The Neurocritic

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Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.

The Neurocritic
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  • February 9, 2014
  • 08:21 PM
  • 391 views

I Wanna Hold Your Hand (after 23 sessions of Emotionally Focused Therapy)

by The Neurocritic in The Neurocritic

Can neuroscience illuminate the nature of human relationships? Or does it primarily serve as a prop to sell self-help books? The neurorelationship cottage industry touts the importance of brain research for understanding romance and commitment. But any knowledge of the brain is completely unnecessary for issuing take-home messages like tips on maintaining a successful marriage.In an analogous fashion, we can ask whether successful psychotherapy depends on having detailed knowledge of the mechanisms of “neuroplasticity” (a vague and clichéd term). Obviously not (or else everyone's been doing it wrong). Of course the brain changes after 12 sessions of psychotherapy, just as it changes after watching 12 episodes of Dexter. The important question is whether knowing the pattern of neural changes (via fMRI) can inform how treatment is administered. Or whether pre-treatment neuroimaging can predict which therapy will be the most effective.However, neuroimaging studies of psychotherapy that have absolutely no control conditions are of limited usefulness. We don't know what sort of changes would have happened over an equivalent amount of time with no intervention. More importantly, we don't know whether the specific therapy under consideration is better than another form of psychotherapy, or better than going bowling once a week.Enter Love Sense: The Revolutionary New Science of Romantic Relationships, a new book by Dr. Sue Johnson, the clinical psychologist who developed Emotionally Focused Therapy (EFT).1 The book is reviewed by Dr. Helen Fisher in the New York Times:Love in the Time of NeuroscienceBy HELEN FISHER  FEB. 7, 2014In “The Devil’s Dictionary,” Ambrose Bierce defined love as “a temporary insanity curable by marriage.” Enter Sue Johnson, a clinical psychologist and couples therapist who says that relationships are a basic human need and that “a stable, loving relationship is the absolute cornerstone of human happiness and general well-being.” To repair ailing partnerships, she has developed a new approach in marriage counseling called Emotionally Focused Therapy, or EFT, which she introduces in her new book, “Love Sense.”...Johnson believes EFT can help couples break out of patterns, “interrupting and dismantling these destructive sequences and then actively constructing a more emotionally open and receptive way of interacting.” She aims to transform relationships “using the megawatt power of the wired-in longing for contact and care that defines our species,” and offers various exercises to restore trust.Most interesting to me was Johnson’s brain-scanning study. Before EFT therapy, unhappily married women participating in the study reported considerable pain from an electric shock to the ankle as they held their husbands’ hands. After 20 sessions of EFT, however, these now more securely attached women judged their pain as only “uncomfortable” and their brain scans showed no alarm response. Secure attachment appears to change brain function and reduce pain.Initial questions:Is there a “wired-in longing for contact and care that defines our species”? {my needy cat seems to long for contact and care}What's with that hand-holding ankle shock brain-scanning study? {did EFT really eliminate the “alarm response” in these women?}  Then Fisher continues:But Johnson too often focuses on attachment to the exclusion of other “megawatt” brain systems. Remarkably, she lumps romantic love with attachment, saying “adult romantic love is an attachment bond, just like the one between mother and child.” In reality, romantic love is associated with a constellation of thoughts and motivations that are strikingly different from those of attachment. My research bears out that humankind evolved distinct but interrelated brain systems for mating and reproduction: the sex drive (to seek a range of partners); feelings of romantic love (to focus one’s mating energy on a single partner); and feelings of attachment (to drive our forebears to form a pair-bond to rear their young together). Each brain system is associated with different neurochemicals; each is a powerful drive that still plays a continuing role in partnership stability.More questions:Are there distinct (but interrelated) brain systems for the sex drive, romantic love, and feelings of attachment? {I actually find this to be plausible}Is each brain system associated with different neurochemicals? {i.e. testosterone, dopamine, and oxytocin, respectively. I find this to be less plausible, or at least a bit simplistic.} It's time to correct the misperceptions and overinterpretations that have arisen from this research!!This is a job for...MagnetoThis looks like a job for @sarcastic_f! (I imagine him as some sort of BS-fighting super hero) http://t.co/z29q00G80u— Adam J Calhoun (@neuroecology) February 8, 2014Since there are a number of issues to tackle here – too many for a single post – I'll concentrate on only one of them here.I Wanna Hold Your HandIn 2006, Dr. James Coan and colleagues published a neuroimaging paper suggesting that the brains of happily married women showed an attenuation of activity related to emotion and threat when they held the hands of their husbands (Coan et al., 2006). Threat was induced experimentally by presenting a stimulus which occasionally signaled that a mild electric shock would be delivered to the ankle (20% of the time). Holding the hand of a male stranger also attenuated the hemodynamic response in some of these regions, relative to a no hand-holding control condition.2Backing up a bit, the participants in the study were 16 heterosexual couples who rated their marital satisfaction as at least 40 on the Satisfaction subscale of the 50 point Dyadic Adjustment Scale (DAS). Total scores on the DAS were 126 for husbands (on a 151 point scale) and 127 for wives.3 The experimental design is illustrated below. The red X indicated a 20% chance of shock.... Read more »

Coan JA, Schaefer HS, & Davidson RJ. (2006) Lending a hand: social regulation of the neural response to threat. Psychological science, 17(12), 1032-9. PMID: 17201784  

Johnson SM, Moser MB, Beckes L, Smith A, Dalgleish T, Halchuk R, Hasselmo K, Greenman PS, Merali Z, & Coan JA. (2013) Soothing the threatened brain: leveraging contact comfort with emotionally focused therapy. PloS one, 8(11). PMID: 24278126  

  • December 30, 2013
  • 10:36 PM
  • 417 views

How Can We Forget?

by The Neurocritic in The Neurocritic

** This post is meant to be read in tandem with its more complimentary cousin, Electroconvulsive Therapy Impairs Memory Reconsolidation, at The Neurocomplimenter. **spECTrum 5000Q® ECT device (MECTA)Bad memories haunt a significant number of people with serious mental illnesses, such as chronic major depression and post-traumatic stress disorder (PTSD). If it were possible to undergo an experimental procedure that selectively impairs your memory for an extremely unpleasant event, would you do it? If this sounds like the plot of Eternal Sunshine of the Spotless Mind, you're not alone.A pet peeve of mine is reference to this excellent but far-fetched film in scientific journals and popular media coverage of “memory erasure.” The idea that it's possible to selectively remove a complex autobiographical memory that has become intimately entwined with the fabric of our constructed selves is utter science fiction.At some level, even Michel Gondry knew it. One incident in Eternal Sunshine is suggestive of how memories might actually be stored. It was after one of the main characters (Joel) had his memories of his ex-girlfriend Clementine erased, and he couldn't remember who Huckleberry Hound was. He had associated the cartoon character and the song "Darling Clementine" with her. That resembles a semantic network, where an overlapping network of neurons and synapses code different but semantically related things. Take out all episodic and semantic memories of Clementine, and knowledge of Huckleberry Hound goes with it.The latest incarnation of this particular memory erasure meme was provoked by publication of a paper (Kroes et al., 2013) that examined the process of memory reconsolidation in depressed patients administered a course of electroconvulsive therapy (ECT). Here are some of the headlines:Zapping the brain can help to spot-clean nasty memories Absolutely shocking: electrocuting brain can wipe unpleasant memoriesUnwanted Memories Erased in Electroconvulsive Therapy ExperimentShocking Memories AwayMy companion post at The Neurocomplimenter reviews the literature on memory reconsolidation and describes the experiment of Kroes et al. (2013) in some detail. What I'd like to do here is to point out possible weaknesses in the results that could undermine the authors' conclusions. I'll also discuss a much earlier ECT study which did not support the notion that reactivated memories are especially vulnerable to disruption (Squire et al., 1976).To briefly reiterate the methods used in the new paper (Kroes et al., 2013), the participants were 39 patients with moderate to severe major depression. They were either at the end of an acute treatment cycle or receiving maintenance ECT. The study used a between-subjects design with three different experimental conditions, with patients randomly assigned to one of the three groups (n=13 in each). The within-subjects factor was whether or not the patients received a reminder of previously learned material before treatment.All participants learned two different emotionally charged slide stories with audio narration, each consisting of 11 images. In one, a boy is in an accident that severs his feet, which are reattached at the hospital. In the other, two sisters leave their home at night, and one is kidnapped at knife point and attacked by an escaped convict.Memory for one of the stories was reactivated a week later by presenting part of the first slide, and then giving a test for this slide. Only four minutes later, Groups A and B were anesthetized and received ECT. Group C received their ECT treatment at a later date. The final memory test for Groups A and C was 24 hrs after the reminder, while Group B was tested as soon as they woke up from the procedure (mean = 104 min later). The final test consisted of 40 multiple choice questions about each of the stories. The basic idea is that reconsolidation of the reactivated story isn't complete within 104 min, so Group B's test performance should be the same for the two stories. In contrast, reconsolidation is complete by 24 hrs, so for Group A the disruptive effect of ECT should selectively impair memory for the transiently reactivated story, which is in a labile state (relative to the "consolidated" story learned 7 days earlier).Is that what was observed? Statistically speaking, yes. But two patients in Group B (out of 13 total) performed very well on the reactivated story (see purple box in the figure below). Fig. 1 (modified from Kroes et al. 2013). ECT disrupts reconsolidation. Memory scores on the multiple choice test are expressed as percentage correct (y axis). Memory for the reactivated story shown in solid bars and non-reactivated story in open bars. Each circle is the score for an individual patient. The horizontal dotted line is chance performance. Group A is in red, Group B in blue, and Group C in orange. Edited to add: The purple box highlights 2 outliers in ... Read more »

