Alcohol Blackout

This post is for all you New Year's Eve party goers who don't remember where you were or what you did. If that's the case, then you experienced an alcohol-induced blackout. Haven't you always wondered about the clinical manifestations and neurobiological mechanisms of alcohol-induced blackouts? Maybe you have, but you can't remember.

A definitive review of the phenomenon by Rose and Grant (2010) explains that there are two different types of blackout: en bloc, a complete loss of memory for the affected time period; and fragmentary, where bits and pieces of memories remain. The en bloc blackout is more likely to occur when a large quantity of alcohol is ingested within a small time period.

What causes an alcohol blackout? A good source of information on the topic is the NIAAA website: What Happened? Alcohol, Memory Blackouts, and the Brain:

Alcohol primarily interferes with the ability to form new long–term memories, leaving intact previously established long–term memories and the ability to keep new information active in memory for brief periods. ... Blackouts are much more common among social drinkers—including college drinkers—than was previously assumed, and have been found to encompass events ranging from conversations to intercourse. Mechanisms underlying alcohol–induced memory impairments include disruption of activity in the hippocampus, a brain region that plays a central role in the formation of new autobiographical memories.

Rose and Grant (2010) summarize the suspected hippocampal mechanisms as follows:

Blackouts are caused by breakdown in the transfer of short-term memory into long-term storage and subsequent retrieval primarily through dose-dependent disruption of hippocampal CA1 pyramidal cell activity. The exact mechanism is believed to involve potentiation of gamma-aminobutyric acid-alpha [GABA-A]-mediated inhibition and interference with excitatory hippocampal N-methyl-d-aspartate [NMDA] receptor activation, resulting in decreased long-term potentiation [LTP].

In addition...

Another possible mechanism involves disrupted septohippocampal theta rhythm activity because of enhanced medial septal area gamma-aminobutyric acid [GABA]-ergic neurotransmission.

Women are more susceptible to alcohol blackouts than men (and recover more slowly) because of their generally less muscular body composition, and gender differences in pharmacokinetics.

Cheers to knowing what's happening in your brain after downing a few too many Jell-O shots. If you can remember tomorrow...


Reference

Rose, M., & Grant, J. (2010). Alcohol-Induced Blackout Journal of Addiction Medicine, 4 (2), 61-73 DOI: 10.1097/ADM.0b013e3181e1299d

Orthopedic Surgeons vs. Anesthesiologists

from Subramanian et al. 2011 [Image: Clive Featherstone]

Every year, BMJ [British Medical Journal] has a special Christmas issue with spoof articles and silly studies. Favorites from the past include:

• Sword Swallowing And Its Side Effects

• Sex, aggression, and humour: responses to unicycling

• Rage Against the Machine Syncope and the Texting Sign

• Why are the letters "z" and "x" so popular in drug names?

The clear winner this year is a revenge piece by a group of orthopaedic surgeons and trainees (Subramanian et al., 2011) that convincingly demonstrates they are stronger and smarter [?] than their colleagues the anesthesiologists (anaesthetists in the UK). The motivation for such a study is as follows:

A humorous anaesthetic colleague recently repeated the following popular saying while an operating table was being repaired with a mallet: “typical orthopaedic surgeon—as strong as an ox but half as bright.” Making fun of orthopaedic surgeons is a popular pastime in operating theatres throughout the country. This pursuit has recently spread to the internet; a humorous animation entitled “orthopedia vs anesthesia” had received more than half a million hits at the time of writing.1 Several comparisons of orthopaedic surgeons to primates have been published, and the medical literature contains suggestions that orthopaedic surgery requires brute force and ignorance.2 3 4

The stereotypical image of the strong but stupid orthopaedic surgeon has not been subject to scientific scrutiny. Previous studies have shown that the average hand size of orthopaedic surgeons is larger than that of general surgeons.2 3 However, a search of the worldwide scientific literature found no studies assessing the strength or intelligence of orthopaedic surgeons. In the absence of a cohort of willing oxen as a control group, and given that the phrase is popular with anaesthetists, we designed this study to compare the mean grip strength of the dominant hand and the intelligence test score of orthopaedic surgeons and anaesthetists.

The participants in the study were 36 male orthopaedic surgeons (there were no female OS's available) and 40 male anaesthetists (the six women who volunteered were excluded). They were recruited from three hospitals over a 2 week period. Grip strength was tested with a hand dynamometer. The proxy for IQ was rather unacceptable however - the Mensa Brain Test version 1.1.0 administered on an iPhone 4. The validity of the IQ measure was apparently irrelevant and the results were actually laughable, befitting the spoof study format.

Fig 3 (Subramanian et al. 2011). Box plot of intelligence test score by specialty. Upper and lower whiskers represent 1.5 times and −1.5 times interquartile range; upper and lower hinges represent 25% and 75% quartiles; middle represents median or 50% quartile

The means for IQ were 98.38 for the anaesthetists vs. 105.19 for the orthopaedists, which squeaked in as a significant difference at p=0.0489 (although there was quite a bit of overlap between the groups). A few more things are notable about this result:

(1) mean IQ for the entire population is 100, and it would be surprising if licensed professionals who are graduates of medical schools and residency programs were of entirely average intelligence. A 2002 paper {PDF} on male high school graduates in Wisconsin (class of 1957)¹ found that doctors had the highest IQ (120) of all professions.

