Wednesday, January 30, 2008

Psychedelic Healing?

Brown, D.J. (January 2008). Psychedelic Healing? Scientific American Mind, 66-71.

Between 1897 and 1972, many studies were conducted on the therapeutic effects of psychotropic drugs; however, there were virtually no such studies conducted between 1972 and 1990 largely due to political reasons. Since then, research has begun anew, specifically into tryptamines (e.g. LSD, psilocybin) and phenethylamines (e.g. mescaline, MDMA). Tryptamine hallucinogens are thought to bind to serotonin-2A receptors in the cortex, effectively interfering with the processing of sensory information. The beneficial effects observed, such as positive changes in mood, reduction of anxiety, and raising of the pain threshold, may arise from subsequent 5HT-2A receptor downregulation. Phenethylamines are believed to mimic the effects of the dopamine neurotransmitter, but may also bind to the same serotonin receptors activated by the tryptamines. As psychedelics are known to elicit behavioral processes that are useful in the therapeutic context, such as enhanced symbolism and imagery, increased suggestibility, increased contact between emotions and ideations, and controlled regression, with the proper set and setting drug-assisted psychotherapy may show the potential to relieve patients who suffer with treatment-resistant psychiatric disorders.

Facilitation of Extinction of Conditioned Fear by D-Cycloserine

Davis, M., Myers, K.M., Ressler, K.J. Rothbaum, B.O. (2005). Facilitation of Extinction of Conditioned Fear by D-Cycloserine. American Psychological Association, Volume 14, Number 4, 214-219.

Conditioned fear can be suppressed through a process known as extinction, in which repeated exposure to a fearful stimuli minus any aversive effects leads to a gradual reduction in the fear response. Extinction is not thought to be an "unlearning" process, but rather the addition of a supplementary learning process which actively inhibits or suppresses fear responses that are no longer adaptive. Although not much is known about the neural underpinnings of extinction, it is known that the process depends on NMDA receptors within the amygdala which help to consolidate extinction. The compound D-cycloserine binds to the NMDA receptor and improves its efficiency, and administration of D-cycloserine in rats was shown to dose-dependently enhance extinction.

Taking this laboratory research to the clinic, researchers were curious to see if similar effects would be witnessed in human subjects. This article showed that D-cycloserine used alongside exposure therapy for acrophobics (people suffering from a fear of heights) resulted in significantly larger reductions in phobic symptoms and faster improvement as compared with placebo-controlled subjects. While this paints an optimistic picture for the use of D-cycloserine with phobias, it remains to be seen whether the compound will show equally impressive results in improving cognitive behavioral therapies for more complex anxiety disorders such as PTSD.

Tuesday, January 29, 2008

Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops

Tanaka, S.C. et al. (August 2004). Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nature Neuroscience, Volume 7, Number 8, 887-893.

Curiously, lesions in the nucleus accumbens in rats result in a tendency to choose small immediate rewards over larger future rewards. And low activity in the central serotonergic system is also associated with impulsive behavior in humans. This article argues that the lateral orbit-frontal cortex (OFC) takes on the role of predicting immediate rewards, while the dorsolateral prefrontal cortex (dlPFC), dorsal pre-motor cortex (dMC), and inferior parietal cortex (IPC) are involved in prediction of future outcomes. Therefore, different sub-loops of the cortico-basal ganglia network are specialized for reward prediction at different time scales. The last piece of the puzzle, the dorsal raphe nucleus, is thought to use serotonin influence to control the effective time scale of reward prediction, allowing flexible selection of a relevant time-scale appropriate for the task at the time of decision-making.

Sunday, January 27, 2008

Using human brain lesions to infer function

Rorden, C. & Karnath, H. (October 2004). Using human brain lesions to infer function: a relic from a past era in the fMRI age? Nature Reviews, Vol. 5, 813-819.