  • December 30, 2013
  • 10:24 PM
  • 417 views

Electroconvulsive Therapy Impairs Memory Reconsolidation

by The Neurocritic in The Neurocritic

** This post is meant to be read in tandem with its more critical cousin, How Can We Forget? at The Neurocritic. **Thymatron® System IV (Somatics, LLC)“Memories are constantly changing, each time we recall them they're physically different.”- me, July 7, 2006The precision of memory over time is a quaint idea. A large body of research shows us that memories are not fixed entities (Alberini & Ledoux, 2013). Every time a specific memory “trace” is reactivated, it enters a transiently unstable state where it's subject to change before becoming consolidated and stored again (Nader & Hardt et al., 2009). In the most widely studied model systems, new protein synthesis in the hippocampus and/or amygdala is required for reconsoldation of fear memories. Fig. 1 (Alberini & Ledoux, 2013). Two Views of Memory. In the reconsolidation view (bottom), when a memory is activated, the version stored during the last retrieval (rather than the version stored after the original experience) is called up.Although these concepts and mechanisms of memory reconsolidation are not universally accepted, they've formed the basis for a thriving area of basic neuroscience research. Furthermore, the principles learned from animal studies have been applied to Pavlovian fear conditioning in humans (Schiller et al., 2010).By precisely timing the presentation of a fear memory reminder (i.e., within the reconsolidation window), extinction of the skin conductance response to a conditioned stimulus (a colored square previously associated with a mild shock) occurred when tested 24 hours later (Schiller et al., 2010). A subset of participants returned one year later, and the “extinction-during-reconsolidation” procedure prevented reinstatement of the fear response, unlike in the group where extinction training was conducted outside the reconsolidation window.This finding was greeted with optimism for potential future applications in treating anxiety disorders, including PTSD. However, sweaty palms in anticipation of a mild shock is not exactly the same as the trauma of a disfiguring accident or a sexual assault.Now, a group of Dutch researchers (Kroes et al., 2013) has taken a completely different approach to disrupt reconsolidaton in humans – namely, by reactivating recently learned memories in depressed patients immediately before administration of clinically prescribed electroconvulsive therapy (ECT).ECT is sometimes used as a last resort in treating chronically depressed patients who've failed to respond to pharmaceutical and psychological therapies. Despite its floridly negative depiction in Hollywood movies, ECT is generally accepted within the psychiatric community as a highly effective treatment for intractable major depression (Kellner et al., 2012).1The participants were 39 patients (mean age = 57 yrs) diagnosed primarily with moderate to severe recurrent major depressive disorder. They were either at the end of an acute treatment cycle or receiving maintenance ECT. The study used a between-subjects design with 3 different experimental conditions, with patients randomly assigned to Group A, B, or C (n=13 in each). The within-subjects factor was whether or not the patients received a reminder of previously learned material before treatment.All participants learned two different emotionally charged slide stories with audio narration, each consisting of 11 images. In one, a boy is in an accident that severs his feet, which are reattached at the hospital. In the other, two sisters leave their home at night, and one is kidnapped at knife point and attacked by an escaped convict.Memory for one of the stories was reactivated a week later by presenting part of the first slide, and then giving a test for this slide. The most surprising part comes next: only 4 minutes later (on average), Groups A and B were anesthetized and received ECT, which induced a seizure. Group C received their ECT treatment at a later date. The final memory test for Groups A and C was 24 hrs after the reminder, while Group B was tested as soon as they woke up from the procedure (mean = 104 min later). The final test consisted of 40 multiple choice questions about each of the stories.Supplementary Fig. 1 (modified from Kroes et al. 2013). Study design. During the first study session, all groups were shown two emotional slide-show stories. During the second session, memory for one of the two stories was reactivated. Immediately after memory reactivation, patients in Groups A and B received ECT. For Group B, memory was tested immediately upon recovery from ECT (blue box). For Groups A and C, memory was tested one day after reactivation (red and orange respectively).The basic idea here is that reconsolidation of the reactivated story isn't complete at 30 or 90 minutes, so Group B's test performance should be the same for the two stories. In contrast, reconsolidation is complete by 24 hrs, so for Group A the disruptive effect of ECT should selectively impair memory for the transiently reactivated story, which is in a labile state (relative to the "consolidated" story learned 7 days earlier).And in fact, this is what the authors observed, as shown in the figure below. The horizontal dotted line depicts chance performance (25% accuracy) – no better than guessing. Group A performed at chance for the reactivated story, but remembered at least some of the non-reactivated story. In contrast, Group B performed significantly better than chance for both stories. Finally, Group C (the control group) remembered significantly more details about the reactivated story (relative to the non-reactivated s... Read more »

  • December 21, 2013
  • 11:58 PM
  • 537 views

When Waking Up Becomes the Nightmare: Hypnopompic Hallucinatory Pain

by The Neurocritic in The Neurocritic

Most of us have had frightening nightmares – someone is chasing after us trying to kill us, or the world is coming to an end. Other disturbing dreams are based on real life anxieties – our partner leaves us, we lose our job, we become homeless. One specific psychiatric condition includes nightmares as part of the diagnosis. Individuals with post-traumatic stress disorder (PTSD) often have terrible nightmares that relive the traumatic event (Pigeon et al., 2013)We're always glad to wake up from such nightmares, whether they were of the supernatural or mundane or terrifying variety. "Thank god it was only a dream," we say.But what if waking up from sleep was the nightmare? Hypnopompic hallucinations are unusual sensory phenomena experienced just before or during awakening. Their better known mirror image, hypnagogic hallucinations, are vivid and frightening episodes of seeing or hearing or feeling phantom sensations while falling asleep (or in early stage 1 sleep). Both are frequently associated with sleep paralysis, the terrifying condition of being half awake but unable to move. This is because the complete muscle atonia typically experienced during REM sleep has oozed into lighter stages of non-REM sleep.Hypnagogic and hypnopompic hallucinations are usually associated with narcolepsy, but 37% of a representative community sample reported frequent hypnagogic hallucinations, and 12.5% reported hypnopompic hallucinations (Ohayon et al., 1996).1 This went well beyond the low incidence of narcolepsy in that population. Both types of hallucinations were more common in those with insomnia, excessive daytime sleepiness, anxiety disorders, and depression (according to self-report).Night Terrors 1, by Beth RobinsonNocturnal Episodes of Pain and ScreamingA new case study in the journal Sleep (Mantoan et al., 2013) reports on the terrifying hypnopompic hallucinations of a 43 year old woman who experiences intense limb pain when waking up, which vanishes within 30 seconds. This is a very unusual manifestation of a non-REM parasomnia, a sleep disorder involving partial arousal during the transition between non-REM and wakefulness. The phenomenology might be best characterized as a night terror. According to the case report (Mantoan et al., 2013), the patient had......a history of nocturnal screaming episodes within 1–2 h of sleep onset from the age of 30 years. Her husband was habitually awoken by his wife screaming loudly, usually flapping either her right or left hand against the bed in a semi-purposeful fashion. Her husband reported that the events were sometimes heralded by an inspiratory sigh, she looked terrified and would not respond to him. The screaming would usually last 5–10 sec, and she would then complain to her husband of intense pain affecting the fingers of either hand or arm and occasionally her legs, with no associated numbness or paraesthesia. She would become fully orientated within 30 sec and would be partially amnesic for the event, but would recall an accompanying sense of “fighting to stay alive” associated with intense panic and often accompanied by fast regular palpitations. Otherwise no dream mentation or visualizations were reported in association with the episodes. She initially had these episodes monthly, but they increased in frequency to 2-5 times a week with 1-2 episodes per night.She was unable to identify any triggers for the episodes, and neither she nor her husband considered her to be stressed, anxious, or depressed. There was no history of sleep violence, sleep sex, sleep eating, or any other NREM parasomniac automatisms. The authors could not identify any standard physical source for the pain. Thoracic outlet syndrome, cervical radiculopathy, focal nerve entrapment, and median neuropathy (carpal tunnel syndrome) were all ruled out.Pharmacological treatments were unsuccessful. A low dose (0.5–1 mg) of clonazepam was poorly tolerated (it made her feel depressed) and had no effect on her symptoms. Paroxetine was poorly tolerated (due to sedative effects), and gabapentin was also a complete failure. Trazodone, a sedating antidepressant most often prescribed for insomnia, actually made the symptoms worse.An MRI ruled out a thalamic or hypothalamic lesion. Sleep EEG revealed sudden arousals from deep sleep, accompanied by looks of pain and/or fear on the patient's face. The episodes were consistent with a NREM parasomnia. In the example below, the patient was shaking her arm – muscle activity (EMG) is shown in the green trace.adapted from Fig. 1B (Mantoan et al., 2013). EEG showing delta waves of stage 3 sleep before an episode of arousal with shaking of one arm and looks of fear. Channels 1-12 are EEG; channels 13 and 14 are electro-oculogram (EOG) activity; channel 15 is electromyography (EMG); channel 16 is electrocardiogram (ECG); channel 17 is oxygen saturation by pulse oximetry (SpO2). What did the doctors do to help this poor woman? Nothing, it seems. A few more musculoskeletal causes need to be ruled out. The authors end on a vague note about the possible mechanism(s):In conclusion, to our knowledge this is the first report of a NREM parasomnia associated with painful paroxysms, for which we postulate the following underlying pathophysiological mechanism: an internal or external stimulus triggers arousal, facilitating the activation of innate motor pattern generators in the brainstem and activating somatosensory cortical areas to produce hypnopompic hallucinatory pain.So instead of the more typical visual hallucinations, the patient experiences pain hallucinations that originate.... where?? It seems to me that the sleep EEG could be analyzed more thoroughly, beyond merely ruling out seizure occurrence. Perhaps another imaging modality like PET could be tried (PET would be quieter than fMRI and would better tolerate movement). Identifying the neurophysiological correlates of her phantom night terr... Read more »

Ohayon MM, Priest RG, Caulet M, & Guilleminault C. (1996) Hypnagogic and hypnopompic hallucinations: pathological phenomena?. The British journal of psychiatry : the journal of mental science, 169(4), 459-67. PMID: 8894197  

  • December 14, 2013
  • 04:26 PM
  • 362 views

The Manifestation of Migraine in Wagner's Ring Cycle

by The Neurocritic in The Neurocritic

German Composer Richard Wagner (1813-1883) wasn't the healthiest guy. He suffered from heart disease, skin disorders, acute infections, minor ailments, and most prominently, recurring headaches – the “main plague” of his life (Göbel et al., 2013). He complained of “Headache, ‘sick headache,’ ‘dyspepsia,’ ‘nervousness,’ melancholy, insomnia, indescribable suffering... Wagner had all of them all of the time.” (Gould, 1903). Wagner wrote many letters to his doctor, Dr. Pusinelli, over a 35 year period (Gould, 1903): They begin with, "I have headache," and continue with complaints of bad weather and bad health; of growing old and loss of joy (aged 33 years); of increase of illness; working at composition with consequent frightful suffering; with prayers for peace, peace; moans at the uselessness of life; regrets at inability to get a good photograph; and sleeplessness. Baths and douches drive him nearly crazy. There is longing for his natural joyfulness; reiteration of physical and mental exhaustion; the thought of suicide ; emphasis of his irritability and of his inability to write another line, etc.A new article in the Christmas edition of BMJ by a trio of Göbels (Göbel, Göbel, & Göbel, 2013) focuses on Wagner's migraines and how he incorporated the attacks and auras into his operas. The specific example of interest is the opera Siegfried (1876), which is the third part of the Ring Cycle.The first scene of act 1 of the opera Siegfried provides an extraordinarily concise and strikingly vivid headache episode. The music begins with a pulsatile thumping, first in the background, then gradually becoming more intense. This rises to become a directly tangible almost painful pulsation. While the listener experiences this frightening headache sensation, Mime is seen pounding with his hammer, creating the acoustic trigger for the musically induced throbbing, painful perception. At the climax Mime cries out: “Compulsive plague! Pain without end!” A contemporary staging of Siegfried by Anthony Pilavachi portrays the character of Mime as a scientist in a white lab coat. Göbel et al. (2013) identify a “migraine aura leitmotif” that occurs in act 1, scene 3. It depicts the visual disturbances that accompany migraine aura. Mime sings, “Loathsome light! Is the air aflame? What is it flaring and flashing, glittering and whirring, what is swirling and whirling there and flickering around? It glistens and gleams in the sunlight’s glow. What is it rustling and humming and blustering there?”Wagner's disabling migraines contributed to a 12 year disruption in his work on Siegfried, which was finally completed in 1871. In a January 1857 letter to Franz Liszt, he wrote (Gould, 1903):My health, too, is once more so bad that for ten days after I had finished the sketch for the first act of Siegfried, I was literally not able to write a single bar without being driven away from my work by a most alarming headache. Every morning I sit down, stare at the paper, and am glad enough when I get as far as reading Walter Scott. The fact is I have once more overtaxed myself, and how am to recover my strength? With Rheingold I got on well enough but the Valkyrie caused me much pain. At present my nervous system resembles a pianoforte very much out of tune. The Göbels summarize their paper in the video below. Here's hoping that your holiday season is headache-free!References Carl H Göbel, Anna Göbel, Hartmut Göbel (2013). “Compulsive plague! pain without end!” How Richard Wagner played out his migraine in the opera Siegfried BMJ DOI: 10.1136/bmj.f6952... Read more »

