing that systemic administration of α7-nAChR agonists can rescue WM deficits induced by NMDAR blockade (26, 27). However, the location and physiological roles of α7-nAChR in dlPFC circuits had not been known. The current study used electron microscopy and recordings from cognitively engaged monkeys to reveal α7-nAChR localization and actions in primate dlPFC. We report that α7-nAChRs are situated in the postsynaptic density of glutamatergic synapses in deep layer III of dlPFC, and that α7-nAChR stimulation is essential for the excitation of NMDAR-mediated WM circuits.

Read the whole article.

This is a good introductory overview of PTSD, with a nice section explaining the impact of trauma on the amygdala and hippocampus (I've formatted this section as an inset for easier access). While the explanation is good, I disagree with the treatment model they propose, for two different reasons.

(1) Exposure therapy may, over time, create habituation to the stimuli that trigger flashbacks or anxiety. This does not address the hypervigilance, the sense that one must be continually alert to possible threats in the environment, or testing people to make sure they are safe. Nor does it address the numbing that can result from trauma, and the desire to numb feelings with addictive behaviors.

(2) Those who experience PTSD, which is only 20-35% of those who experience trauma (depending on the trauma), generally have a history of big T traumas (physical, emotional, or sexual abuse; severe neglect; natural disaster; refugee status; death of parent) or a collection of small T traumas (bullying, shaming and humiliation, emotionally distant caregivers, etc). It is the reduction in resilience created by these earlier traumas that make one vulnerable to PTSD. Part of recovery has to be addressing and resolving these prior traumas, and the model presented in the article.

With that, here's the article.

Understanding PTSD: Researchers explore causes, treatment

by Pete Zrioka

Eric Batory, pictured during his time as a special operations medic, assigned to the U.S. Army's 1st Ranger Battalion, 75th Ranger Regiment. Batory went through two years of extensive medical and special forces training to qualify for the position. Credit: Eric Batory

(Medical Xpress)—In 2005, ASU student Eric Batory was a long way from Arizona. He was in Mosul, Iraq on his first deployment as a special operations medic with the U.S. Army's 1st Ranger Battalion, 75th Ranger Regiment.

During a night raid to extract a high-value target, his unit came under fire as they were entering a compound. The squad leader was shot on his right side, where the round glanced off his body armor and came to rest near his heart. The only medic on the scene, Batory began rendering aid to the Ranger in the midst of a heated firefight, feeling the concussive force of grenades and gunfire all around him.

"That's what really rung my bell," says Batory, who is now a student in ASU's College of Liberal Arts and Sciences. "I'm in a closed room, with an LED light on this guy, all this stuff blowing up, concrete raining down."

Batory's patient survived and Batory was awarded the Bronze Star with Combat 'V' for his actions, the fifth-highest combat decoration. After that, Batory says he started to feel a little bit "off." He became withdrawn from his platoon, obsessing over every possible medical scenario. He distanced himself from his fellow Rangers, afraid he'd lose someone as a result of his actions.

Two years and two deployments later, he left the Army as a sergeant, joining the scores of veterans living with cognitive and psychological wounds from the Global War on Terror.

Six years and a world away from the battlegrounds of Iraq and Afghanistan, Batory still lives with post-traumatic stress disorder (PTSD) from his time in combat.

Any traumatic experience, such as combat, violent assault or natural disaster, can cause PTSD. Symptoms can include flashbacks to the event, nightmares, avoiding triggering situations, numbness and withdrawal, fear and increased emotional arousal. 

Why do these kinds of experiences create such a painful and long-lasting effect? The answer lies in very old structures in the human brain, called the amygdala and the hippocampus. These are nestled within the temporal lobe, which manages sensory input, speech and language, and memory formation and association. Memories are formed, stored and contextualized by the hippocampus. The amygdala is tied to our emotions, particularly those felt in fearful, life-or-death situations. 

"The hippocampus' job is to remember the context of the situation and the amygdala ensures the longevity of that memory, especially the emotional memory," says Harold Burke, a faculty associate in ASU's College of Health Solutions. "It's not just the context of the visual and audio cues, but the emotional experience of fear." 

In addition to branding these memories in the brain, the amygdala also regulates part of the sympathetic nervous system, commonly known as the fight or flight system. 