Patients with brain lesions have historically provided neuroscience with momentous insights into brain function. However, with the advent of non-invasive in vivo imaging techniques such as CT, MRI, fMRI, DTI, and the like, researchers are questioning the role of lesion methods going forward. This article argues that lesions studies will continue to fill a unique niche in the future, especially in combination with new imaging protocols: "The power of cognitive neuroscience comes from using convergent tools to investigate the same theoretical question."

Saturday, January 26, 2008

Looking into the Functional Architecture of the Brain with Diffusion MRI

Le Bihan, D. (June 2003). Looking into the Functional Architecture of the Brain with Diffusion MRI. Nature Reviews, Vol 4, 469-480.

Diffusion Magnetic Resonance Imaging (dMRI) is an exciting new addition to non-invasive neuroscience imaging, providing a view of anatomical connectivity in the brain based on the principle of molecular diffusion. Diffusion of water molecules in the direction of axonal myelinated fibres is about three to six times faster than in the perpendicular direction. In applying this maxim to detailed MRI measures of water displacement, it is possible to map the orientation in space of the white matter tracks in the brain. Utilizing the diffusion tensor imaging (DTI) technique provides even more exquisite detail on tissue microstructure. Information about the structural and dynamic wiring that determines how brain areas are networked has particular applicability to the study neurological and psychiatric disorders in which connectivity dysfunction is thought to be part of the underlying etiology.

Friday, January 25, 2008

CBT vs. Pharmacotherapy for Chronic Primary Insomnia

Sivertsen, B. et al. (June 2006). Cognitive Behavioral Therapy vs. Zopiclone for Treatment of Chronic Primary Insomnia in Older Adults. The Journal of the American Medical Association, Vol 295, No. 24, 2851-2858.

This study compared the effects of cognitive behavioral therapy (CBT) against sleep medication (Lunesta) and placebo intervention for chronic insomnia in older adults. The results showed that CBT resulted in improved short-term and long-term outcomes compared with pharmacotherapy on 3 out of 4 measures. Interestingly, for most outcomes Lunesta did not differ significantly from placebo.

Wednesday, January 23, 2008

Behavioral control, the medial prefrontal cortex, and resilience

Maier, S.F., Amat, J., Baratta, M.V., Paul, E., & Watkins, L.R. (2006). Behavioral control, the medial prefrontal cortex, and resilience. Dialogues in Clinical Neuroscience, Vol. 8, No. 4, 397-406.

In a previous article reviewed, "Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotrophin-releasing factor", Maier et al showed that the degree of control an organism has over a stressor modulates the impact of this stressor. But how, exactly, controllability enters the equation neurobiologically was undiscussed. This article tackles that issue with some interesting conclusions drawn.

Although the dorsal raphe nucleus (DRN) plays a critical role in learned helplessness, it is unlikely that it is the brain structure responsible for detecting whether or not a stressor is under behavioral control or not. It has neither the processing power nor the appropriate inputs to make such an assessment. However, the ventral medial pre-frontal cortex (vmPFC) is thought to be that structure. Electrical stimulation of this area leads to inhibition of serotonin neurons in the DRN. And inactivating this region eliminates the differential effects of controllability -- that is, both inescapable and escapable shocks produce the same behavioral outcomes. Further, directly activating the vmPFC during inescapable and escapable shocks produces responses in the both groups equivalent to an escapable shock, eluding learned helplessness.

So-called 'immunization effects' are also interesting. Initial experiences with controllable shock appears to attenuate the typical behavioral response to a later exposure to uncontrollable shock. The article shows how the vmPFC becomes associated with the stressor during controllable shock trials and later becomes re-activating again during subsequent uncontrollable trials, thereby inhibiting the DRN.