  • November 29, 2013
  • 03:29 AM
  • 716 views

The Phases of Shopping Addiction

by The Neurocritic in The Neurocritic

The blight of Black Friday is upon us. What better time to look at a recent paper on compulsive shopping? Sohn and Choi (2013) adopted a qualitative approach and recruited a small group of Korean housewives with problematic shopping habits via consumer news websites. These nine women ranged in age from 22 to 40. The authors identified their target group as individuals with compulsive buying disorder, who reported a "preoccupation with shopping, pre-purchase tension or anxiety, and sense of relief following the purchase defined by Faber and O’Guinn (1992)." The participants all had high scores on the Faber and O’Guinn 14 item "compulsive buying checklist."The authors conducted in-depth 2 hour interviews with each participant and analyzed the data according to a six-step contents analysis (Kim et al. 1999) that derived concept clusters, subcategories, and categories. Of note are these Five Sequential Phases of Shopping Addiction (Sohn & Choi, 2013):Phase 1. Retail therapy, “Filling up emptiness with shopping”Phase 2. Denial, “Ignoring overconsumption”Phase 3. Debt-ridden, “Ran out of money, while nothing left”Phase 4. Impulsive buying, “Driving ones-self to hasty buying”Phase 5. Compulsive buying, “It is crazy but I cannot stop” Accompanying these phases are 5 themes, 15 subthemes, and 43 codes (shown in detail below).- click on image for a larger view -Do you have a strong urge to purchase the latest Xbox One or PS4 before they sell out? Would you feel anxious if you didn't get one? If so, then you may be in Phase IV, Impulsive Buying.But if you go to the mall every morning and shop online every day, it's all over. You've reached Phase V, Compulsive Buying.ReferenceSang-Hee Sohn and Yun-Jung Choi (2013). Phases of Shopping Addiction Evidenced by Experiences of Compulsive Buyers. International Journal of Mental Health and Addiction DOI: 10.1007/s11469-013-9449-y

... Read more »

  • November 21, 2013
  • 05:13 AM
  • 520 views

New Deep Brain Stimulation System Measures Neurotransmitter Release

by The Neurocritic in The Neurocritic

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) Patient Module printed circuit board & sterilizable case. (Fig. 1, Kimble et al. 2009). Last month, the New York Times reported that the Defense Advanced Research Projects Agency (DARPA) will spend $70 million to further the development of technologies that use deep brain stimulation (DBS), which has been highly successful in treating Parkinson's Disease (PD). The SUBNETS program (Systems-Based Neurotechnology for Emerging Therapies) is part of the BRAIN Initiative that aims to "revolutionize our understanding of the human mind."DARPA issued their call for proposals on October 25. My original take was that the goals were overly ambitious and nearly impossible to achieve within the specified time frame:To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing. At least, that's how I interpret it.  How close are we to seeing a DBS implant that not only stimulates neural tissue, but also records electrical or chemical signals and then uses this information to adjust the stimulation parameters? Closer than I originally suspected. A recent Nature News article reported on the Mayo Clinic's efforts to develop a DARPAesque, state-of-the-art implant that aims to track brain signals in real time:Researchers hope that the device will identify the electrical and chemical signals in the brain that correlate in real time with the presence and severity of symptoms, including the tremors experienced by people with Parkinson’s disease. This information could help to uncover where and how DBS exerts its therapeutic effects on the brain, and why it sometimes fails, says Kendall Lee, a neurosurgeon at the Mayo Clinic in Rochester, Minnesota, who is leading the project.. . ....Using a method called fast-scan cyclic voltammetry, the device applies a localized voltage change in the brain. This transiently pulls electrons off certain neurotransmitters — the brain chemicals that activate or inhibit neurons — giving rise to electrical currents that can be measured. Each neurotransmitter molecule produces a different electrochemical signature, which can be used to identify it and estimate its concentration every 10 milliseconds.Studies in awake behaving rats have used fast-scan cyclic voltammetry to measure phasic dopamine release associated with burst firing (Robinson et al., 2003).Fig, 3 (Robinson et al., 2003). Heterogeneity of electrically evoked dopamine release in the nucleus accumbens of a freely moving rat.Further information about the device is provided in this article from the Mayo Clinic, which indicates that the WINCS has already been tested in 15 human patients with Parkinson's disease or essential tremor. The study registered in clinicaltrials.gov is described as an Efficacy Study whose primary purpose is basic science:Neurotransmitter Measurements Using Wireless Instantaneous Neurotransmitter Concentration System (WINCS) During Deep Brain Stimulation NeurosurgeryIn this study, the investigators will monitor extracellular neurotransmitter levels using a probe that is able to perform real time electrochemical detection during deep brain stimulation surgery. The overall question this study is designed to answer is: Are there neurotransmitters released during deep brain stimulation? Interestingly, the primary outcome measure is adenosine1 release recorded by WINCS, and the secondary outcome measure is dopamine release (pre-, during, and post-DBS, over a time frame of 30 min). Adenosine A2A antagonists may extend the duration of action of L-dopa, a primary treatment for PD. Preliminary studies in rats were able to detect subsecond dopamine and adenosine release at an implanted sensor in the striatum during high-frequency stimulation of ascending fibers (Kimble et al., 2009). It seems the early results in patients were also successful in measuring neurotransmitter release.The WINCS will be integrated with another device, the MINCS (Mayo Investigational Neuromodulation Control System), which is optically linked to WINCS. The entire system is being tested in animal models to deliver brain stimulation wirelessly. Fig 1B (Chang et al., 2013). Photograph of the MINCS-WINCS hardware showing relative size, optical connection, and recording and stimulating electrode leads. ADC = analog-to-digital converter; DAC = digital-to-analog converter; LPF = low-pass filter; MC = microcontroller; TIA = transimpedance amplifier; V/I Sense = voltage/current sense. Numbers 1 and 4 indicate the microcontrollers; 2 and 3 are the Bluetooth modules.These developments in DBS devices for Parkinson's disease are very impressive indeed, but DARPA wants to go 7 steps further by developing similar clos... Read more »

Kimble CJ, Johnson DM, Winter BA, Whitlock SV, Kressin KR, Horne AE, Robinson JC, Bledsoe JM, Tye SJ, Chang SY.... (2009) Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring. Conference proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society., 4856-9. PMID: 19963865  

  • November 9, 2013
  • 09:15 PM
  • 474 views

Now Is That Gratitude?

by The Neurocritic in The Neurocritic

Now is that Gratitude,Or is it really love?Some kind of reality That fits just like a glove--Danny Elfman, GratitudePraise and condemnation serve a powerful purpose in our social and internal lives. They prop us up and tear us down. We reward ourselves (and others) when we perform good deeds, give a pat on the back for a job well done. Conversely, we punish bad behavior. Some people are more vengeful than others when they're wronged; other individuals might be more inclined to blame themselves, even when it's not their fault.Laws and religions and etiquette and complex ethical systems enforce the rules of behavior. For most human beings of a certain age, moral emotions are the result of abiding by or violating these social norms. Moral emotions can be defined as “those emotions that are linked to the interests or welfare either of society as a whole or at least of persons other than the judge or agent” (Haidt, 2003). They can entail reacting to events that don't directly involve the self, as in the case of sympathy or contempt.Zahn and colleagues (2013) refer to these feelings and reactions as moral sentiments, “following philosophers of the Scottish enlightenment who pointed to their role as key motivators of moral behaviour (Bishop, 1996).” In a recent study, they conceptualized four of these moral sentiments in a 2 x 2 grid, depending upon whether the emotion involved praise or blame, of oneself or of another (Zahn et al., 2013).                          SELF        OTHER     PRAISE      Pride       Gratitude BLAME      Guilt        Indignation Their goal was to determine whether there are individual differences in cortical gray matter volumes associated with self-reports on the Value-related Moral Sentiment Task (VMST), which attempts to quantify personally felt human emotions.Moral PhrenologyDoes the tendency to experience each of these moral sentiments correlate with the size of different regions of the brain? The strong form of this question assumes the brain is modular and divisible into separate regions that oversee distinct processes. It also reflects a belief in the “brain is like a muscle” analogy, with discrete regions growing larger with use and smaller with disuse. In Franz Gall's original formulation of phrenology, there were 27 “organs” or mental faculties that could be measured by palpating bumps on the skull. The list of faculties was further refined and developed by Spurzheim (1815), Combe (1834 & 1847), and Lundie (1844). 1 Phrenological Chart, via Wikimedia CommonsFor example, the organ of Benevolence is “situated at the upper part of the frontal bone... When it is large, the frontal bone rises with an arched appearance; when small, the forehead is low and retreating.”Zahn et al. (2013) didn't palpate bumps on the skull, of course. Instead, they used voxel-based morphometry (VBM) to quantify regional gray matter (GM) volumes in 63 participants. In turn, these GM volumes were related to scores for each moral sentiment, controlled for positive and negative valence (Zahn et al., 2013):We examined the effects of each moral sentiment measure (e.g. pride-proneness) on GM volume across the whole brain while using the other moral sentiment of equal valence (e.g. gratitude-proneness) as a covariate of no interest to control for effects of valence. We thus used two separate models to test for positive and negative emotions. All reported results were thus partial effects of one moral sentiment controlled for the adjusted effect of the equal-valence moral sentiment.The Value-related Moral Sentiment Task (VMST) consisted of 180 descriptions of positive or negative interactions between a participant and their best friend in which either they (self-agency, N=90), or their best friend (other-agency, N=90), acted in accord with (N=90) or counter to (N=90) social and moral values. The four conditions thus measured proneness to:Pride (POS_SELF): positive self-agency (e.g. ‘Yourself acting in a generous way towards Sam [best friend]’)Gratitude (POS_OTHER): positive other-agency (e.g. ‘Sam acting in a generous way towards you’)Guilt (NEG_SELF): negative self-agency (e.g. ‘Yourself acting in a stingy way towards Sam’)Indignation (NEG_OTHER): negative other-agency (e.g. ‘Sam acting in a stingy way towards you’)The task was to choose the most fitting label (pride, gratitude, embarrassment [not examined here], guilt, indignation/anger, or none/other) for what they'd feel in response to each example. Participants then rated the unpleasantness or pleasantness of their projected feelings on a scale of -4 to +4.Based on the authors' previous s... Read more »