(2) One anaesthetist tested in the mentally retarded range: below 70, which is over two standard deviations from the average IQ of 100. This would make him a very unique savant anesthesiologist. At any rate, if you threw out his score, the difference between groups would no longer be significant.

(3) Test results from two more anaesthetists suggested borderline intellectual functioning (between 70–84). A couple more doctors from each category were right on the edge of this borderline, which again would be highly improbable.

The authors did acknowledge some of these weaknesses:

The intelligence scores were lower than anticipated for IQ in the medical profession. This is likely to be a reflection of the way in which intelligence was tested, and the scores derived from the rather difficult Mensa brain test may not be directly comparable to IQ scores. We selected the abbreviated Mensa test carried out by touch screen for speed and convenience. Full formal IQ testing is more time consuming and cumbersome and would have affected doctors’ willingness to participate in this study.

Moving on to the other major finding, it was no surprise that the orthopaedic surgeons had greater grip strength than the anaesthetists (p=0.0274). But a quick peak at Fig 2 shows that one exceptionally strong OS helped drive this small difference.

But who am I to be a scrooge and spoil the fun of the orthopaedic surgeons, who think they finally have intellectual bragging rights over the anesthesiologists?

Conclusion

The stereotypical image of male orthopaedic surgeons as strong but stupid is unjustified in comparison with their male anaesthetist counterparts. The comedic repertoire of the average anaesthetist needs to be revised in the light of these data. However, we would recommend caution in making fun of orthopaedic surgeons, as unwary anaesthetists may find themselves on the receiving end of a sharp and quick witted retort from their intellectually sharper friends or may be greeted with a crushing handshake at their next encounter.

Footnote

¹ Obviously, that study (Hauser, 2002) was based on very old data from one US state. Results may differ in the contemporary UK, as described in this authoritative report in the Daily Mail: Why doctors are not as clever as they used to be.


Reference

Subramanian, P., Kantharuban, S., Subramanian, V., Willis-Owen, S., & Willis-Owen, C. (2011). Orthopaedic surgeons: as strong as an ox and almost twice as clever? Multicentre prospective comparative study BMJ, 343 (dec15 1) DOI: 10.1136/bmj.d7506

The Pirate Party Empowers Patients

An editorial in the Christmas issue of BMJ maintains that the three planks of the Swedish Pirate Party -- reform of copyright law, respect for right to privacy, and the abolition of patents -- are potentially empowering for patients (Ingdahl, 2011). The Pirate Party was originally started on January 1, 2006 and gained notoriety when file sharing host The Pirate Bay was raided by Swedish police.

Science journalist Waldemar Ingdahl explains the implications of Pirate policy for both doctors and patients:

The Pirate Party is critical of the copyrighting of scientific articles and anything else that reduces their accessibility because it believes that knowledge has intrinsic value. The reform of copyright law could dramatically speed up the rate of discovery in many disciplines and change the scientific process radically. Similarly, researchers will need to rise above their petty rivalries and be prepared to share their data with others. The internet provides tools to facilitate this.

Many large organisations that fund or host research are now mandating that the results of this research be made ”open access,” and many journals have adopted revenue models where the authors (or their employers) pay to enable this to happen. Open access journals such as PLoS Biology and PLoS Genetics are already among the most prestigious in their field. Once the contents of scientific monographs have also been made available, the Pirate Party dream that publicly funded science should be open science will have become a reality.

As medical knowledge becomes increasingly available over the internet, the role of doctors will change. Pirates have discussed empowering patients by transferring the control of medical records to patients themselves. This would make the doctor more of the patient’s partner and less of a figure of authority. Collecting all relevant medical data in a single file controlled by the patient would increase security and privacy. With medical research becoming more reliant on gathering large datasets on the entire population, the need to protect patients’ privacy becomes crucial. Pirate parties are suspicious of giving insurance companies access to medical data.

The Swedish and German parties have called for the abolition of drug patents.2 3 Here’s how. Thanks to universal health insurance, government subsidies account for most of the income of drug companies in Europe. Only 15% of this income actually goes into research, with most of the remainder being spent on marketing. Instead, governments should allocate 20% of today’s drugs bill directly to the universities for research. More funds should produce more research findings. Without the need for drug companies to undertake the research themselves, there would be no need for medical patents to protect their investment. The price of drugs would drop if they were manufactured in a competitive market, rather than by patent protected monopolies. People in developing countries would also benefit because their governments wouldn’t be forced to buy expensive patent drugs.

Argh, matey! Yo ho ho and a Merry Christmas to you.

Pirate Santa, by Neill Cameron

Reference

Ingdahl W (2011). Three planks of the Pirate Party’s platform that matter to doctors. BMJ 2011;343:d8101.

The Disconnection of Psychopaths

Functional connectivity between the right amygdala and anterior vmPFC is reduced in psychopaths. From Fig. 2 of Motzkin et al., (2011).


The last post discussed the case of a 14 yr old boy with congenital brain abnormalities and severe antisocial behavior said to be "consistent with" psychopathy. This label is quite stigmatizing and the diagnosis is a controversial one (Skeem et al., 2011),¹ particularly in children. What is psychopathy, exactly? According to Ermer and colleagues (2011),

Psychopathy is a serious personality disorder marked by affective and interpersonal deficiencies, as well as behavioral problems and antisocial tendencies (Cleckley, 1976). Affective and interpersonal traits (termed Factor 1) include callousness and a profound inability to experience remorse, guilt, and empathy; antisocial and behavioral problems (termed Factor 2) include impulsivity, stimulation seeking, and irresponsibility. These symptoms tend to manifest at an early age, continue throughout adulthood, and pervade numerous aspects of psychopaths’ daily functioning.