Furthermore, this 'trained' vmPFC projects to other structures besides the DRN. One of particular importance is the amygdala which is known to play a critical role in classical fear conditioning. The article shows how the pathway from the vmPFC to the central nucleus of the amygdala (CE) can be used to inhibit CE function, thereby retarding fear conditioning. As has been shown, inescapable shock prior to fear conditioning exaggerates fear conditioning. But escapable shock, a stressful event in itself, before fear conditioning is actually shown to reduce the phenomena of fear (in comparison with never-before-shocked animals). The authors remarked, "We know of no other position that would predict, or even explain, how exposure to a highly stressful event could retard the later development of fear." In other words, repeated exposure to aversive stimuli hyper-sensitize the animal to fear. But, repeated exposure to aversive stimuli which the animal can exercise some control over actually helps to desensitize the animal to fear by involving the vmPFC. Still more encouraging, this mechanism of resilience may generalize broadly to quite different situations and circumstances.

Tuesday, January 22, 2008

Polyvagal Theory and developmental psychopathology

Beauchaine, T.P., Gatzke-Kopp, L., & Mead, H.K. (2007). Polyvagal Theory and developmental psychopathology: Emotion dysregulation and conduct problems from preschool to adolescence. Biological Psychology, Vol 74, 174-184.

Polyvagal Theory specifies two distinct branches of the vagus, each originating in the medulla. The evolutionarily older branch originates in the dorsal motor nucleus (DMX), while the newer branch originates in the nucleus ambiguus (NA). Both branches provide inhibitory input to the viscera, including the heart. However, each does so in service of distinct evolutionary functions. The DMX branch is tasked with primary survival strategies, enacting defensive behaviors such as fighting, flighting, or freezing. The NA branch, only found in mammals, is used in modulating the fight/flight response towards the execution of social affiliation behaviors (read: emotional regulation).

Functional organization of the autonomic nervous system is thought to be phylogenetically hierarchical, with response strategies to threat dictated by the newest neural structures first, then falling back on older structures when a given response strategy fails. Therefore, polyvagal theory predicts that the NA branch will inhibit acceleratory sympathetic nervous system (SNS) input to the heart when attention and social engagement are adaptive, and withdraw this inhibitory influence when fighting or fleeing are adaptive.

Beauchaine et al argue that an under-responsive central reward system coupled with deficient vagal modulation of emotion leads to sensation-seeking and aggressive behaviors characteristic of externalizing disorders, such as conduct disorder and delinquency, while an over-responsive central inhibition system coupled with deficient vagal modulation of emotion leads to withdrawal behaviors characteristic of internalizing disorders, such as anxiety and panic.

True to form, vagal deficiencies were observed in aggressive children and adolescents, manifested in attenuated respiratory sinus arrhythmia (a measure of vagal activity and thus an index of parasympathetic influence) at baseline and while watching sad and threatening films. Onset of motivational deficiencies appear as early as preschool years (central dopamine systems maturing quite early), but the study reveals that reduced vagal tone and excessive vagal reactivity don't appear until after preschool and into the middle school years. Therefore, socialization of strong emotion regulation skills during these formative years may buffer at-risk children from going on to develop conduct disorders and delinquency.

Monday, January 21, 2008

Stressor controllability and learned helplessness

Maier, S.F. & Watkins, L.R. (2005). Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotrophin-releasing factor. Neuroscience and Behavioral Reviews, Vol. 29, 829-841.

This paper discusses the roles of serotonin, the dorsal raphe nucleus (DRN) structure, and corticotropin-release hormone (CRH) in the phenomenon of learned helplessness. It also discusses the implications of such research to models of depression and anxiety.

It has long been observed that animals who are exposed to an inescapable aversive conditioning procedure later fail to learn to escape from avoidable aversive stimuli. And beyond this learning deficit, subjects exposed to inescapable shocks (IS) are likely to suffer from ulcers, reduced appetite, reduced motor activity, reduced aggression and social dominance, reduced social interaction, exaggerated fear and fear conditioning, and neophobia, compared to subjects exposed to escapable shocks (ES). This constellation of behavioral changes following exposure to uncontrollable stressors is known as 'learned helplessness'.