  • October 29, 2013
  • 06:12 AM
  • 484 views

A Tale of Two BRAINS: #BRAINI and DARPA's SUBNETS

by The Neurocritic in The Neurocritic

Image credits. Left: SUBNETS program (DARPA). Right: BRAIN interim report presentation (NIH).In April, the White House announced the $100 million Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. The goals of this bold new research effort are to "revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer's, schizophrenia, autism, epilepsy, and traumatic brain injury." A series of high-profile journal articles traced the genesis of this initiative from the Brain Activity Map idea to develop nanotechnologies and "image every spike from every neuron" (Alivisatos et al., 2012) to its current emphasis on neural circuits and systems neuroscience more broadly construed (Insel et al., 2013). In the first year (FY 2014),1 $50 million will be allocated to DARPA and $40 million to NIH.2The two federal agencies have taken starkly different approaches to the challenge, in terms of timing and scope. They also address different levels of nervous system function. Both are ambitious, but one surpasses earlier calls for a "moon shot" to the mind.  IF successful,3 it would render much of pre-clinical neuroscience research quaint and obsolete (except for providing mechanistic details).The Tale of Two BRAINS1. The National Institute of Health (NIH) sponsored a series of meetings and solicited public feedback. The NIH Director's BRAIN Advisory Committee issued its Interim Report (PDF) on September 16. The report focuses primarily on animal models, including improved technologies for recording neuronal activity and manipulating circuit function.4 Here are the high-priority research areas for FY 2014:#1.  Generate a Census of Cell Types.#2.  Create Structural Maps of the Brain.  #3.  Develop New Large-Scale Network Recording Capabilities. #4.  Develop A Suite of Tools for Circuit Manipulation.#5.  Link Neuronal Activity to Behavior. #6.  Integrate Theory, Modeling, Statistics, and Computation with Experimentation.   #7.  Delineate Mechanisms Underlying Human Imaging Technologies.#8.  Create Mechanisms to Enable Collection of Human Data.#9.  Disseminate Knowledge and Training. These are very ambitious projects, each delineated in more detail in the full report (PDF). However, the NIH has yet to issue a Request for Applications that outlines the requirements for grant proposals submitted through this program.2. On the other hand, the Defense Advanced Research Projects Agency (DARPA) announced their goals for the BRAIN Initiative via the New York Times on October 24 and and issued a broad agency announcement (call for proposals) on October 25. The focus is on developing technologies and treatments that use deep brain stimulation (DBS), which has been highly successful in Parkinson's Disease. There are 3 Technical Areas that are covered in the announcement. All applicants must address Area One, and teams of investigators are encouraged to address all three.TA One is comprised of clinical trials in order to establish mechanistic models of awake, behaving human brain activity. TA Two encompasses the hardware development component in order to create safe and effective sensing and stimulation systems.In TA Three, investigators will use human-relevant animal models [primates, not rodents] to generate safety and efficacy data as well as establish preliminary theories and rapidly prototype hypotheses regarding the links between neural data and clinical outcomes.  To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing. At least, that's how I interpret it. Brainstorm (1983). Brain-computer interfaces have improved a bit in the last 30 yrs.Systems-Based Neurotechnology for Emerging Therapies (SUBNETS)Let's take a closer look at TA One of DARPA's SUBNETS program.SUBNETS is distinct from current therapeutic approaches as it seeks to develop the ability to create a closed-loop diagnostic and therapeutic system. Through measuring pathways involved in complex systems-based brain disorders such as depression, compulsion, debilitating impulse control, and chronic pain, SUBNETS will attempt to establish the capability to record and model how these systems function in both normal conditions, among volunteers seeking treatment for unrelated neurologic disorders, as well as impaired clinical research participants. SUBNETS will then use these models to determine appropriate therapeutic stimulation methodologies that meet guidelines for both safety and efficacy in human participants. These models will be adapted onto next-generation, closed-loop neural stimulators that exceed currently developed capacities for simultaneous stimulation and recording and provide a research investigator, a clinician, and a human research participant with the ability to record, analyze, and stimulate multiple brain regions for therapeutic purposes. Seven disorders are targeted: Post-Traumatic Stress Disorder (PTSD), Major Depression, Borderline Personality Disorder (BPD), General Anxiety Disorder (GAD), Traumatic Brain Injury (TBI), Substance Abuse/Addiction, and Fibromyalgia/Chronic Pain. To the best of my knowledge, there is no published literature on DBS for PTSD, BPD, GAD [as opposed to OCD], or TBI [except for minimally conscious state]. At clinicaltrials.gov, a Pilot Study of DBS of the Amygdala for Treatment-Refractory Combat PTSD was withdrawn prior to enrollment. There's one DBS ... Read more »

Alivisatos AP, Chun M, Church GM, Greenspan RJ, Roukes ML, & Yuste R. (2012) The brain activity map project and the challenge of functional connectomics. Neuron, 74(6), 970-4. PMID: 22726828  

Insel TR, Landis SC, & Collins FS. (2013) Research priorities. The NIH BRAIN Initiative. Science, 340(6133), 687-8. PMID: 23661744  

  • October 12, 2013
  • 05:38 AM
  • 581 views

Existential Neuroscience: a field in search of meaning

by The Neurocritic in The Neurocritic

What separates prior from subsequent is exactly nothing. This nothing is absolutely impassable, just because it is nothing...–Jean-Paul Sartre, Being and Nothingness (p. 28).If you read the journal Social Cognitive and Affective Neuroscience (SCAN), you might think that Existential Neuroscience is a hot new field, since three recent papers on the topic have been published there. Can it provide profound new insights into the human condition? From what I can tell, these references to a formal discipline of “Existential Neuroscience” are based entirely on terror management theory, which was developed by Greenberg and colleagues in the 1980s (Greenberg et al., 1986; Rosenblatt et al., 1989). How does this relate to existentialism?“Existence precedes essence” (Sartre, 1946). But first, what is Existentialism? The Stanford Encyclopedia of Philosophy is reluctant to admit that it's an actual philosophy, rather than a literary or artistic trend:By the mid 1970s the cultural image of existentialism had become a cliché, parodized in countless books and films by Woody Allen. It is sometimes suggested, therefore, that existentialism just is this bygone cultural movement rather than an identifiable philosophical position; or, alternatively, that the term should be restricted to Sartre's philosophy alone. Stanford Encyclopedia eventually tells us that the most distinctive aspect of existentialism is that standard notions of identity are wrong:The fundamental contribution of existential thought lies in the idea that one's identity is constituted neither by nature nor by culture, since to “exist” is precisely to constitute such an identity. It is in light of this idea that key existential notions such as facticity, transcendence (project), alienation, and authenticity must be understood.The first known account of “Existential Neuroscience” (EN) was written by mirror neuron researcher Dr. Marco Iacoboni in 2006 (PDF).1 It was published as a book chapter in Social Neuroscience: Integrating Biological and Psychological Explanations of Social Behavior (Harmon-Jones & Winkielman, 2007). Thus, EN appears to be a branch of Social Neuroscience.But what is Existential Neuroscience, exactly? A group of French intellectuals discussing brain research in a cafe while smoking and sipping espresso? An authentic neuroscience of utter freedom that embraces a state of perpetual despair2 over the meaninglessness of existence? Or independent groups of German-speaking neuroscientists who scan subjects while they ponder death?Sartre and FriendsIf you guessed the latter, you'd be correct.  More precisely, EN thus far consists of neuroimaging studies of mortality salience, as you might expect by its reliance on terror management theory (TMT).3  Therefore, EN should be called “Fear of Death” Neuroscience. TMT holds that when people are confronted with their own mortality, they respond in ways to boost their self-esteem, reinforce their own values, and punish outsiders.In an ironic twist for the existentialist neuroscientists, however, Existentialism rejects science as means of understanding what it is to be human. Here's Sartre on the futility of science:From the outset physiology is condemned to understand nothing of life since it conceives life simply as a particular modality of death, since it sees the infinite divisibility of the corpse as primary, and since it does not know the synthetic unity of the "surpassing towards" for which infinite divisibility is the pure and simple past. Even the study of life in the living person, even vivisection, even the study of the life of protoplasm, even embryology or the study of the egg can not rediscover life; the organ which is observed is living, but it is not established in the synthetic unity of a particular life; it is understood in terms of anatomy—i.e., in terms of death. -Jean Paul Sartre, Being and Nothingness (p. 348).Even if one is a firm believer in the potential of neuroscience to lead to better treatments for mental illness, it's hard to envision what brain research can tell us about a philosophical system opposed to science (or most other philosophies, for that matter). Can we imagine what a Taoist Neuroscience or an Epicurean Neuroscience would be like? Not to mention the prospect of a Nihilist Neuroscience or a Post-Structural Neuroscience...By necessity, a true Existential Neuroscience must deal with human beings as the focus of study, since the withdrawal reflex of Aplysia might not be a valid model of existential angst. It's unlikely we'll see circuit models and optogenetic studies of the alienated self any time soon. As currently formulated, EN has more concrete goal: to study one specific element of existentialist thought that might be more closely related to Heidegger's views (see Quirin et al., 2012).This leads us to the most recent of the EN studies in SCAN (Silveira et al., 2013), which I'll discuss in some detail. This study is based on a different reaction to mortality salience, one that is derived from evolutionary psychology: the drive to reproduce. The heterosexual participants in the study viewed attractive opposite-sex faces and made decisions about whether they would like to meet them (a proxy for sexual desire) after being primed by death-related words (or not). Already, this seems like a bridge too far, but let us go on.Sixteen female and 16 male subjects participated in this fMRI experiment. They viewed a series of attractive faces (as judged by an independent group of participants) and decided, in separate blocks, if the faces were attractive or not (explicit evaluation) or whether they'd like to meet the person or not ("implicit" evaluation). The task was cued at the beginning of a block by the words Meet? or Attractive? Participants make their choice when the ? appears on the monitor. Below is an example of the implicit no-prime condition shown to the male subjects.... Read more »