"It's a very old part of brains from an evolutionary standpoint," says Burke, who teaches courses in ASU's Doctor of Behavioral Health program. "It's been designed over millions of years of evolution to trigger in an emergency situation to save our lives." 

In these emergency situations, like the heated combat Batory experienced, the sympathetic nervous system pumps out norepinephrine. 

Norepinephrine increases heart rate as well as oxygen supply to the brain, allows us to breathe faster and deeper, dilates pupils to take in more visual information and triggers the release of glucose stores for extra energy. 

"It also activates the upper part of the brain, namely the cerebral cortex, so you can be very alert and make quick decisions," says Burke. 

A secondary system, which takes longer to kick in, lasts longer and aids the body's recovery. The hypothalamic-pituitary-adrenal axis, or HPA axis, is a conglomerate of structures throughout the body that responds to highly stressful situations by releasing the hormone cortisol. 

Cortisol is incredibly beneficial to both the body and mind in small, measured doses. But with chronically stressful situations, cortisol becomes more of a problem than a solution. 

Back in the hippocampus, there are neurons that act as a thermostat that regulates cortisol production. But prolonged or repeated release of cortisol kills the very neurons that help inhibit it, resulting in a negative feedback loop of more cortisol and fewer neurons to stop its release. 

"It's like smashing the thermostat," Burke explains. 

Furthermore, repeated exposure to similar high-stress trauma not only kills neurons and can inhibit cognition, but can also result in the strengthening of the memories being encoded in the hippocampus and amygdala. 

"Here's the issue: with PTSD, the activation of the amygdala and HPA axis is so intense that the synapses, the various connections between the neurons, how well they communicate, are strengthened as a product of that intensity and it can last a very, very long time," says Burke. 

It's like tracing a picture over and over again. The more you go over those lines, the clearer and more distinct an image becomes, just as repeated exposure to trauma enhances the emotional memory and deeply encodes a fear response. 

To make matters worse, the job of the hippocampus and amygdala together is to not just remember that exact, specific situation, but to remember things that are similar to it. 

"The brain generalizes the stimuli, so that if anything else is even somewhat similar it will trigger the same response," says Burke. "And that's actually a good thing. We want to be able to generalize our learning to different contexts, but the catch with PTSD is that then other things that are pretty innocent actually trigger the same kind of memories or re-experiencing."

For instance, some veterans who spent time on convoys have difficulty driving if there's trash or debris in the road, as hiding improvised explosive devices in garbage is a common insurgent tactic. In the case of Batory, there's a gamut of different stimuli that trigger an intense fear response for him back in the civilian world.

"Dogs barking, alarms or phones ringing. Anything beeping or with a high pitch," says Batory, listing the things that send his heart racing. "Noise in the dark, or a lot of light at night ... I don't like bright lights at night, I feel like you're exposed."

The sound and concussive force of fireworks has sent him diving to the ground before.

"Even at Fourth of July, knowing what it was, just feeling the concussions or hearing the blasts gets my heart rate up," says Batory.

Batory's struggle with PTSD and its lingering effects aren't limited to barking dogs or fireworks. When he was honorably discharged from the Army in 2007, he was bored. After deploying three times as a special operations medic and working through two years of intensive schooling to qualify for the coveted position, a desk job left him restless.

"I was so dissatisfied with feelings of insignificance and lack of stimulation, compared to what I was used to," says Batory.

Distracted, depressed and disillusioned with civilian life, Batory joined the Army Reserves, which only seemed to exacerbate his symptoms. Batory had trouble sleeping, and when he did, he was sleepwalking. He started to fear social events and public places like movie theatres, malls or sporting events.

"I started to get overwhelming anxiety being around groups of people," says Batory. "Whenever I was around large crowds, I'd want to leave because I'd feel overwhelmed, because there was no structure and no order. That all started to compound until I started having dissociative episodes, getting in car accidents where I would zone out and think about Iraq or Afghanistan. I'd hit a median or rear end someone. Started getting a lot of tickets and got into financial trouble."

Eventually, Batory's car was repossessed and he became homeless, all in the midst of trying to attain his undergraduate degree. He put in a disability claim with the VA and sought additional help there, receiving neuropsychological testing. He found some relief with medication, but he wasn't happy about it.