A key feature of learned helplessness is that it alters behavior in circumstances different from the original "shocking" experience. When shocked in new environments, this learning deficit reappears and will even last for 48-72 hours after the original uncontrolled stress experience. Further, if the animal is reintroduced to the original environment, the learning deficit will persist much longer (i.e. the animal will not try to escape the aversive experience).

The behavioral changes that take place in this paradigm can be summarized as reduced fight/flight defensive behaviors and increased fear/anxiety related behaviors. The DRN was quickly implicated here since it is well known that stimulation of serotonin neurons within this structure affect fight/flight via projections to the periaqueductal gray (PAG) and potentiate fear/anxiety via projections to the amygdala. Indeed, inescapable shock produced large increases in extracellular serotonin in the DRN, while escapable shock did not. To account for the lasting effects witnessed, researchers looked for signs of sensitization in the DRN which might result in exaggerated serotonin release under later testing conditions. As expected, evidence shows that inhibitory serotonin autoreceptors may be desensitized following IS, thereby sensitizing these DRN neurons to further inputs. Interestingly, lesioning the DRN prevents exaggeration of fear conditioning produced by IS altogether.

In addition to serotonin, CRH also plays a crucial role in enacting the body's stress response. Oddly, it appears that CRH initially inhibits the serotonergic neurons but as dosage increases actually becomes less inhibitory and more excitatory in effect. At least in certain regions of the DRN, evidence suggests CRHR1 activation inhibits serotonin activity while CRHR2 activation excites serotonin neurons. However, it is believed that CRHR2 may play different roles in different brain regions (and possibly even within different areas of the DRN). Thus, global statements about the roles of serotonin, CRH, and their interaction may be problematic.

All of this evidence provides some help in creating the distinction between 'fear' and 'anxiety'. While fear is a motivational system responsible for enacting defensive behaviors in response to either learned or unlearned signals of danger, anxiety may be better understood to be a state within the organism that leads to the exaggeration of fear when it is threatened. Thus, long duration responses that build and dissipate slowly characterize anxiety, while responses that are closely driven by specific stimuli characterize fear.

Finally, the article discusses the relation between learned helplessness and the disorders of depression and anxiety. It is not quick to propose learned helplessness as a proper model for either one, but it does mention that it will be far easier to relate enhanced serotonin activity to anxiety than to depression based on the current literature available. (The model may shed light on the effectiveness of antidepressants against anxiety disorders, as one example. The acute effect of SSRI treatment, increasing serotonergic activity, is known to lead to increased anxiety. However, chronic administration of SSRIs has been shown to desensitize/downregulate post-synaptic serotonin receptors, reducing the anxiety response.)

Friday, January 18, 2008

What should animal models of depression model?

Frazer, A. & Morilak, D.A. (2005). What should animal models of depression model?, Neuroscience and Biobehavioral Reviews, Volume 29, 515-523.

Experimentation with animals offers researchers great liberties in studying a disorder. However, proper animal models must first be developed and agreed upon. Animals models for testing fear, as an example, are made possible because fear is an emotion that is conservative across species; that is, fight, flight, or freeze responses appear consistently. However, researchers have struggled with defining models for other disorders which lack such obvious behavioral patterns. Depression is such a disorder. This article asks the question, "What should we be attempting to model with animal models of depression?".

Major depressive disorder (MDD) is a syndrome with a constellation of behavioral features. Making matters worse, the etiology of MDD remains unknown. That MDD is a diagnostic construct and is comorbid with many other psychiatric diagnoses also does not help. This article suggests placing an emphasis on modeling specific behavioral dimensions (or characteristics) that are dysregulated in depression, rather than trying to recreate or mimic the entire spectrum of symptoms of depression or even specific symptoms associated with it. This will be more conducive to experimentation and to understanding the regulatory mechanisms by which antidepressant drugs alleviate such a cluster of symptoms. Three dimensions were put forth in the paper: negative affect, loss of positive affect, and physiological hyperarousal.