As for the brain regions implicated in psychopathy, dysfunction in the amygdala and ventromedial prefrontal cortex (vmPFC) have been suspected for quite some time (Abbott, 2001; Blair, 2007; Koenigs et al., 2011). From this perspective, a recent study on the structural and functional connectivity of these two regions (Motzkin et al., 2011) isn't entirely groundbreaking. However, the logistics of conducting those experiments were anything but simple: the participants were male inmates of a medium security prison in Wisconsin.

Kent Kiehl outside the mobile scanner he has used to look at the brains of inmates at a New Mexico prison. Credit: Nature News.

Dr. Kiehl's work with criminal psychopaths has been featured in the New Yorker. In the present study, diffusion tensor imaging (DTI) and resting state fMRI were used to examine the structural and functional connectivity of the vmPFC (Motzkin et al., 2011), which has been associated with decision making and the regulation of emotional behavior. The Psychopathy Checklist-Revised (PCL-R) (Hare, 2003)² was administered to the participants. Those with scores >30 were classified as psychopaths, while the non-psychopaths scored <20.

In the DTI study of structural connectivity, 13 non-psychopaths were compared to 14 psychopaths, 7 of whom were low-anxious or primary psychopaths and 7 were high-anxious/secondary psychopaths.³ The uncinate fasciculus (UF) is the main pathway connecting the vmPFC and the anterior temporal lobe (including the amygdala). Fractional anisotropy (FA), a measure of white matter structural integrity, was compared between the groups for regions of interest (after scaling for overall whole brain FA, which was reduced in the psychopaths). For comparison, FA in other frontal-temporal tracts was examined. Results indicated that FA was indeed reduced in the right UF, which replicates an earlier study (Craig et al., 2009).

Fig. 1 (modified from Motzkin et al., 2011). DTI results: reduced white matter integrity is specific to the right UF in psychopaths. b, The UF ROI (red) superimposed on an entire UF tract, as computed with tractography. f, Bar plots of mean scaled FA values in the UF. Psychopaths exhibited significantly lower scaled FA values only in right UF. Error bars indicate SEM. *p < 0.05.

Resting state fMRI, which measures spontaneous, low-frequency fluctuations in BOLD signal, was used to examine functional connectivity. In this experiment, 20 prisoners who were not psychopaths were compared to 20 prisoners who were considered psychopaths. Based on the DTI study, the right amygdala was used as a "seed region" to examine functional connectivity with vmPFC. In addition, the medial parietal cortex (precuneus and posterior cingulate) was used as a seed region, because this area is also reciprocally interconnected with vmPFC. If the amygdala-vmPFC and medial parietal-vmPFC circuits are not functioning properly, it was expected that correlated activity between regions would be lower. And indeed, that's what was observed in the psychopaths: resting vmPFC BOLD signal was less correlated with amygdala and medial parietal activity.

Fig. 3 (modified from Motzkin et al., 2011). Functional connectivity between medial parietal cortex and vmPFC is reduced in psychopaths. [...] The group difference map indicates two separate clusters within vmPFC where non-psychopaths have significantly greater connectivity with the precuneus/PCC seed than psychopaths (vmPFC and rACC). b, Group differences in connectivity were assessed in the vmPFC mask (red) for correlation coefficients computed using the mean time series extracted from the PCC seed (blue; x = −5, y = +49, z = +40). c, The bar plots depict group differences in connectivity estimates (Fisher z-transformed correlation coefficients) within each significant cluster.

Reduced connectivity between vmPFC and precuneus/posterior cingulate cortex (PCC)? What might this mean? Those two regions are major nodes in the default mode network (DMN), and activity in this circuit might be related to "self-reflective cognition" (Qin & Northoff, 2011), which might be defective in psychopaths. But the authors are cautious in further interpreting this result:

However, at this point it may be premature to speculate on the precise functional significance of reduced vmPFC–medial parietal connectivity in psychopathy.

But if one isn't so circumspect, it would be easy to postulate that the reduction in vmPFC–medial parietal connectivity is a reflection of a fragmented sense of self in individuals with psychopathy. Here we can veer way off course into object relations theory, which is exactly what Gullhaugen and Nøttestad (2011) did in their review paper on case studies of psychopaths.

Object relations theory is a collective term for theories focusing on how early interpersonal interaction, or object relations, construct psychological structure (an inner experience of a self and an other; St. Claire, 2000), which serves as a foundation for future relationships. ...

According to this theory, “narcissism and disorders of the self imply that the very central structures of the personality (inner experiences of self and others) are defective” (St. Claire, 2000, p. 139). In the PCL-R, narcissism is covered by Item 2: Grandiose sense of self-worth, and research has demonstrated that the PCL-R Factor 1 (the interpersonal and affective domain) is correlated with narcissistic personality disorder. Individuals with defective personality structure/pathologically developed object relations are distinguished by a tendency to define others as one-dimensional need-satisfying objects (part–objects), deviances in self- and affect regulation, primitive feelings such as anxiety and rage, and projection and splitting as primitive defense.