"It's disheartening to know that you have this pile of pills in front of you and you're dependent on it to feel human," says Batory.

Batory sought out additional resources available to ASU students. Fortunately for him, ASU offers a range of counseling services and has been named a Military Friendly School four years running.

He began therapy with Andrea Hekler, a clinical psychologist at ASU Health Services - NP Healthcare, located near the Downtown Phoenix campus. Hekler provides two types of evidence-based psychotherapies for PTSD patients: cognitive processing therapy and prolonged exposure therapy. Both are a class of therapies called cognitive behavioral therapies.

"Cognitions refer to the thoughts we have and how we perceive life through a certain lens," says Hekler, who has previously worked with the National Center for PTSD. "When individuals experience a trauma – be it combat, Hurricane Sandy, 9/11 in New York or being sexually assaulted – having those traumatic experiences leads us to perceive the world in different ways. People tend to start thinking the world is a much more dangerous place than most people believe and they're not able to handle and cope with the world."

Cognitive processing therapy focuses on the assumptions that PTSD victims have as a result of their trauma. Prolonged exposure therapy homes in on a victim's behavior.

Cognitive processing therapy teaches patients how their thoughts are connected to how they behave and feel.

"It's essentially using logic and rational thinking to help them understand the assumptions they have and challenge those assumptions," says Hekler.

Prolonged exposure therapy can be more challenging as it's based on the premise that PTSD victims haven't processed their trauma or even talked about it, according to Hekler.

This therapy breaks down into four parts: education on what PTSD is and its symptoms, breathing exercises to relax the patient and two types of exposure. In the first, imaginal exposure, patients close their eyes and describe their trauma as if it were happening in the moment, not the past. This process is repeated, recorded and listened to outside of the sessions as well.

"Through this rehearsal, they come to something called habituation," says Hekler. "Essentially, stimuli that once had a very strong intensity, over time reduces that intensity. Each time, when someone comes back to therapy they recite the event again and typically what happens is they don't become as emotionally distressed or upset about it. Eventually it becomes a memory, not one that you want to revisit all the time, but without the same emotional intensity."

The second type of exposure is in vivo exposure, where patients list all of the situations they avoid and then insert themselves in them. This fosters a similar process of habituation, where the patient learns to manage the crippling fear or anxiety they experience in situations they avoid.

"At the heart of PTSD is avoidance," says Hekler. "Avoidance is really good in the short term because it makes anxiety go away – what it's really doing is telling your brain that this is terrifying and we need to get away."

In other words, it's only serving to strengthen the fear conditioning in the amygdala and hippocampus. The process of habituation doesn't seek to overwrite those incredibly intense emotional memories, but to create a separate set of circuits that associate the same stimuli with a safe emotional response.

"Cognitive behavior therapy literally sets up and strengthens circuits to inhibit fear," says Burke. "You don't get rid of the original trauma, but you overlay it with other behavior."

For Batory, in vivo exposure proved to be a beneficial form of therapy.

"It was effective not because it changed what I feel or think, but because I learned to deal," says Batory. "Even though I feel anxiety, it's not as severe and I know how to keep it in check."

While both therapy and medication can be effective, Burke believes that PTSD demands a holistic approach to treatment in which different health professionals work closely together.

"I think ASU is on the cutting edge of integrated health solutions," says Burke. "We can have Dr. A doing one thing to a person and Dr. B doing something else to the same person across town, especially when Dr. A is just physical medicine and Dr. B is just psychological. Those two groups have not been talking nearly enough over the last decades, and that's got to change. And ASU is right on the cusp of it. The Doctorate of Behavioral Health program is the first of its kind in the whole country."

Batory now lives with a group of other veterans and is on track to graduate with a bachelor's degree in microbiology in December 2013. After spending years of attaching negative associations to his military experience, even when saving lives, he has newfound perspective and direction. He is applying to medical schools in the coming months, saying he wants to get back to helping people.

"I've taken up an interest in medicine again, and I think it's a good measure of the return of myself and my life's purpose," says Batory. "But I really had to rebuild myself to get back to that point."

To others suffering from PTSD, Batory offers pretty straightforward advice: "You're not weak. You're not any less of a person for acknowledging you're struggling, and the sooner you do that, the sooner you'll be on the road to recovering."