Wednesday, January 16, 2008

A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee

Moseley, J.B. et al. (July 2002). A Controlled Trial of Arthoscopic Surgery for Osteoarthritis of the Knee, The New England Journal of Medicine, Volume 347, Number 2, 81-88.

Over 650,000 knee surgeries are performed each year to relieve the pain of osteoarthritis. However, there is no evidence to support that arthroscopy cures or arrests osteoarthritis. Amazingly though, about half of the patients report relief from pain. This paper set out to see if the surgeries were being successful due to some direct medical benefit being received or whether they were equivalent to placebo, and thus successful for other, psychological reasons. The outcomes showed that arthroscopic lavage and arthroscopic debridement were in fact no better than a placebo procedure. Therefore, the successes being witnessed were likely related to placebo effect. (Ergo, researchers should not underestimate the power of placebo.)

Tuesday, January 15, 2008

The Amygdala

LeDoux, J. (October 2007). The amygdala, Current Biology, Vol. 17, R868-R874.

This is a fantastic overview of a very important brain structure by one of the world's leading experts on the subject. The article covers the amygdala's anatomic organization (its different nuclei), its connectivity (both inputs and outputs), its cellular mechanisms (neurotransmission and neuromodulation), its role in emotional processing, and its implication in a variety of human disorders. The article even covers neuronal processes related to classical conditioning (i.e. fear memory consolidation and reconsolidation), such as changes in synaptic strength (upregulation of post-synaptic receptors by LTP), structural changes in synaptic connectivity (post-synaptic cytoskeletal alterations, presumably dendritic and microtubule changes), and pre-synaptic feedback mechanisms (release of nitric oxide as a messenger).

Sunday, January 13, 2008

The Placebo Effect

Brown, W.A. (January 1998). The Placebo Effect, Scientific American, p. 90-95.

The placebo effect, where the very act of undergoing treatment helps the patient to recover, has been known for some time. However, its neural correlates still remain elusive. A wide range of afflictions seem to respond to placebo, especially those in which stress directly affects the symptoms. Animal and human studies have shown that the functioning of the immune system falters under stressful conditions, stymied by release of the stress hormone cortisol. Therefore, reducing fear and anxiety by restoring some sense of control might help to prevent exacerbation of symptoms.

To practitioners, the article recommends a good bedside manner, a proper diagnosis and prognosis, and presentation of different treatment options for the patient to choose from whenever possible. While the author believes every effort should be made to understand and harness this powerful phenomena to affect treatment outcomes, he cautions doctors against prescribing placebos deceptively on ethical grounds.

Transcranial magnetic stimulation and cognitive neuroscience

Walsh, V. & Cowey, A. (October 2000). Transcranial magnetic stimulation and cognitive neuroscience, Nature Reviews, Volume 1, 73-79.

Transcranial magnetic stimulation (TMS) is an investigative tool used in neuroscience to transiently interfere with brain functions, temporarily interrupting normal brain activity in a restricted region of the brain. This non-surgical technique introduces random activity as disorder into the information processing system, disrupting cognitive task performance. When coupled with a neuroimaging technique such as fMRI or EEG, TMS has proven very useful in experimentation to elucidate brain function.

Throughout the history of neuropsychology, patients with brain injuries ranging from mild to major have provided critical insights into the way the brain operates. As a mechanism of interference, TMS is unique in that it can be used to create 'virtual lesions', short-lived and reversible. Real lesioned brains will have undergone months if not years of neural reorganization following an accident to compensate for the deficit. Since TMS interference is typically not prolonged, no such opportunities exist for long-term reorganization processes to kick in. While this may seem like a poor approximation of classical lesioning, researchers believe that studying these types of temporary lesions may in fact be more useful to scientific examination without the introduction of the brain's compensatory coping strategies.

In addition to pure interference studies, the effects of TMS at the primary site of application have been shown to correspond very well with activation produced by self-induced behavior. For example, in one study activation was presented to the motor cortex above the motor threshold, creating behavior in the arm. When subjects were asked to reproduce the same arm movement voluntarily, there was great similarity between the two compared brain activations. However, one restriction of non-surgical TMS is that stimulation is limited to superficial cortical regions.