Now before you say, "Really!?! I did not know that The Neurocritic was a proponent of neuropsychoanalysis," let me state that I am not a proponent of neuropsychoanalysis,⁴ although I have written about it in the past. I just happened to be reading these two papers at the same time and wondered how they might be related (odd as that may seem). Clearly, Gullhaugen and Nøttestad (2011) themselves are not interested in the neural correlates of psychopathy, and Motzkin et al. (2011) aren't especially curious about the psychopath's early interpersonal interactions. The true model for this sort of mapping is Professor Karl Friston, one of the most prominent (and prolific) researchers in the field of neuroimaging. In collaboration with Robin Carhart-Harris, he developed a neurobiological account of Freudian ideas (Carhart-Harris & Friston, 2010).

...Freud argued that the ego modulates and suppresses both exogenous and endogenous signals. In neurobiological terms, exogenous signals correspond to interoceptive and exteroceptive signals from thalamic and unimodal sensory areas that convey sensory signals (prediction-errors) to polymodal and medial temporal lobe structures. Endogenous signals could be equated with subsequent bottom-up prediction errors (excitation) arising in limbic and paralimbic systems, which are passed up to high-level polymodal cortical areas that comprise the nodes of the default-mode.

The ego (normal adult human consciousness) was more or less equated with activity in the brain's "default mode" network (Raichle et al., 2001), measured as spontaneous fluctuations in the BOLD signal during unconstrained cognition. Activity in the DMN is anti-correlated with activity in "active task" networks, which are engaged by typical neuroimaging experiments. Although they didn't mention psychopathy or antisocial personality disorder specifically, reduced activity in the DMN was associated with primitive thought and emotion. See Friston is Freudian and A Bayesian Brain is a Freudian Brain for further details.

Returning to the Gullhaugen and Nøttestad review, Table 2 summarized the case histories of 11 severely psychopathic offenders, which included your classic serial killers with horrific childhoods [you can skip the Hannibal Lecter analysis]. One of the most salient things (in my view) was the extensive co-morbidity with other disorders, both Axis II (borderline, narcissistic, histrionic, and schizoid personality disorders) and Axis I (major depression, anxiety, substance abuse, schizophreniform disorder). Although these individuals were completely devoid of remorse and empathy for other people, evidence that they experienced psychological pain included self-injury, suicidal thoughts and plans, very low self-esteem, hypervigilance, and "feelings of emptiness and longings for love."

This brings up the possible distinction between primary (low-anxious) and secondary (high-anxious) psychopathy. In the neuroimaging study, the primary psychopaths showed significantly greater functional connectivity than secondary psychopaths for the vmPFC–amygdala correlation map but not for the vmPFC–medial parietal one (Motzkin et al., 2011). The authors did not interpret this finding, but perhaps the disinhibited and antisocial behavior associated with PCL-R Factor 2 goes more awry in secondary psychopaths, whereas the "fragmented sense of self" is more similar in the two subtypes. The observation that led me to the uneasy DMN/object relations synthesis was the prevalence of identity disturbances in the psychoanalytic case material (Gullhaugen and Nøttestad, 2011), which included descriptors like fragmented personality, reality-testing deficit, derealization, and unstable self-image.

A huge caveat is in order here, as the the populations of Motzkin et al. (male prisoners in a medium-security prison) and Gullhaugen and Nøttestad (serial killers and other severe offenders, with women grossly overrepresented [3 of 11]) were entirely different. My limited knowledge led me to believe that the majority of the latter population were secondary psychopaths with multiple diagnoses. Although Motzkin et al. matched their psychopath subtypes for substance abuse history, the co-morbidity of other mental disorders is unknown [except for the exclusion of psychosis and bipolar disorder].

In the end, we might say that psychopathic individuals show both literal (white matter)⁵ and metaphorical (interpersonal relations) disconnections.


Footnotes

¹ To quote from the paper (Skeem et al., 2011):

Few psychological concepts evoke simultaneously as much fascination and misunderstanding as psychopathic personality, or psychopathy. Typically, individuals with psychopathy are misconceived as fundamentally different from the rest of humanity and as inalterably dangerous. Popular portrayals of “psychopaths” are diverse and conflicting, ranging from uncommonly impulsive and violent criminal offenders to corporate figures who callously and skillfully manuever their way to the highest rungs of the social ladder.

Thanks to @Keith_Laws for linking to this 68 page tome while I happened to be working on this post. No, I haven't read the whole thing.

² Forensic psychologist Dr. Karen Franklin has written about multiple controversies surrounding the PCL-R, including the failure of Factor 1 to predict violence and Dr. Hare's attempt to block publication of a critical article. Also see this NPR series on Weighing The Value Of A Test For Psychopaths.

³ For a thorough discussion of primary vs. secondary psychopathy and the dual process-model, see Skeem et al. (2011):

...the dual-process model is an etiologic theory that posits distinct mechanisms underlying the interpersonal-affective (i.e., meanness/boldness) and antisocial (i.e., disinhibition) features of psychopathy. From the dual-process perspective, boldness and, to a lesser extent, meanness reflect a weakness in emotional reactivity, particularly defensive (fear) reactivity. This temperamental deficit is presumed to go hand-in-hand with differences in the functioning of affective-motivational systems including the amygdala and affiliated brain structures. [. . .] ...a second temperamental process underpins the disinhibition component of psychopathy: externalizing-propensity, or the liability toward impulse-control problems of various types, including antisocial behavior and substance use. This propensity may be associated with dysfunction in fronto-cortical brain systems that help to regulate emotion and guide decision making and action.