Mark Edwards - Towards an Integral Meta-Studies: Describing and Transcending Boundaries in the Development of Big Picture Science

In the newest issue of The Integral Review (9:2; June 2013), integral scholar Mark Edwards offers an excellent article on efforts toward an integrally-based meta-studies model, particularly in the realm of "big picture science."

I propose a general schema, called integral meta-studies, that describes some of the characteristics of this meta-level science. Integral here refers to the long tradition of scientific and philosophic endeavours to develop integrative models and methods. Given the disastrous outcomes of some of the totalising theories of the nineteenth century, the subsequent focus on ideas of the middle-range is entirely understandable. But middle-range theory will not resolve global problems. A more reflexive and wider conceptual vision is required.

This article appears as part of the special issue on transdisciplinary studies (International Symposium: Research Across Boundaries, Part 1).

[Image at the top is from Edwards' article at Integral World, Where's the Method to Our Integral Madness? An Outline for an Integral Meta-Studies.

Towards an Integral Meta-Studies: Describing and Transcending Boundaries in the Development of Big Picture Science [1]

by Mark G. Edwards [2]

Abstract 

We are entering a period in human civilisation when we will either act globally to establish a sustainable and sustaining network of world societies or be enmired, for the foreseeable future, in a regressive cycle of ever-deepening global crises. We will need to develop global forms of big picture science that possess institutionalised capacities for carrying out meta-level research and practice. It will be global in that such research cannot be undertaken in isolation from practical global concerns and global social movements. In this paper I propose a general schema, called integral meta-studies, that describes some of the characteristics of this meta-level science. Integral here refers to the long tradition of scientific and philosophic endeavours to develop integrative models and methods. Given the disastrous outcomes of some of the totalising theories of the nineteenth century, the subsequent focus on ideas of the middle-range is entirely understandable. But middle-range theory will not resolve global problems. A more reflexive and wider conceptual vision is required. Global problems of the scale that we currently face require a response that can navigate through theoretical pluralism and not be swallowed up by it. In saying that, twenty-first-century metatheories will need to be different from the monistic, grand theories of the past. They will have to be integrative rather than totalising, pluralistic rather than monistic, based on science and not only on philosophy, methodical rather than idiosyncratic, find inspiration in theories, methods and interpretive frameworks from the edge more than from the centre and provide means for inventing new ways of understanding as much as new technologies. Integrative metastudies describes an open system, inquiry space or clearing that has a place for many forms of scientific inquiry and their respective theories, methods, techniques of analysis and interpretive frameworks.

1. The word “integral” is used here to refer to the long tradition of integrative big pictures as exemplified in the work of such figures as Thomas Aquinas, Georg Hegel, Michil Bakunin, Vladamir Solovyov, Pitrim Sorokin, Rudolph Steiner, Jean Gebser, Aurobindo Ghose, Jacques Maritain, Bill Torbert, Ken Wilber, Ervin László, Fred Dallmyr, Ronnie Lessem and Alexander Schieffer. 

2. Mark Edwards is Assistant professor at the Business School, University of Western Australia where he teaches in the areas of business ethics and organisational transformation. Mark’s PhD thesis (awarded with distinction) was published in a series on business ethics by Routledge/Taylor-Francis in August 2010 and was awarded book of the year by Integral Leadership of the year in 2011. The book focuses on the integration of knowledge as applied to the fields of organisational transformation and sustainability. Mark’s research has been published in several leading academic journals and covers a diverse range of topics including business ethics, management studies, systems research, futures studies, psychotherapy and spirituality, sustainability and organisational transformation. mark.edwards@uwa.edu.au 