  • September 30, 2013
  • 04:42 AM
  • 586 views

A Neural Circuit for Voracious Overeating in Mice: Translation to Humans

by The Neurocritic in The Neurocritic

Optogenetic activation of inhibitory GABA neurons projecting from the limbic forebrain to the lateral hypothalamus causes this mouse to binge on cheese. The rapid onset and offset of the intense feeding behavior is striking. Credit: Jennings et al. (2013).The hypothalamus is a collection of discrete nuclei in the vertebrate diencephalon that control a variety of metabolic, neuroendocrine, and circadian functions. Since the 1940s, the ventromedial nucleus (VM) has been known for its important role in satiety — lesions of this nucleus cause rats to become obese, while electrical stimulation of this structure curtails feeding. On the other hand, the lateral hypothalamus (LH) controls hunger. In 1953, Delgado and Anand implanted multilead electrodes into the brains of cats and found that electrical stimulation of the LH caused an increase of food intake to 500-1,000% of control levels.Sixty years later, Jennings and colleagues (2013) set out to delineate the precise circuitry and neuronal population responsible for these effects using modern optogenetic techniques. They targeted a projection pathway from the bed nucleus of the stria terminalis (BNST), a part of the "extended amygdala" in the limbic forebrain, to the LH. These inhibitory GABAergic neurons synapse onto excitatory glutamatergic neurons in the LH. This specific cell type was targeted by using a genetically modified mouse line. The mice express a recombination enzyme only in neurons that express the vesicular GABA transporter (vGAT-ires-cre mouse).  A viral construct was used to insert a gene that codes for Channelrhodopsin-2, a light-sensitive protein that was fused to yellow fluorescent protein, directly into the BNST via microinjection. The BNST projections are stimulated by exposing them to blue light using specially implanted optical fibers. Since these neurons are GABAeric, they inhibit the postsynaptic LH neurons. This is shown schematically in the figure below. Fig. 1 (modified from Jennings et al., 2013). VgatBNST→LH circuit activation induces feeding in well-fed mice. (A) Schematic showing VgatBNST→LH circuit targeting.A different circuit was targeted in control mice, the projection from BNST to the ventral tegmental area (VTA). Activation of the VgatBNST→VTA projection did not induce voracious feeding behavior. But the mice did find it rewarding, which isn't a surprise... the VTA contains the dopaminergic cell bodies of the mesocortical dopamine system.This is very impressive work in tune with the priorities of the BRAIN Initiative. Unaffiliated expert commenters have noted:“This is a really important missing piece of the puzzle,” says neuroscientist Seth Blackshaw of Johns Hopkins University in Baltimore. “These are cell types that weren’t even predicted to exist.” A deeper understanding of how the brain orchestrates eating behavior could lead to better treatments for disorders such as anorexia and obesity, he says. And this:Cynthia Bulik, Distinguished Professor of Eating Disorders at UNC School of Medicine and the Gillings School of Global Public Health, says, “Stuber’s work drills down to the precise biological mechanisms that drive binge eating and will lead us away from stigmatizing explanations that invoke blame and a lack of willpower.”Finally, we have one minor skeptic:Previous studies from other groups had shown the opposite of what Stuber's team found: when other researchers activated the LH by exposing it to the neurotransmitter glutamate or by electrically stimulating the neurons, animals would start eating. However, B. Glenn Stanley, a professor at UC Riverside who studies the brain mechanisms of eating behavior, said Stuber's team’s results are not necessarily in conflict with earlier findings. “To see an inconsistency would be an oversimplification,” said Stanley.Stanley noted that Stuber's group focused on a subset of neurons in the LH, those interacting with neurons from the BNST.  ...It's possible that some areas of the LH stimulate feeding when they're activated, and others when they are inhibited, Berthoud added. “The lateral hypothalamus is really a big area,” he said, adding that the authors didn't describe precisely where those neurons turned off by the BNST reside.Two weeks ago, the BRAIN Working Group issued its Interim Report (PDF). High priority areas for 2014 include a focus on cell types and circuit manipulation:#1. Generate a Census of Cell Types. It is within reach to characterize all cell types in the nervous system, and to develop tools to record, mark, and manipulate these precisely defined neurons in vivo. We envision an integrated, systematic census of neuronal and glial cell types, and new genetic and non-genetic tools to deliver genes, proteins, and chemicals to cells of interest. Priority should be given to methods that can be applied to many animal species and even to humans. #4. Develop A Suite of Tools for Circuit Manipulation. By directly activating and inhibiting populations of neurons, neuroscience is progressing from observation to causation, and much more is possible. To enable the immense potential of circuit manipulation, a new generation of tools for optogenetics, pharmacogenetics, and biochemical and electromagnetic modulation should be developed for use in animals and eventually in human patients. Emphasis should be placed on achieving modulation of circuits in patterns that mimic natural activity.Translation to Treatments for Human Obesity and Binge Eating DisordersHow close are we to applying this knowledge to treat people with severe intractable obesity? Not very. Optogenetics is a very invasive method. That's why development of new technologies is another high priority area of BRAIN (i.e., "advancing innovative neurotechnologies"). Nevertheless, it's a key component that will advance basic knowledge of neurocircuit functioning.Has the potential for breakthrough treatments been overblown? Or is it all part of generating enthusiasm and public support (and hen... Read more »

  • September 27, 2013
  • 03:44 AM
  • 466 views

Now we know the brain is "neuroplastic"... in the 19th century

by The Neurocritic in The Neurocritic

Until recently, scientists believed our brains were fixed, their circuits formed and finalised in childhood, or "hardwired". Now we know the brain is "neuroplastic", and not only can it change, but that it works by changing its structure in response to repeated mental experience.-Norman Doidge, M.D. (2013). Brain scans of porn addicts: what's wrong with this picture? Wow! I never knew that! You mean the brain can actually learn? And it changes with experience? Really?? Thank you, Norman Doidge, for that brilliant insight, and for many other gems in your wonderful Comment is Free piece on porn addiction in the Guardian.Let's see what physicians and psychologists of yesteryear have to say about these newly discovered "neuroplastic" brains. Here it may be asked whether the organs [of the brain] increase by exercise? This may certainly happen in the brain as well as in the muscles; nay, it seems more than probable, because the blood is carried in greater abundance to the parts which are excited, and nutrition is performed by the blood. In order however, to be able to answer this question positively, we ought to observe the same persons when exercised and when not exercised; or at least observe many persons who are, and many others who are not, exercised during all periods of life.-J.G. Spurzheim (1815). The physiognomical system of Drs. Gall and Spurzheim; founded on an anatomical and physiological examination of the nervous system in general, and of the brain in particular; and indicating the dispositions and manifestations of the mind. The question is not whether neural events change the status of the tissue in which they occur. The only question which may still be debated is: whether such changes as do undoubtedly occur have the permanence and those other properties which we must attribute to memory-traces. According to our present knowledge the primary effect which nerve impulses produce in ganglionic layers is chemical activity. . .-Wolfgang Köhler (1938), The Place Of Value In A World Of Facts.These quotes were taken from a 1964 review paper by Edward L. Bennett, Marian C. Diamond, David Krech, and Mark R. Rosenzweig. The title? Chemical and Anatomical Plasticity of Brain. Changes in brain through experience, demanded by learning theories, are found in experiments with rats.Fig. 1 (Bennett et al., 1964). Animals in Environmental Complexity and Training Cage.The authors compared the brains of rats exposed to complex, enriched environments to those housed in isolated cages. They found increases in cortical thickness, increases in cortical tissue weight (not related to overall brain or body size), and in increases acetylcholinesterase activity in rats who had lived in the fun and social cages. The project was launched 60 years ago, in 1953... so it's a bit disingenuous for Dr. Doidge to call neuroplasticity a "recent" discovery. Furthermore, Doidge's Freudian interpretation of porn would be rather quaint, if it weren't so disturbing:Porn sites are also filled with the complexes Freud described: "Milf" ("mothers I'd like to fuck") sites show us the Oedipus complex is alive; spanking sites sexualise a childhood trauma; and many other oral and anal fixations. All these features indicate that porn's dirty little secret is that what distinguishes "adult sites" is how "infantile," they are, in terms how much power they derive from our infantile complexes and forms of sexuality and aggression. Porn doesn't "cause" these complexes, but it can strengthen them, by wiring them into the reward system. And of course, reward = dopamine. And we all know that "dopamine is the ultimate feminist chemical in the female brain."  Oh wait...Guess Doidge hasn't watched any feminist porn.Further ReadingFeminist Dopamine, Conscious Vaginas, and the Goddess ArrayIs There Any Evidence for the "Porn-Addicted Brain"?Neuroplasticity is a dirty wordNeuroplasticity is not a new discoveryReferenceBENNETT EL, DIAMOND MC, KRECH D, & ROSENZWEIG MR (1964). CHEMICAL AND ANATOMICAL PLASTICITY of BRAIN. Science, 146 (3644), 610-9 PMID: 14191699My Love Affair With the Brain:The Life and Science of Marian Diamond
... Read more »

BENNETT EL, DIAMOND MC, KRECH D, & ROSENZWEIG MR. (1964) CHEMICAL AND ANATOMICAL PLASTICITY BRAIN. Science (New York, N.Y.), 146(3644), 610-9. PMID: 14191699  

  • September 22, 2013
  • 06:56 AM
  • 518 views

Neurological Art History

by The Neurocritic in The Neurocritic

“Wound man” woodcut by Johannes de Ketham, originally appearing in Fasciculus medicinae (1491). This image is from Fasiculo de medicina (1494), a translation into Italian by Sebastiano Manilio.We rationalize, we dissimilate, we pretend: we pretend that modern medicine is a rational science, all facts, no nonsense, and just what it seems. But we have only to tap its glossy veneer for it to split wide open, and reveal to us its roots and foundations, its old dark heart of metaphysics, mysticism, magic and myth. Medicine is the oldest of the arts, and the oldest of the sciences: would one not expect it to spring from the deepest knowledge and feelings we have?-Oliver Sacks, AwakeningsIs medicine an art or a science? Now you don't have to decide! Volume 203 of Progress in Brain Research examines the historical relationship between art and neurology.The Fine Arts, Neurology, and Neuroscience: Neuro-Historical Dimensions begins with the Renaissance anatomists, including the prolific Andreas Vesalius, author of the seven-volume De humani corporis fabrica (On the fabric of the human body). Illustrated anatomy textbooks were a still novelty at this time, and Vesalius was controversial for overturning some of Galen's tenets from the 2nd century AD, including the theory of animal spirits. The realistic woodcut illustrations in De humani were based on careful dissection of human cadavers (Russell, 2013). Andreas Vesalius (1543). De Humani Corporis Fabrica, Plate 49. Brain with seven cranial nerves. Woodcut.The talented artist is often assumed to be Jan Steven van Calcar from the studio of Titian, but the actual identity of this person(s) is unclear (Russell, 2013):But who were the artists? Who created such compelling images? Vesalius neither identifies nor acknowledges his exceptional artist(s) or his woodblock cutters. The absence of their identity has remained a subject of debate. Proto-Bloggers or Plagiarists?Vesalius tried valiantly to preserve his intellectual property from unlawful reproduction, to no avail. This is a bit ironic, since he never gave credit to the artists, and even seemed a bit annoyed with them (Lanska & Lanska, 2013):In 1546, 3 years after publication of the first edition of the Fabrica, Vesalii expressed frustration at the plurality of artists he had supervised: “[No longer] shall I have to put up with the bad temper of artists and sculptors [wood-block cutters] who made me more miserable than did the bodies I was dissecting” (translation in O’Malley, 1964, p. 124). Regardless of Vesalii’s frustrations with the artists, the beauty, accuracy, and utility of these woodcuts led to frequent plagiarism, despite Vesalii’s attempts to protect his work with the various privileges that were listed at the foot of the title page.Piracy and plagiarism of images vs. "fair use" for educational [or entertainment] purposes isn't a new problem that began with commercialization of the internet in 1995, nor with the rise in the popularity of Tumblr about four or five years ago.1Lanska and Lanska (2013) raised the issue of how the printing press made image theft easier in their chapter on Medieval and Renaissance anatomists: The printing and unauthorized copying of illustrations, and the dissemination of ideas:With the advent of the printing press and moveable type at this time, printed books began to supersede hand-copied medieval manuscripts, and labor-intensive techniques were soon developed to integrate text and illustrations on the printed page. The same technology was used to pirate the illustrations of prior authors with varying fidelity. Specific medieval and Renaissance anatomical illustrations can often be traced from their inceptions through different stages of development to the final printed images, and then through subsequent pirated versions in various abridgements or other compendia. The most important milestone in the development of anatomy and anatomical illustration was the publication in 1543 by Andreas Vesalii of De humani corporis fabrica... With this work, Vesalii succeeded in coordinating a publication production team (author, artists, block cutters, publisher, and typesetters) to achieve an unprecedented integration of scientific discourse, medical illustration, and typography. However, despite Vesalii’s valiant efforts to prevent unauthorized duplication, the illustrations from the Fabrica were extensively plagiarized. Although Vesalii found such piracy frustrating and annoying, the long-term effect was to make Vesalii’s ideas known to a wider readership and to help solidify his own revolutionary contributions to anatomy.Vesalius was angry because of the amount of work he put into the dissections, but the benefit was greater exposure of his ideas and an increase in stature.  Kind of like high profile (non-critical) science blogging?? 2  Except unauthorized reproduction was more laborious in the 16th century... e.g. copying woodcuts prints in a close but approximate form by freehand engraving onto copper plates (Lanska & Lanska, 2013b).  But at least one imitator did give him credit and even corrected his mistakes:Vesalius bitterly complained about Valverde's unauthorized abridgement of his work: “Valverde who never put his hand to a dissection and is ignorant of medicine as well as of the primary disciplines, undertook to expound our art in the Spanish language only for the sake of shameful profit.” (O'... Read more »