⁴ OMG! Has the Frontiers franchise gone too far? Introducing Frontiers in Psychoanalysis and Neuropsychoanalysis. Really!?!

⁵ Whole brain FA was reduced in the psychopaths, but functional connectivity maps from resting state fMRI (i.e., correlated BOLD fluctuations) do not necessarily imply direct anatomical connections. "White matter" sounded better in that context, though. For more on white matter, see the Neurological Correlates blog.


References

Abbott A. (2001). Into the mind of a killer. Nature. 410:296-8.

Blair RJ. (2007). The amygdala and ventromedial prefrontal cortex in morality and psychopathy. Trends Cogn Sci. 11:387-92.

Carhart-Harris R, Friston,K. (2010). The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas. Brain 33:1265-1283.

Ermer E, Cope LM, Nyalakanti PK, Calhoun VD, Kiehl KA. (2011). Aberrant paralimbic gray matter in criminal psychopathy. J Abnorm Psychol. Dec 12. [Epub ahead of print].

Sundt Gullhaugen A, & Aage Nøttestad J (2011). Looking for the hannibal behind the cannibal: current status of case research. International journal of offender therapy and comparative criminology, 55 (3), 350-69 PMID: 20413645

Koenigs M, Baskin-Sommers A, Zeier J, Newman JP. (2011). Investigating the neural correlates of psychopathy: a critical review. Mol Psychiatry 16(8):792-9.

Motzkin JC, Newman JP, Kiehl KA, & Koenigs M (2011). Reduced prefrontal connectivity in psychopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (48), 17348-57 PMID: 22131397

Qin P, Northoff G (2011) How is our self related to midline regions and the default-mode network? Neuroimage 57:1221–1233.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. (2001). A default mode of brain function. Proc. Natl. Acad. Sci. 98: 676–682.

Skeem JL, Polaschek DLL, Patrick CJ, Lilienfeld SO (2011). Psychopathic Personality: Bridging the Gap Between Scientific Evidence and Public Policy. Psychological Science in the Public Interest 12:95-162.

Born This Way?

A group of investigators from the University of Iowa have published a case report about a 14 year old boy with severe antisocial behavior (Boes et al., 2011):

He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance.

MRI findings revealed a small congenital malformation in his left ventromedial prefrontal cortex (vmPFC), which has been associated with decision making and the regulation of emotional behavior (Grabenhorst & Rolls, 2011; Mitchell, 2011).

Figure 1 (Boes et al., 2011). MRI Images. 1A. This is an oblique coronal T2 image at the level immediately anterior to the horn of the lateral ventricles. Note the hyperintense white matter just deep to the gyrus rectus (indicated by arrow) with a linear extension tapering as it courses toward the anterior horn of the ventricle. Also note the cortical thickening of the left gyrus rectus relative to the right gyrus rectus. 1B. This coronal T1 MPRAGE image shows thickening of the left ventromedial prefrontal cortex [PFC] and blurring of the gray-white interface in this same region. 1C. This is a surface rendering of B.W.'s brain viewing the medial left hemisphere surface with thickened cortex highlighted, which approximates the lesion site.

The boy (patient B.W.) had MRI scans at the ages of 4, 11, and 13. The three main neuroanatomical findings remained stable across the three scans. Although the abnormalities appear to be relatively minor, the authors described them as consistent with a focal cortical dysplasia affecting portions of Brodmann areas 11, 12, 25, and 32.

Did these anatomical anomalies cause B.W.'s aberrant behavior? He reached normal developmental milestones until the age of 4, when he started having seizures. He was prescribed divalproate, an anticonvulsant (and mood stabilizer) which temporarily controlled his seizures. But they returned between the ages of 6-11 yrs, when he started having complex partial seizures every few months. Complex partial seizures are typically associated with an alteration of consciousness and foci in the medial temporal lobes, although they can also originate in the frontal lobes (Williamson et al., 1985). More details of B.W.'s behavior from the case history:

At age six B.W.'s parents reported the onset of defiance at home and at school, including: stealing, lying, aggression, rage, rude language, and disobedience. His parents referred to this as his 'contraband' period because he would consistently bring prohibited items to school (e.g. a pocketknife). He also stole cookies and would sell them to peers. The parents were very concerned about this behavior because it did not seem characteristic of B.W.‟s previous temperament. Moreover, neither parent nor any sibling of B.W. had similar behavioral problems. He was seen by a child psychologist and diagnosed with oppositional defiant disorder and started counseling, which was discontinued after a few visits.

During ages seven to nine B.W.'s parents describe a 'cause and effect problem' in which he would behave badly and be punished and the following day would engage in the same behavior that led to the punishment. Along with his lack of response toward punishment, B.W. was impulsive and showed a lack of respect toward authority, including teachers and parents. In an effort to provide greater structure and discipline than the school could provide the parents decided to begin home-schooling B.W. and his siblings when he was nine years old... Despite behavioral problems and lack of self-motivation he was noted to be intelligent and academically capable. The following year a child psychiatrist diagnosed B.W. with attention deficit hyperactivity disorder and bipolar disorder, for which he was prescribed carbemazepine, topiramate,¹ and dexmethylphenidate [the d-enantiomer of Ritalin]. Counseling was again attempted briefly without effect.