Introduction 

We are entering a period in human civilisation when we will either act globally to establish a sustainable and sustaining network of world societies or be enmired, for the foreseeable future, in a regressive cycle of ever-deepening global crises. If we are to take the former pathway then we must, as a matter of some urgency, develop and institutionalise integrative and meta-level forms of scientific sense-making. This meta-level form of sense making will complement existing disciplines to establish a multi-layered understanding of science that will have the capacity to take a reflexive perspective on current scientific and philosophical theory building and testing. We will need to develop global forms of big picture science that possess institutionalised capacities for carrying out meta-level research. It will be global in that such research cannot be undertaken in isolation from practical global concerns and global social movements. In this paper I propose a general schema, called integral meta-studies, that describes some of the characteristics of this meta-level science. Integral here refers to the long tradition of scientific and philosophic endeavours to develop integrative models and methods. There are many precursors and formative examples that I draw on in developing the integral meta-studies framework and what I want to do here is present something an overview that can help to situate meta-level scientific and philosophical studies within the current landscape of knowledge quests. Integrative metatheorising is an ambitious project. It is based on the premise that the critical appreciation and integration of diverse theoretical and methodological perspectives offers a new way forward in the development of science. It seeks to find insights through the connection of knowledge rather than the specialisation of knowledge. It takes an appreciative rather than a depreciative view towards systems of knowledge, irrespective of their place within the mainstream or the periphery. The big pictures that emerge from this process stand in contrast to the goals of mainstream social science which are almost exclusively concerned with the building and testing of middle-range theory.

Given the disastrous outcomes of some of the totalising theories of the nineteenth century, the subsequent focus on ideas of the middle-range is entirely understandable. But middle-range theory will not resolve global problems. A more reflexive and wider conceptual vision is required. Global problems of the scale that we currently face require a response that can navigate through theoretical pluralism and not be swallowed up by it. In saying that, twenty-first-century metatheories will need to be different from the monistic, grand theories of the past. They will have to be integrative rather than totalising, pluralistic rather than monistic, based on science and not only on philosophy, methodical rather than idiosyncratic, find inspiration in theories, methods and interpretive frameworks from the edge more than from the centre and provide means for inventing new ways of understanding as much as new technologies. Integrative metastudies describes an open system of knowledge acquisition that has a place for many forms of scientific inquiry and their respective theories, methods, techniques of analysis and interpretive frameworks. We have, in fact, been developing these meta-level capacities and models for a very long time and the time is now ripe for a more overt description and institutionalisation of these perspectives and practices.

The Challenge of Pluralism

The great proliferation in empirical studies that occurred through the 1970s and 1980s brought with it the rise of meta-data-analysis. The sheer outpouring of empirical information, particularly in the health and medical sciences, required a scientific response that could somehow make sense and form some overarching big picture of the mass of data pouring out of journals and scientific laboratories. Gene Glass was one of the pioneers of these early approaches to the integration of empirical findings and he proposed the term meta-analysis to describe the “analysis of a large collection of analysis results from individual studies for the purposes of integrating the findings” (Glass, 1976, p. 3). Glass described the emergence of meta-analysis as follows (1977, pp. 351–352):

By the late 1960s, the research literature had swollen to gigantic proportions. Although scholars continued to integrate studies narratively, it was becoming clear that chronologically arranged verbal descriptions of research failed to portray the accumulated knowledge. Reviewers began to make crude classifications and measurements of the conditions and results of studies. Typically, studies were classified in contingency tables by type and by whether outcomes reached statistical significance. Integrating the research literature of the 1970s demands more sophisticated techniques of measurement and statistical analysis. The accumulated findings of dozens or even hundreds of studies should be regarded as complex data points, no more comprehensible without the full use of statistical analysis than hundreds of data points in a single study could be so casually understood. Contemporary research reviewing ought to be undertaken in a style more technical and statistical than narrative and rhetorical. Toward this end, I have suggested a name to make the needed approach distinctive; I referred to this approach as the meta-analysis of research. 

Precisely this situation exists today, for not only research data but, for the multitudinous varieties of theory, methods and interpretive systems that are employed to make scientific sense of the complex worlds we inhabit today. And we need corresponding meta-level schools of scientific research in each of these realms. Indeed, we can see many different forms of these meta-level studies emerging today across all kinds of scholarly outputs. On the theory side we see the emergence of meta-level theoretical frameworks, multiparadigm studies and overarching conceptual models in many social sciences. In the study of scientific research methods we see the development of meta-methods and the associated approaches of mixed and multi-methodologies and with the variety of new epistemological orientations we see the rise of meta-level and general hermeneutics. Together, these overarching forms of analysis constitute a meta-level science and they formalise a way of developing knowledge that has been part of the human story of meaning-making for a very long time. What makes these meta-level disciplines different is that now we can build and test these big pictures from a scientific perspective.