  • September 16, 2013
  • 01:23 AM
  • 625 views

Everything's Unscented

by The Neurocritic in The Neurocritic

If you were forced to sacrifice one of your five senses, which would it be? Most people wouldn't consider losing their vision or hearing. It would be really dangerous to completely lose your sense of touch, so that won't be an option in our hypothetical scenario. So we're left with the chemical senses of smell and taste. I think most of us would choose one of these two.But what about someone who can't smell?  How can they miss something they've never known?“If I had to lose one of my senses, it would probably be smell... even though it's gone. I mean, if I had to choose between them, because it's the least hindering...”-Deven James Langston in his short video, Anosmia (embedded below).A World Without SmellCongenital anosmia is a rare condition where individuals are born without the ability to smell. This condition might not seem so bad to the osmic population (especially when cleaning up after your pet), but lack of smell can affect safety (e.g., can't detect a gas leak or burning toast), body weight, hygiene, and mate selection (Karstensen & Tommerup, 2011). But if you've never had the experience of odors, whether they're from cinnamon buns or rotting fish, this is a completely normal state of affairs (Tafalla, 2013).Isolated congenital anosmia unrelated to another condition (such as Kallmann syndrome) has been linked to genetic locus 18p11.23-q12.2 in two different families (Ghadami et al., 2004). However, no disease-causing mutations were found by sequencing eight candidate genes in this region. Studies in other families have suggested that the genetic basis of this trait is heterogeneous. Therefore, the specific genetic causes of isolated congenital anosmia remain elusive (Karstensen & Tommerup, 2011).Smells Like WordsRebecca Steinitz has congenital anosmia. She reached adulthood without knowing that other people actually do possess a sense of smell, as opposed to just pretending that they do. In an essay she describes what it's like to live in a world without smell.I don’t know what a rose smells like, though when I hold my nose to a full-blown bloom and inhale deeply, I sense a vague sweetness.I don’t know what my husband’s shirt smells like. If he died, I wouldn’t think to sleep in it so I could feel that he was with me.I don’t know what a baby’s head smells like – not my babies, not anyone else’s babies. I couldn’t pick my babies out of a crowd with my eyes closed, and I don’t miss that baby smell when I hug my growing children.I don’t know the smell of feet, chalk, lilacs, gardenias, sour milk, rain, new cars, Chanel No. 5, Old Spice, greasepaint, or napalm.I don’t know what old books smell like. I don’t know what new books smell like either.Ex Libris Anima Perfume Oil - 5 ml.“The bottled essence of an old, rare book - antique paper, old leather bindings, parchement, dust, and the faint scent of a wooden lecturn.”“I learned smells from books, which made me think they were fictional. When real people said That stinks, or I can smell the sea from here, I thought they were faking, that they were willing to pretend those smells existed beyond the page. I only discovered the word for people like me a few years ago. We are anosmic; we have anosmia: lack of the sense of smell.”-Rebecca Steinitz, Smells Like WordsSmells Like Teen SpiritSteinitz noted that she can't smell her husband's shirt or her baby's head. These types of scents bind us to people and cement our relationships. Odors have a way of linking us to times and places of the past, evoking remembrances in a sterotypically literary way, eliciting endless soliloquies of youthful memories. -graffiti by Kathleen Hanna (before the song was written) 1Do smells have a uniquely intimate connection to memory? Olfactory information reaches the piriform cortex after only two synapses. A chemical odorant activates receptors on sensory neurons in the nasal epithelium, which synapse onto mitral cells in the olfactory bulb. These mitral cells synapse onto neurons in the piriform (olfactory) cortex located in the temporal lobe, near the hippocampus and amygdala. What is it like to be a smeller?Anosmic philosopher Marta Tafalla, in a nod to the famous paper by Thomas Nagel, compares the foreignness of olfactory qualia to the exotic system of echolocation in bats (Tafalla, 2013).Neither do I have the sensation that I lack a sense, a window onto reality, that something in my body or my brain does not function properly. And because of all that, it would have been impossible for me to come up with the improbable idea that everyone else can perceive another dimension of reality, which consists of volatile chemical particles that are perceived in the mere act of breathing. It sounds as strange to me as the echolocation system of bats or some birds' capacity to align their flight with the earth's magnetic field.In this meditative and philosophical piece, Tafalla tells the story of when she first realized she was different from other people. At the age of eight, she spent some time at a summer boarding school. One of the teachers tactfully remarked on her smelly feet. Tafalla didn't understand, and didn't connect body odor to a lack of hygienic rituals. In response, she put cologne on her feet and in her shoes. Her teacher and her mother both found this odd, so she started wondering if something was wrong. A year or two later, ... Read more »

Karstensen HG, & Tommerup N. (2012) Isolated and syndromic forms of congenital anosmia. Clinical genetics, 81(3), 210-5. PMID: 21895637  

Tafalla M. (2013) A world without the olfactory dimension. Anatomical record (Hoboken, N.J. : 2007), 296(9), 1287-96. PMID: 23907763  

  • September 8, 2013
  • 03:47 AM
  • 527 views

Update on Ketamine in Palliative Care Settings

by The Neurocritic in The Neurocritic

Many recent headlines have heralded a new use for the old veterinary anesthetic ketamine, which can provide rapid-onset (albeit short-lived) relief for some patients with treatment-resistant depression (aan het Rot et al., 2012). This finding has been inflated into “arguably the most important discovery in half a century” by Duman and Aghajanian (2012). While finding a cure for refractory depression is undoubtedly an important research priority, might ketamine be useful for other conditions that cause profound human misery? The care of terminally ill patients suffering from unbearable pain is not a sexy topic, and hospice and palliative medicine is not a glamorous subspecialty. You probably haven't seen the studies examining whether ketamine is effective as an add-on agent to opioid analgesics for cancer pain (Hardy et al., 2012), or as a treatment for depression and anxiety in patients receiving hospice care (Irwin et al., 2013).Three years ago, my father died of cancer. He had been released from the palliative care unit to a hospice, suffering with uncontrolled cancer pain. It was unbearable to watch, and beyond excruciating for him. During this time, I was writing a post for the Nature Blog Focus on hallucinogenic drugs in medicine and mental health. It included a section on drugs that might alleviate pain and anxiety in cancer patients. I told him about this, and he said to “get the word out.”As a tribute to my father, I wanted to present a brief overview of new developments in the field.Efficacy and Toxicity of Ketamine in the Management of Cancer PainIn 2008, BMJ published a set of clinical practice guidelines on pain control in adults with cancer. They called for further research to investigate the role of ketamine as an adjuvant analgesic – a drug with a primary indication other than pain that might have analgesic properties in some conditions.A recent Cochrane review evaluated the state of the literature on ketamine to alleviate cancer pain (Bell et al., 2012). Three new randomized controlled trials (RCTs) were identified since 2003, and all were excluded from further analysis. Among the older studies, the adverse effects of ketamine included hallucinations (as expected, since the drug is a dissociative anesthetic used at raves), drowsiness, nausea and vomiting, dry mouth, and confusion. The authors concluded that “Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More RCTs are needed.” They also noted that clinical trials were ongoing, and that data by Hardy and colleagues were awaiting assessment. Unfortunately, the outcome of the trial conducted by Hardy et al. (2012) was not positive.  In this large RCT, 185 cancer patients with refractory chronic pain were randomized to receive either ketamine or placebo as an adjunct to their regular doses of opioids and other analgesics. Ketamine was administered subcutaneously in a dose-escalating regimen over 5 days. The response rate was 31% (29 of 93) in the treatment group compared to 27% (25 of 92) for placebo, which was not significantly different (p=.55). In addition, ketamine was associated with twice the number of adverse events relative to placebo. The authors concluded that ketamine did not have a net clinical benefit when used along with standard medications to treat cancer pain.However, Jackson and colleagues (2013) objected to this “sweeping conclusion” in a letter to the Journal of Clinical Oncology titled “Ketamine and Cancer Pain: The Reports of My Death Have Been Greatly Exaggerated”. Their major arguments were that ketamine has been used in this fashion for the last decade, and previous open-label studies were more successful. They also suggested that Hardy et al. were too quick to call ketamine a treatment failure, and too late in administering drugs to counteract any hallucinogenic side effects.1  Hardy et al. (2013) replied to the first set of objections by stating the obvious about the value of RCTs: “Open-label studies do not meet the specific scientific definition of control.” They stood by their “sweeping conclusions” that ketamine was not beneficial in this population. On the other hand, I can see why clinicians would be desperate to help their patients. The 27% placebo response in Hardy's study is quite high. So if you're a patient in terrible pain and grape Kool-Aid improves your condition, why argue with that?Ketamine for the Treatment of Depression and Anxiety in Hospice Patients Speaking of open-label studies, a 2010 study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.2 A more recent open-label study by Irwin et al. (2013) enrolled 14 hospice patients with depression or depression + anxiety to receive oral ketamine for 28 days. Only 8 patients completed the study, but all showed a 30% or greater improvement in their depression or anxiety scores. Four withdrew from the study at day 14 because of no response to the drug, one dropped out earlier due to unrelated rapid decline, and one withdrew at day 21 because of a change in mental status (apparently unrelated to ketamine). “Few adverse events” were noted, the most common being diarrhea, trouble sleeping, and trouble sitting still (which to me sound problematic in an extremely ill population). It seems that dissociative symptoms, hallucinations, etc. were not evaluated. The authors again call for further studies using RCT designs to evaluate whether ketamine can improve the quality of the end-of-life experience.Although they were not entirely successful, these studies have aimed to achieve an important goal of any civil, caring society: to provide a manner of death that minimizes fear, pain, and suffering.Further ReadingThe entire Pallimed Blog"Do you have something stronger than this dilaudid?" The case for opioid rotationLimbaugh/Palin "death panels" extend the lives of terminally ill patientsKetamine for Depression: Yay or Neigh?Footnotes1 Jackson et al. reported using low doses of haloperidol (an antipsychotic) or midazolam (a benzodiazapine) prophy... Read more »