At age 11 B.W. presented to the emergency room of a large tertiary care center with his mother for suicidal ideation. While at a nearby shopping mall he expressed feelings of hopelessness, unworthiness, and wanting “to kill myself… I would cut or burn myself.” The talk of suicide had been ongoing for two months and had been accompanied by suicidal gestures such as jumping from a second story deck onto a trampoline and a superficial laceration to the left hand because “I wanted to kill myself.” Along with the suicidal gestures the parents were alarmed about escalating aggression, destructive behavior, wandering off, and hypersexual behavior that included masturbation, accessing porn sites on the web, and asking younger peers to disrobe in a domineering manner (despite being pre-pubescent at the time). During the admission interview he reported that he had been hearing voices at night from God and the devil motivating him to do good and bad things, respectively.

When he was hospitalized, B.W. admitted that he was fabricating the psychotic and suicidal symptoms, along with his self-reported levels of high anxiety and depression. Hospital staff found him manipulative and easily angered. He was given the diagnoses of oppositional defiant disorder, ADHD, and mood disorder not otherwise specified. He was no longer considered bipolar. After discharge his antisocial behavior escalated. He started fires, assaulted the principle, resisted arrest, threatened his mother with a knife, and hit his father over the head with a wrench "in cold blood, without any emotion."

Neuropsychological testing revealed his IQ and cognitive functioning to be in the average range, although he had problems with planning and with the Iowa Gambling Task, where he could not learn which decks were safe (vs. risky). He was also given a moral judgment task:

On his first attempt, B.W. skipped several questions and scribbled over the entire second sheet and drew a goblin. He completed the task at a later date.

He eventually tested at a “relatively immature, preconventional, stage of moral development, in which moral dilemmas were approached primarily from the perspective of avoiding negative consequences for one's self.”

On the Antisocial Process Screening Device filled out by his parents, his scores were at the 99-100th percentile for callous-unemotional, narcissism, impulsivity, and total score.

Recently (summer 2011), B.W. underwent intracranial mapping of the left ventromedial frontal and anterior temporal regions for monitoring of seizure foci, and subsequent surgical resection of left prefrontal and left temporal regions (including the amygdala). Pathological examination of this tissue revealed dysplastic neurons. Post-surgery, B.W. is on lamotrigine and has remained seizure-free.

The authors concluded that B.W.’s bad behavior was caused by the vmPFC abnormality for the following reasons:

1) The behavioral and neuropsychological profile described in the results section is strikingly consistent with prior cases of focal vmPFC lesions. … The severity of behavioral problems is more extreme than previously reported following vmPFC damage but this may represent an extension of prior reports of more severe outcomes following early-onset lesions... 2) There is a complete absence of externalizing and antisocial behavioral problems in B.W.’s family, suggesting a lower likelihood of a genetic predisposition. … 3) B.W. has exceptionally few social risk factors. He has intelligent, extraordinarily caring and motivated parents. They are raising his five siblings without behavioral problems. 4) One could argue that microscopic dysplastic tissue of the left amygdala and anteromedial temporal cortex may also have contributed significantly to B.W.’s behavioral problems. … [but] we believe it is safe to attribute the severe behavioral impairment to B.W.’s vmPFC malformation or the combination of the vmPFC and anteromedial pathology...

My assumption is that all of the testing took place before surgery, which was only mentioned as an afterthought. So we have no measure of long-term outcome. And since he is only 14 yrs old, he cannot (or should not) be diagnosed as a psychopath:

... psychopathy is not normally diagnosed in children or adolescents, and some jurisdictions explicitly forbid diagnosing minors with psychopathy and similar personality disorders. This is because such a diagnosis "fails to capture the emotional, cognitive, and interpersonality traits — egocentricity and lack of remorse, empathy, or guilt — that are so important in the diagnosis of psychopathy."^[65]

However, Boes et al. explicitly asked, “Is B.W. a psychopath?” They seem to think he is but then backed off with the following statement:

We used the Antisocial Process Screening Device, a tool to evaluate “psychopathic tendencies” in children. B.W. scored high in all domains of the test with an overall score in the 99.8 percentile. The authors of this screening tool caution against applying the label psychopath to any child because of its derogatory connotations. In this regard we agree and will instead say that B.W. shares several of the interpersonal and affective characteristics commonly seen in developmental psychopathy.

At any rate, this was the first report of antisocial behavior in an adolescent with congenital abnormalities in this specific region. Although most previously reported patients with vmPFC damage have acquired the lesions as adults, an earlier study by the Iowa group tested two individuals whose lesions occurred before the age of 16 months (Anderson et al., 1999). Those two patients were said to have “defective social and moral reasoning” and “a syndrome resembling psychopathy.” Or as so charmingly stated in the headline of a news article at the time:

Brain Damage Found to Impair Morals

October 19, 1999 | Sandra Blakeslee, New York Times

Scientists have identified rare cases in which injuries to the brain in infancy prevented people from learning normal rules of social and moral behavior in childhood and adolescence. When the infants reached adulthood, they showed no guilt or remorse for their bad behavior and seemed destined never to get along in social situations.