Thursday, January 10, 2008

What does fMRI tell us about Neuronal Activity?

Heeger, D.J. & Ress, D. (February 2002). What does fMRI tell us about Neuronal Activity?, Nature Reviews, Volume 3, 142-151.

The linear transform model refers to a fundamental assumption guiding the analysis of fMRI studies, namely that fMRI signal is approximately proportional to a measure of local neural activity. Clearly, the ultimate success of this research depends on a clear relationship between the fMRI signal and the underlying neuronal activity. However, some scientists believe reasons exist to be skeptical of this pervasive assumption. Heeger and Ress provide a review of arguments on both sides, concluding that this model is a reasonable and useful approximation, but only for some recording sites, in some brain areas, and using certain experimental protocols.

Wednesday, January 9, 2008

This is Your Brain on Politics

Iacoboni, Freedman, & Kaplan. (November 11, 2007). This Is Your Brain on Politics, The New York Times.

Easily one of the most bogus articles ever published on topics related to neuroscience. In short, the article claimed that it is possible to read the minds of people by examining their brain activity a la fMRI and glean insight into their cognitive reactions to American presidential candidates. The most fallacious reasoning employed by the authors was the assumption that activity in certain brain regions can have a 1:1 mapping to mental states such as anxiety, disgust, equivocation, empathy, and interest, e.g. the amygdala was active so they must be anxious with regard to this candidate. Additionally, the article was not peer reviewed, did not provide any scientific detail which could be used to evaluate the conclusions drawn, and only "studied" 20 subjects.

Luckily, there were some expedient retorts by subject matter experts, but probably not before millions of readers were led to believe that this is acceptable science and produced reasonable logical conclusions. Letters to the Editor, Nature

Thursday, January 3, 2008


Gosline, A. (December 2007.) Bored?, Scientific American Mind.

This article suggests boredom is not merely the result of circumstance. Instead, it may also be affected by emotional factors, personality traits, and attention. It may also come in many varieties, ranging from situational boredom to pathological boredom. People who are predisposed to boredom are more likely to suffer from ills such as depression and drug addiction; they also tend to be socially awkward and poor performers at school or work. A Boredom Proneness Scale (BPS), developed by Richard Farmer at the University of Oregon, may help clinicians to identify boredom as a component of other ailments.

Boredom is complicated, but what we have learned from research suggests low arousal and insufficient motivation both play critical roles in this cognitive state. Men are more likely to be bothered by boredom than women. "Men are more likely to say, ‘There is not enough stuff coming through the environment, and that’s why I am bored.’" Similarly, extroverts seem to be more susceptible, requiring a constant and changing supply of stimulation to achieve optimal arousal levels.

Boredom may also be related to the struggle to maintain attention, a pathological inability to focus. Scores on the BPS were correlated with measures for adult ADHD. A chronic inability to focus on activities may render them effectively meaningless. Psychologist Al Cheyne goes so far as to say, "Attention is the common link between lack of meaning, depression and boredom." Others describe boredom as the antithesis of 'flow' (when a person's skills match the challenge presented by the environment). Tasks that are too easy are quickly boring.

Emotional factors may also play a part. Obsessive mood monitoring seems to detract from intense concentration and thus full engagement in the activity at hand. And boredom can arise from an inability to identify activities that will lead to personal happiness and fulfillment. An inability to know what will make you happy can lead to a more profound existential ennui arising from a pervasive sense of meaninglessness. Existential boredom might also occur when a person abandons important drives, desires, and life goals. Thus, being bored is a form of disengagement from the world.

The article suggests methods of combating boredom on all of these axes. Changing jobs or the complexity of tasks, beginning new hobbies and interests, developing inner skills for stimulation, and being more mindful of the beauty of self and surroundings may all help.