These meta-level studies form a new layer of global research in that they emerge out of the pluralism of diverse views of reality that are present across different cultures, different political and geographical regions different social histories. Where modernistic forms integrative science have attempted to develop unified grand theories and the single big Theory of Everything, the new integrative meta-level approach recognises the postmodern turns towards interpretive, methodological and theoretical diversity. The goal then is not for a unified grand monism but an open space for pursuing scientific big picture inquiry in which multiple perspectives can be appreciatively and critically considered. Hence, this new meta-level inquiry offers a scientific response to one of the central questions of the 21st century - how are we to develop global conversations around, what Raiman Panikkar call, “the pluralisms of truth” (Panikkar, 1990, p. 16).

... truth is pluralistic because reality itself is pluralistic, not being an objectifiable entity. We subjects are also part of it. We are not only spectators of the Real, we are also co-actors and even co-authors of it. This is precisely our human dignity. 

During the twentieth-century we saw a procession of big pictures come and go with some useful insights and advances but also with often disastrous results. In the domains of politics, economics, education, commerce and trade and organisation and management we have seen a litany of big scientific ideas come and then drift off into marginality. While each of them had their partial truths and valid points, overall, when championed as complete and universal schemes of salvation, big pictures have not had a good track record. From Marxism to monetarism, from rational choice theory to marketism, from globalism to the promises of hyper-technologies - all of these big pictures have their respective insights and have resulted in great advances in understanding but they have also resulted in ideologies of various kinds that are fundamentally degrading the environmental, social, economic and intellectual resources of the planet. The human predilection for creating big pictures will continue and will grow even more as we enter further into the age globalisation. Given this, how can we develop and validate our metatheories via a more conscious form of doing science? How can we build a deep science which is integrative, pluralistic, reflexive, and appreciative of contending views rather than specialist, monistic, objectifying and aimed at finding the one true theory or method? Before looking at this I should first discuss a little more about what I mean by science and social science. I argue that meta-studies, or big picture science, will play an important role in the development of planetary culture in the coming decades and so it might be useful to describe in further detail how I view scientific activity and its role in contemporary society.

Read the whole article.

Socioeconomic Adversity and Depression Linked to Diabetes - Inflammation Is the Link

Two new studies have linked diabetes to socioeconomic status and to depression. Both are linked, socioeconomic status directly and depression indirectly (supported by research Charles Raison and others), to inflammation. Chronic inflammation is known to aggravate diabetes as well as lead to development of the disease.

Both of these articles show that lifestyle and quality of life have a powerful impact on our health.

Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study

Silvia Stringhini, G. David Batty, Pascal Bovet, Martin J. Shipley, Michael G. Marmot, Meena Kumari, Adam G. Tabak, Mika Kivimäki

Abstract

Background

Socioeconomic adversity in early life has been hypothesized to “program” a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation.

Methods and Findings

We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991–1993 until 2007–2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48–2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26–1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%–58%).

Conclusions

In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible.

Editors' Summary

Background

Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. 

Why Was This Study Done?

Socioeconomic adversity in childhood seems to increase the risk of developing type 2 diabetes but why? One possibility is that chronic inflammation mediates the association between socioeconomic adversity and type 2 diabetes. Inflammation, which is the body's normal response to injury and disease, affects insulin signaling and increases beta-cell death, and markers of inflammation such as raised blood levels of C-reactive protein and interleukin 6 are associated with future diabetes risk. Notably, socioeconomic adversity in early life leads to exaggerated inflammatory responses later in life and people exposed to social adversity in adulthood show greater levels of inflammation than people with a higher socioeconomic status. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers test the hypothesis that chronically increased inflammatory activity in individuals exposed to socioeconomic adversity over their lifetime may partly mediate the association between socioeconomic status over the lifecourse and future type 2 diabetes risk. 

What Did the Researchers Do and Find?