  • August 25, 2013
  • 05:27 PM
  • 554 views

The Art of Resurrection

by The Neurocritic in The Neurocritic

Resurrection, Raffaellino del Garbo (1510)In the world outside of Christianity, horror, and science fiction, the dead cannot be brought back to life. Or can they? A feature in the The Observer from earlier this year profiled Dr. Sam Parnia, critical care physician and author of Erasing Death: The Science That Is Rewriting the Boundaries Between Life and Death (called The Lazarus Effect in the UK). The article begins in a dramatic fashion:Sam Parnia – the man who could bring you back from the deadSam Parnia MD has a highly sought after medical speciality: resurrection. His patients can be dead for several hours before they are restored to their former selves, with decades of life ahead of them.That's a pretty outrageous claim! Clinically dead for several hours? No brain activity the entire time? Even if anyone could emerge alive and conscious from such a state (unless it's a state of suspended animation, perhaps), they'd have severe brain damage (as we'll see below). There'd be no way they could have encoded their near-death experiences (NDEs), much less remembered any light at the end of a tunnel or a soothing presence drawing them home.There may be a semantic problem here: the definition of “death.” I haven't read the book, but the issue is described in a one-star review at Amazon:The core of this linguistic mess is his inconsistent use of the word "death". At times he uses this term properly, as defined by the Uniform Determination of Death Act (UDDA, 1981): "An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem is dead." This definition was developed in cooperation with the American Medical Association ... [etc.] and has been adopted by most states. It is the standard definition of death. [NOTE: I thought brain death is THE standard definition of death.] 1Unfortunately, he also refers to "death" as cardiac arrest (e.g. pages 1, 2, 23, 42, 43, 128, 131, 139, 140, and many more). This definition of death is inconsistent with the UDDA because cardiac arrest is reversible in some cases. In fact, much of this book includes accounts of individuals who have suffered cardiac arrest and been resuscitated... Dr. Parnia was quoted in my previous post about the “End of Life Gamma Waves” study in rats. He was skeptical that EEG during the 30 second interval after the heart stopped beating was anything more than a massive influx of calcium into the dying neurons. It wasn't a state of heightened consciousness that can explain the NDEs reported by 10-20% of his cardiac arrest patients. Instead, Parnia is a mind-body dualist, believing that the soul (or self) can persist separately from the body for several hours at a time:"It seems that when consciousness shuts down in death, psyche, or soul – by which I don't mean ghosts, I mean your individual self – persists for a least those hours before you are resuscitated. From which we might justifiably begin to conclude that the brain is acting as an intermediary to manifest your idea of soul or self but it may not be the source or originator of it… I think that the evidence is beginning to suggest that we should keep open our minds to the possibility that memory, while obviously a scientific entity of some kind – I'm not saying it is magic or anything like that – is not neuronal."Memory is not neuronal! And Death can be cured. Who knew. But how?? [NOTE: according to Parnia and The Observer, at least.]Extracorporeal membrane oxygenation (ECMO) is a temporary method of life support that introduces and circulates oxygen into the bloodstream of patients with acute respiratory failure or cardiac failure. It involves placing one or more large catheters into the patient's vessels (cannulation) and relies on an external pump to circulate and oxygenate blood and remove carbon dioxide (PDF). Primarily used in critically ill infants, its application to adults is risky and controversial, and the benefits are unclear.A meta-analysis of ECMO in adult patients found a mortality rate of 54% at 30 day follow-up, with almost half the fatalities occurring during ECMO (Zangrillo et al., 2013). On the other hand, the procedure is a last-ditch life saving effort in critically ill patients, so a 46% survival rate seems like an improvement over probable death. However, one review stated that "Credible evidence for mortality benefit of ECMO is lacking" in cases of acute respiratory distress (Hirshberg et al, 2013). Another study concluded that ECMO is even less successful in cases of acute heart failure, with the worst survival rate for those who experience cardiac arrest (Tsuneyoshi & Rao, 2012).Complications can be severe (Zangrillo et al., 2013) and include renal failure (occurring in 52%), bacterial pneumonia (33%), bleeding (33%), oxygenator dysfunction requiring replacement (29%), sepsis (26%), and liver dysfunction (16%).The rest of the post will focus on the possible neurological complications of ECMO (Mateen et al., 2011).Neurological Injury Associated with Heroic ResuscitationI do not want to detract in any way from the dedication of practioners who do heroic things every day to save people's lives, or from advances in medicine. What I would like to point out, however, is that sometimes one may resuscitate the heart but lose the brain (to paraphrase Horstman et al., 2010).Modified from Fig. 4 (Mateen et al., 2011). Brain scans of adult patients who received extracorporeal membrane oxygenation (ECMO). (A) parafalcine subarachnoid hemorrhage and hydrocephalus on axial-view head CT, (B) diffuse subarachnoid hemorrhage on T1-weighted MRI, and (C) septic cerebral emboli on axial-view MRI.Neurological events occurred in at least 50% (n=42) of patients treated with ECMO at one medical center over an 8 year period (... Read more »

Mateen FJ, Muralidharan R, Shinohara RT, Parisi JE, Schears GJ, & Wijdicks EF. (2011) Neurological injury in adults treated with extracorporeal membrane oxygenation. Archives of neurology, 68(12), 1543-9. PMID: 21825216  

  • August 18, 2013
  • 03:43 AM
  • 634 views

Remembering the Work of Dr. Patricia Goldman-Rakic

by The Neurocritic in The Neurocritic

A touching and comprehensive review article in Cerebral Cortex commemorates the life and work of Dr. Patricia Goldman-Rakic on the ten year anniversary of her death (Arnsten, 2013). The author of over 600 publications, Goldman-Rakic worked at NIMH from 1965-1979 and was a professor at Yale from 1979-2003. She served as President of the Society for Neuroscience in 1989-90 and was elected to the National Academy of Sciences in 1990. The review was written by one of her former post-docs, Dr. Amy F.T. Arnsten, herself a professor at Yale.Keeping a Life "in mind" Dr. Goldman-Rakic is best known for her research on working memory and the prefrontal cortex (PFC). Working memory is a transient form of memory that actively maintains and manipulates information for brief periods of time (Goldman-Rakic, 1995):Working memory in its most elementary form, the ability to keep events "in mind" for short periods of time, has been studied in nonhuman primates by delayed-response paradigms. Whereas in humans, facts and events accessed from long-term memory stores can be instigated by verbal instructions, in experiments with animals, the information to be processed has to be provided by the experimenter.Building on the work of Fuster and colleagues, her studies demonstrated that neurons in the dorsolateral portion of the PFC fire more rapidly when a spatial location cue is removed from the visual field and must be remembered over a brief delay. The sample neuron in the figure below codes for targets located at 270 degrees and not for targets at other locations. Note that the neurons's response is specifically enhanced over the delay period (D).Fig 1 (modified from Goldman-Rakic, 1995). Neuron during the Many Trials over Which a Monkey Performed an Oculomotor Delayed-Response Working Memory Task. The neuron's response for all trials at the preferred target location is shown as a histogram of the average response per unit time for that location. The activity is also shown in relation to task events (C, cue; D, delay; R, response) on a trial-by-trial basis. These neurons are located in the dorsal bank of the principal sulcus in monkey dorsolateral PFC, equivalent to Brodmann area 46 in humans. Goldman-Rakic and colleagues conducted extensive neuroanatomical tracing studies in the 1980's to map out the connections of this region and the posterior parietal cortex, major hubs in the brain's larger scheme of visuospatial processing.Fig. 2 (Arnsten, 2013). The cortical circuitry for spatial cognition, based on the work of Goldman-Rakic and Selemon. Note that both the dlPFC (area 46) and parietal cortex have many shared connections to subcortical structures that are not shown in this illustration, as well as “nonshared” connections that are not included in this diagram {from L. Selemon}.Goldman-Rakic's work was enormously influential, as shown in the figure below.Fig. 1 (Arnsten, 2013). Timeline of the discoveries of the PFC role in working memory (WM) and the key contributions of Goldman-Rakic. The graph shows the number of papers cited on PubMed using the search term “prefrontal cortex” for each decade ending in the year noted. Key publications by Goldman-Rakic and other early pioneers are indicated. Other major areas of research reviewed by Arnsten (2013) include the Key Role of Dopamine and Neuromodulation (e.g., D1 vs. D2 Receptor Actions, the D1 Receptor “inverted-U” Dose–Response), the Neurobiological Foundations of Schizophrenia (e.g., Insults to dlPFC Microcircuitry), and the dlPFC Microcircuits that Generate Mental Representations. The tribute article is open access and can be read freely by all.A Life of the Mind, Shaped by Working Memory The significance of working memory for higher cortical function is not necessarily self-evident. Perhaps even the quality of its transient nature misleads us into thinking it is somehow less important than the more permanent archival nature of long-term memory. However, the brain’s working memory function, i.e., the ability to bring to mind events in the absence of direct stimulation, may be its inherently most flexible mechanism and its evolutionarily most significant achievement. Thus, working memory confers the ability to guide behavior by representations of the outside world rather than by immediate stimulation, and thus to base behavior on ideas and thoughts.- Pat Goldman-Rakic (1991)ReferencesArnsten AF (2013). The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003. Cerebral Cortex PMID: 23926115Goldman-Rakic PS (1995). Cellular basis of working memory. Neuron, 14 (3), 477-85 PMID: 7695894... Read more »

  • August 15, 2013
  • 11:16 PM
  • 472 views

End of Life Gamma Waves: Altered State of Consciousness or Artifactual Brain Activity?