In the case of B.W., it is critical to follow up with additional observation and testing. Did removal of the anatomically and electrically abnormal brain tissue have a positive effect on his behavior?


Footnote

¹ Presumably, the divalproate (Depakote) that controlled his seizures wasn't helping his "bipolar disorder" symptoms, so two different anticonvulsants/mood stabilizers were prescribed. His diagnosis was later changed to "mood disorder not otherwise specified" along with ADHD and oppositional defiant disorder.


References

Anderson SW, Bechara A, Damasio H, Tranel D, Damasio AR. (1999). Impairment of social and moral behavior related to early damage in human prefrontal cortex. Nat Neurosci. 2:1032-7.

Boes, A., Hornaday Grafft, A., Joshi, C., Chuang, N., Nopoulos, P., & Anderson, S. (2011). Behavioral effects of congenital ventromedial prefrontal cortex malformation BMC Neurology, 11 (1) DOI: 10.1186/1471-2377-11-151

Grabenhorst F, Rolls ET. (2011). Value, pleasure and choice in the ventral prefrontal cortex. Trends Cogn Sci. 15:56-67.

Mitchell DG. (2011). The nexus between decision making and emotion regulation: a review of convergent neurocognitive substrates. Behav Brain Res. 217:215-31.

Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson RH. (1985). Complex partial seizures of frontal lobe origin. Ann Neurol. 18:497-504.

An Invitation to Edit a Review Book for Research Signpost

...and we'll only charge you $899!!

Research Signpost

Publishers

December 12, 2011

Official E-mails: editorpandalai@journals.academicpursuits.us, OR Personal ID: rsp.editor.pandalai@journals.academicpursuits.us

Websites: www.ressign.com/home.aspx , www.trnres.com , eBooks: www.signpostebooks.com

Tel: 0091-471-2452918, Fax: 0091-471-2573051

Dear Neurocritic, Related titles can be found at:: www.ressign.com/home.aspx , www.trnres.com and www.signpostebooks.com ; UNSUBSCRIBE Option Given at the End

Research Signpost (www.ressign.com/home.aspx ), leaders in scientific publishing with over 2500 titles of merit, invites you to:

Edit a Conventional Hard Copy, Hard-Bound Review Book in your area of specialization in Neurobiology Research.

The details are given at: www.trnres.com/invitation.html

We will send you the step by step instructions once you evince your interest.

{NOTE from The Neurocritic -- Here are the details:

"We will also be sending alerts to about 5000 scientists working in your area of research internationally to make your work more visible. To support the Open Access e-Publication, a total charge of U.S.$899/- will be levied for a whole book up to 150 pages."}

Kindly consider the same and let me know.

Sincerely yours,

Dr. S.G.Pandalai

Managing Editor.

Neurobiology Research List.

To UNSUBSCRIBE, please hit the reply button and send the mail back with the subject line: ‘UNSUBSCRIBE- Neurobiology Research’

-------------

Dear Dr. S.G.Pandalai,

Thank you for your kind offer, but I will have decline to pay you $899 for editing a review book for Research Signpost.

Regards,
The Neurocritic

Medical Research Paper For Sale: A Laughable Publishing Scam

Medical Research

Medical Research Paper For Sale

Jack,Ph.D.Supervisor

Hello,My name is Jack,Ph.D. Supervisor,
Welcome to My WebSite
E-Mail:medpaper@hotmail.com
TEL:1-888-786-998A

© 2011 Medical Research. All rights reserved.

This morning, I saw a link to 'A university librarian draws up a list of "predatory" open access publishers' (via @carlzimmer):

Beall's List of Predatory, Open-Access Publishers

Predatory, open-access publishers are those that unprofessionally exploit the author-pays model of open-access publishing (Gold OA) for their own profit. Typically, these publishers spam professional email lists, broadly soliciting article submissions for the clear purpose of gaining additional income. Operating essentially as vanity presses, these publishers typically have a low article acceptance threshold, with a false-front or non-existent peer review process. Unlike professional publishing operations, whether subscription-based or ethically-sound open access, these predatory publishers add little value to scholarship, pay little attention to digital preservation, and operate using fly-by-night, unsustainable business models.

I also found a link to Medical Research Paper For Sale, which is so transparently awful that a similar warning needn't be issued. Just for fun, I decided to look into the site anyway. Not surprisingly, RES-MEDICAL.COM is registered through Go Daddy:

Registrant:
wenben zhou
hu li road
jing bei, huabei 885554
China

Registered through: GoDaddy.com, Inc. (http://www.godaddy.com)
Domain Name: RES-MEDICAL.COM
Created on: 29-Oct-11
Expires on: 29-Oct-12
Last Updated on: 29-Oct-11

Administrative Contact:
zhou, wenben resmedicalcom@qq.com
hu li road
jing bei, huabei 885554
China
1-334-646-7777

The link that first came to my attention was this one:

The Brain Structural and Functional Mechanism of Facial Emotion Recognition in Patients with a First Episode of Major Depression

Pages	156
Price	US$70.00

From what I can tell, that document is a dissertation by Tang Yanqing.


But even better is this:

White Matter Tractography by Diffusion Tensor Imaging Play an Important Role in Prognosis Estimation of Acute Ischaemia Stroke

...We examined 28 patients of pyramidal tract strokes at the acute phase （< 3 days） with a marked motor deficit.