To assess the extent to which chronic inflammation explains the association between lifecourse socioeconomic status and type 2 diabetes incidence (new cases), the researchers used data from the Whitehall II study, a prospective occupational cohort study initiated in 1985 to investigate the mechanisms underlying previously observed socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees ranging from clerical/support staff to administrative officials and monitored inflammatory marker levels and type 2 diabetes incidence in the study participants from 1991–1993 until 2007–2009. Of 6,387 participants who were not diabetic in 1991–1993, 731 developed diabetes during the 18-year follow-up. Compared to participants with the highest cumulative lifecourse socioeconomic score (calculated using information on father's occupational position and the participant's educational attainment and occupational position), participants with the lowest score had almost double the risk of developing diabetes during follow-up. Low lifetime socioeconomic status trajectories (being socially downwardly mobile or starting and ending with a low socioeconomic status) were also associated with an increased risk of developing diabetes in adulthood. A quarter of the excess risk associated with cumulative socioeconomic adversity and nearly a third of the excess risk associated with low socioeconomic trajectory was attributable to chronically increased inflammation. 

What Do These Findings Mean?

These findings show a robust association between adverse socioeconomic circumstances over the lifecourse of the Whitehall II study participants and the risk of type 2 diabetes and suggest that chronic inflammation explains up to a third of this association. The accuracy of these findings may be affected by the measures of socioeconomic status used in the study. Moreover, because the study participants were from an occupational cohort, these findings need to be confirmed in a general population. Studies are also needed to examine the extent to which social inequalities in diabetes risk that are attributable to chronic inflammation are reversible. Importantly, if future studies confirm and extend the findings reported here, it might be possible to reduce the social inequalities in type 2 diabetes by promoting interventions designed to reduce inflammation, including weight management, physical activity, and smoking cessation programs and the use of anti-inflammatory drugs, among socially disadvantaged groups. 

Additional Information

• Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1​001479.
• The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
• The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes peoples stories about diabetes
• The nonprofit Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the nonprofit Healthtalkonline has interviews with people about their experiences of diabetes
• MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
• Information about the Whitehall II study is available

Full Citation: 

Stringhini S, Batty GD, Bovet P, Shipley MJ, Marmot MG, et al. (2013) Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study. PLoS Med 10(7): e1001479. doi:10.1371/journal.pmed.1001479

* * * * * * *

Association of Depression With Increased Risk of Severe Hypoglycemic Episodes in Patients With Diabetes

Wayne J. Katon, MD, Bessie A. Young, MD, MPH, Joan Russo, PhD, Elizabeth H. B. Lin, MD, MPH, Paul Ciechanowski, MD, MPH, Evette J. Ludman, PhD, Michael R. Von Korff, ScD

Abstract

PURPOSE Although psychosocial and clinical factors have been found to be associated with hypoglycemic episodes in patients with diabetes, few studies have examined the association of depression with severe hypoglycemic episodes. This study examined the prospective association of depression with risk of hypoglycemic episodes requiring either an emergency department visit or hospitalization.

METHODS In a longitudinal cohort study, a sample of 4,117 patients with diabetes enrolled between 2000 and 2002 were observed from 2005 to 2007. Meeting major depression criteria on the Patient Health Questionnaire-9 was the exposure of interest, and the outcome of interest was an International Classification of Disease, Ninth Revision code for a hypoglycemic episode requiring an emergency department visit or hospitalization. Proportional hazard models were used to analyze the association of baseline depression and risk of one or more severe hypoglycemic episodes. Poisson regression was used to determine whether depression status was associated with the number of hypoglycemic episodes.

RESULTS After adjusting for sociodemographic, clinical measures of diabetes severity, non–diabetes-related medical comorbidity, prior hypoglycemic episodes, and health risk behaviors, depressed compared with nondepressed patients who had diabetes had a significantly higher risk of a severe hypoglycemic episode (hazard ratio = 1.42, 95% CI, 1.03–1.96) and a greater number of hypoglycemic episodes (odds ratio = 1.34, 95% CI, 1.03–1.74).

CONCLUSION Depression was significantly associated with time to first severe hypoglycemic episode and number of hypoglycemic episodes. Research assessing whether recognition and effective treatment of depression among persons with diabetes prevents severe hypoglycemic episodes is needed.

Full Citation:
Katon, WJ, Young, BA, Russo, J, Lin, EHB, Ciechanowski, P, Ludman, EJ, Von Korff, MR. (2013, May/Jun). Association of Depression With Increased Risk of Severe Hypoglycemic Episodes in Patients With Diabetes. Annals of Family Medicine; vol. 11 no. 3, 245-250. doi: 10.1370/afm.1501