by The Neurocritic in The Neurocritic

"I had been in labor for my daughter for 16 hours. The labor was difficult and the Dr. approached me and told me it may come down to a choice between the child or myself.  ...  The labor dragged on and on and finally they came in and broke my water. I was rushed into delivery and within minutes my heart had stopped. I remember seeing a beautiful being of light enter the room. She told me I had to return as it was not my time yet. I was sucked back into my body as they restarted my breathing. My daughter began crying the moment I opened my eyes."-Description of a near-death experience1Are you afraid to die? We all are. Fear of pain and suffering, fear of the unknown, fear of eternal damnation (for the religious), fear of nothingness (for the atheist). Fear of the end. The finality of it all.The existential fear of death is part of the human condition. For a neuroscientist, studying what happens to conscious thought during the brain's own demise is one of the most profound of all questions. Short of conducting ill-advised scifi experiments on your med school classmates, how does one go about studying such a phenomenon? By using an animal model of cardiac arrest.thanks to Chris Chambers for the video ideaSurge of neurophysiological coherence and connectivity in the dying brainA popular new study by Borjigin et al. (2013) recorded EEG activity directly from the brains of nine dying rats. This paper was widely reported in mainstream media outlets, and has been nicely covered by bloggers Ed Yong, Mark Stokes, Chris Chambers, and Shelly Fan. What I would like to do here is to more closely examine the conditions surrounding the clinical death of these rats. Fig. 1A (modified from Borjigin et al., 2013). The time scale is in seconds.The y-axis is in microvolts.The figure above shows brain waves recorded from six electrodes implanted on the cerebral cortex, along with electrical activity from the muscles (EMG) and heart (EKG). The time period is 80 minutes before and 20 minutes after cardiac arrest (at time zero), which was induced by injection of potassium chloride into the heart. On its own, potassium chloride would cause a very painful death. Along with anesthetic and paralytic agents, potassium chloride is part of the drug sequence used for lethal injection in some U.S. states. In the present study, the animals were deeply anesthetized using ketamine (a dissociative anesthetic) and xylazine (veterinary sedative/analgesic which affects alpha-2 adrenergic receptors), a commonly used method of anesthesia in rodents. Fig. 1A shows that the animals were anesthetized for 30 min before cardiac arrest. The EEG exhibits fairly constant large amplitude activity during this time, shown spread out for a small interval of time in Fig. 1B below.Fig. 1B (modified from Borjigin et al., 2013). The time scale is in seconds. CAS =  cardiac arrest state. CAS3 (from 12 sec to 30 sec after cardiac arrest) is the critical time of increased EEG activity.To briefly summarize, the rats' brains were surprisingly active during the CAS3 period, showing highly coherent neural oscillations in the low gamma frequency band for a 20 sec interval after the heart and lungs stopped working. Fig. 1C below expands the vertical gray bars in Fig. 1B to show greater detail. Of note is the high amplitude rhythmic oscillations during CAS3. This low gamma activity (35-55 Hz) was strongly coupled to EEG activity in other frequency bands (theta and alpha) -- to an even greater extent than during active waking. The authors viewed this as a state of heightened consciousness, but such speculation is premature.- click on image for a larger view - Fig. 1C (modified from Borjigin et al., 2013). CAS = cardiac arrest state.Why would the authors maintain that a dying brain can generate the neural correlates of heightened conscious processing? Gamma (aka 40 Hz activity) has been viewed as a possible solution to the "binding problem" of how consciousness arises since the late 80s. In the visual system, synchronous gamma might be how the brain combines distributed activity conveying separate aspects of a stimulus (e.g., its color, shape, and form) into a unified percept. Furthermore, gamma might account for phenomenal awareness and consciousness, according to some. However, more recent evidence suggests that gamma band responses do not reflect conscious experience.In addition, it is not at all clear how highly synchronized low gamma can index "heightened conscious processing" in deeply anesthetized dying rats. Do the rats transition from ketamine/xylazine anesthesia (associated with altered thalamocortical connectivity) to a hyperaware internal state of....?  Of what?  The CAS3 activity is so abnormal that it might be artifactual or epiphenomenal, "a tale told by an idiot, full of sound and fury, signifying nothing" (Shakespeare, 1606). Near-death experience (NDE) researcher Sam Parnia believes the low gamma activity could be caused by a massive influx of calcium, as he stated in Ed Yong's ... Read more »

Borjigin J, Lee U, Liu T, Pal D, Huff S, Klarr D, Sloboda J, Hernandez J, Wang MM, & Mashour GA. (2013) Surge of neurophysiological coherence and connectivity in the dying brain. Proceedings of the National Academy of Sciences of the United States of America. PMID: 23940340  

  • August 11, 2013
  • 12:54 AM
  • 326 views

Save Us From Misleading Press Releases

by The Neurocritic in The Neurocritic

Exposure to subliminal cues can help us choose the apple instead of the cake. Or can it...  Let's take a look.Our Brains Can (Unconsciously) Save Us from Temptation Aug. 8, 2013 — Inhibitory self control -- not picking up a cigarette, not having a second drink, not spending when we should be saving -- can operate without our awareness or intention. That was the finding by scientists at the University of Pennsylvania's Annenberg School for Communication and the University of Illinois at Urbana-Champaign. They demonstrated through neuroscience research that inaction-related words in our environment can unconsciously influence our self-control. Although we may mindlessly eat cookies at a party, stopping ourselves from over-indulging may seem impossible without a deliberate, conscious effort. However, it turns out that overhearing someone -- even in a completely unrelated conversation -- say something as simple as "calm down" might trigger us to stop our cookie eating frenzy without realizing it.The press release states that overhearing a message of restraint in a background conversation might prevent us from reaching for a second piece of cake at the holiday party. What's the evidence for this?A study by Hepler and Albarracin (2013) recorded EEG activity (brain waves) while 20 participants performed a "go/no-go" task that tests their inhibitory control abilities. The subjects responded every time they saw an "X" on the screen but refrained from responding when they saw a "Y". These target letters were preceded by a visual masking stimulus (&&&&&&) for 16.7 msec, a subliminal prime word for 33.4 msec, and then another masking stimulus (&&&&&&) for 50.1 msec. The idea here is to show the prime word very briefly and to "mask" conscious perception of the word.The prime words were general action words (go, run, move, hit, start), general inaction words (still, sit, rest, calm, stop), and control stimuli (scrambled action and inaction prime words – e.g., rnu). One obvious hypothesis would be that exposure to the masked inaction words would make you better at inhibiting a response to "Y". The authors didn't exactly say that, instead predicting that the amplitude of the P3 component extracted from averaged EEG on no-go trials would reflect the engagement of unconscious inhibitory processes.However, if behavior is unaffected by the masked inaction words, it ultimately doesn't matter what happens to the P3 component. There is nothing you can say about "resisting temptation" -- behavioral change is not the same thing as a change in the size of the P3 component. The latter may indicate that a subject's brain registered sit, rest, calm, or stop implicitly, but this neural activity wasn't enough to improve stopping ability.And in fact, this is exactly what the study demonstrated. The masked primes had a modest effect on the size of the P3 wave to the subsequent no-go stimulus, which reached its peak at around 400 msec post-stimulus (i.e., less than half a second after the "Y"). The inaction primes were significantly different from the action primes, but neither one differed from the neutral condition.1Fig. 1. (Hepler & Albarracin, 2013). Grand average waveforms at electrode Cz to correct no-go trials in Experiment 1. The authors interpreted this effect to indicate that inhibition processes were "engaged" by the subliminal primes.However, the primes had absolutely no impact on how well participants could resist responding to the no-go stimuli [F(2, 38) = .00, p = .99]. Accuracy in the inaction prime condition was exactly the same as in the action prime condition. In other words, the study showed that Our Brains Cannot (Unconsciously) Save Us from Temptation.Or as succinctly stated by Justin Kiggins on Twitter:I did not intend to nitpick about the details of this particular study or to single out the authors. But the press release provided by the University of Pennsylvania Annenberg School for Communication is completely misleading (and poorly communicated).Footnote1 This is somewhat problematic, because you'd rather see each of the experimental conditions differ from the control condition.ReferenceHepler J, & Albarracin D (2013). Complete unconscious control: Using (in)action primes to demonstrate completely unconscious activation of inhibitory control mechanisms. Cognition, 128 (3), 271-9 PMID: 23747649

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  • August 8, 2013
  • 03:37 PM
  • 335 views

Possession Trance Disorder Caused by Door-to-Door Sales

by The Neurocritic in The Neurocritic

Some companies and organizations that employ door-to-door sales tactics are known for their cult-like practices (e.g., Amway, traveling magazine sales, and Jehovah's Witnesses). An unusual psychiatric report included this religious brainwashing element in presenting the case of a 47 year old Japanese housewife who felt possessed by God after a visit by a door-to-door salesman (Saitoh et al., 1996):In Japan, psychiatry has generally regarded the possessive state as symptomatic of religion- related mental disorders. ... Recently, there has been a proliferation of direct sales enterprises that incite anxiety in prospective customers in order to sell their products. Due to the prevalence of door-to-door peddling of items such as amulets and talismans to ward off curses and misfortune, the term ‘door-to-door sales’ has come to have a religious connotation.Recently, we treated a case of possessive state accompanied with suicidal tendencies which are thought to have developed in connection with door-to-door sales. Religious factors and elements of brainwashing were seen both in the conditions that promoted the possessive state and in the state itself.The patient grew up on a family farm in the Tokyo area. She was described as laconic, withdrawn, quiet, unsocial and nervous.When the patient was 47 years old, a male she described as a ‘salesperson type’ came to her home in May. He read her palm and asked for her husband’s family name and birth date. When she gave him this information he predicted that some misfortune would befall her husband. The patient’s husband had fallen in an accident a few days earlier, and she became extremely anxious. The man then said, ‘I have a talisman, a lucky name chop (family seal) which will protect your husband from misfortune’. Although she was hesitant at first, she finally agreed... When she paid for the chop the man recommended that she go to a certain room in a hotel in Saitama prefecture for a more in-depth palm reading ... where she was one of 20 women who received a lecture on subjects such as lineage, marriage, health and happiness.Approximately 1 week later, again at the salesman’s advice, she went to a rented room in a building in Tokyo where she received a scroll called a prayer book. At the same time she was urged to buy a sculpture which was called a ‘Fortune Tree’. Two days later she went to her bank with the salesman and a woman whom she did not know and paid the ¥5,400 000. The patient went to this room twice a month during June, July and August. The room was divided by a partition and she was shown biblical videotapes. In September, she complained of an inability to sleep, and stated, ‘I can hear God’s voice. He possesses me and is controlling my bodily movements’. Thereafter, she episodically gave orders to her family in an uninflected monotone, making unrealistic assertions such as, ‘Don’t eat that or you will die’ and ‘Don’t go out or you won’t come back’. In mid-September, she filed a complaint that she had been deceived into buying the ‘Fortune Tree’ at an exorbitant price. Shortly thereafter, she was taken to a private mental hospital and treated with the antipsychotic drug haloperidol. Two weeks later, she was able to recount her ordeal:... ‘I felt like God had taken over my body. I was ordered by Him to do this or do that. Even if I wasn’t talking, my mouth just moved on its own. I didn’t go so far as to be One with God, but it was almost like that. That’s why I gave orders to my husband and child as though I were God’. The patient showed no subsequent objective signs of abnormality, and was released 2 months after admission.The authors discussed her case in terms of the DSM-IV diagnosis, Dissociative Disorder Not Otherwise Specified, along with depressive symptoms and somatic complaints. Her attendance at the video lectures was described as a form of brainwashing. More specifically, her condition would fall under the category of Dissociative Trance Disorder (possession trance), a disturbance in consciousness or identity with a culturally specific element:Dissociative trance involves narrowing of awareness of immediate surroundings or stereotyped behaviors or movements that are experienced as being beyond one's control. Possession trance involves replacement of the customary sense of personal identity by a new identity, attributed to the influence of a spirit, power, deity, or other person and associated with stereotyped involuntary movements or amnesia...This case is rare not only because of its association with a business practice, but also because possession is usually seen in more isolated communities with traditional belief systems, quite unlike contemporary Tokyo. Further ReadingPossession Trance Disorder in DSM-5ReferenceSatoh S, Obata S, Seno E, Okada T, Morita N, Saito T, Yoshikawa M, & Yamagami A (1996). A case of possessive state with onset influenced by 'door-to-door' sales. Psychiatry and clinical neurosciences, 50 (6), 313-6. PMID: 9014228

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Satoh S, Obata S, Seno E, Okada T, Morita N, Saito T, Yoshikawa M, & Yamagami A. (1996) A case of possessive state with onset influenced by 'door-to-door' sales. Psychiatry and clinical neurosciences, 50(6), 313-6. PMID: 9014228  

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