Pages	184
Price	US$50.00

Hmm, that looks remarkably similar to this 8 page paper published in the British Journal of Radiology:

Lai C, Zhang SZ, Liu HM, Zhou YB, Zhang YY, Zhang QW, Han GC. White matter tractography by diffusion tensor imaging plays an important role in prognosis estimation of acute lacunar infarctions. Br J Radiol. 2007 Oct;80(958):782-9.

...We examined 28 pyramidal tract stroke patients in the acute phase or early subacute phase (< 3 days) with a marked motor deficit.

© 2007 The British Institute of Radiology

That article is available for free, as a PDF. Perhaps it's part of an author's dissertation in Chinese, but save your $50. You can read the abridged version online, courtesy of BJR.

What I want to know is, who is this bearded Caucasian gentleman at IT Research Paper?

Billy HU, Ph.D
E-Mail:itpaper@hotmail.com
TEL:1-888-786-998A

Meth Really Isn't That Bad for You? (Part 2)

Methamphetamine Use and Risk for HIV/AIDS

... Methamphetamine is very addictive, it can be injected, and it can increase sexual arousal while reducing inhibitions. Because of these attributes, public health officials are concerned that users may be putting themselves at increased risk of acquiring or transmitting HIV infection―a valid concern, considering that methamphetamine use has been linked with increased numbers of HIV infections in some populations [1]. ¹

Meth addiction can cause alterations in brain function and cognitive performance, according to hundreds of published studies (reviewed in Barr et al., 2006; Baicy & London, 2007). However, a new paper concludes that prior studies have exaggerated the harmful effects of methamphetamine on brain structure and function, cognition, mental health, and dental health (Hart et al., 2011).

So who's right? The previous post (Meth Really Isn't That Bad for You... Or is it?) covered the acute effects of meth on cognitive performance. This post will focus on the cognitive consequences of chronic meth abuse. The bulk of the literature suggests that long-term use "leads to neurocognitive deficits in a dose-dependent manner, with deficits relating to both the frequency and severity of METH dependence" (McCann et al., 2008). In that study, chronic meth users performed worse than controls on some tests of memory and attention, with intact performance on other tests. Another paper found similar differences between controls and former meth users (abstinent anywhere from 3 months to over 1o yrs) on some tests but not others (Johanson et al. , 2006). Those authors were cautious in interpreting their findings:

In the present study, MA users showed deficits in the DSST [Digit Symbol Substitution Test] of the WAIS-III relative to the controls. However, neither the mean standard score (9.63) nor individual scores were greater than one SD (3) below the age-controlled norm (10.0). This finding suggests that although MA may produce long-term, possibly irreversible deficits in speed and accuracy of information manipulation, these deficits are relatively small and for some may not reach clinical significance.

...and...

In the present investigation, MA users showed significantly poorer performance on several of the subtests of the CVLT [California Verbal Learning Test] including both cued and noncued short and long delayed recall. However, despite this statistically significant difference compared to controls, their performance was not outside the normal range for their age group. Thus, the functional significance of these differences in memory function is questionable. Nevertheless, it seems likely that these deficits are permanent because they were not correlated with duration of abstinence. It is obvious that the possibility remains that these deficits predated drug use but the present study cannot address this possibility.

These statements were much appreciated in the review article, which repeatedly downplayed observations of poorer performance as having any functional significance whatsoever. However, I will draw your attention to Johanson et al. 's inclusionary criteria and their table below:

To qualify for the study, MA participants had to report at least one 3-month period when they experienced MA-induced toxic symptoms (agitation, sleeplessness, paranoia, or tremors).

Table 5 (Johanson et al. , 2006). Other self-reported symptoms

Clearly, every symptom listed above is of functional significance. Meth use was detrimental to many areas of their lives when they were using. However, those participants were given the cognitive tests a mean of 3.4 yrs after they stopped using. We'll return to the issue of recovery a bit later.

Returning now to the comparison of acute low dose meth vs. chronic abuse, in the abstract Hart et al. (2011) stated:

In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between methamphetamine users and control participants have been observed on a minority of measures.

Let’s take a closer look. Of the 16 studies on the acute effects of meth shown in Table 1 of Hart et al., five of them (by the authors) tested inhibitory control. Meth had no effect on inhibition performance in any of those studies.

Am I just being persnickety? Well, if the authors are going to say that long-term meth abuse results in “poorer performance on a minority of cognitive tasks” [which appears to be true in many cases], they should be more precise when describing their own data. Perhaps something like this: "Acute meth sometimes improves the performance of infrequent users on a minority of cognitive tasks, but these results are inconsistent (see Table 1)."

Again, what about the specific cognitive impairments observed in chronic abusers? There was a didactic paragraph on the use on the word “impairment”:

The literature on methamphetamine use is focused on ‘impairment,’ and seems to conflate two different meanings of this term. One meaning is captured by the canonical situation in which one group of participants performs statistically significantly less well on a task than does a control group. Although there is a statistically significant difference, its clinical relevance, or everyday import, is rarely specified. A second meaning of ‘impairment’ is that of a substantial loss of function, a dysfunction, in which performance may even fall outside of normal range and bears clinical significance. (The two meanings probably represent end points on a continuum of meanings of ‘impairment’ that appears in the general literature on group differences.) The problem in the literature on methamphetamine use is that in many studies the results support only the first or difference interpretation, but the results are discussed in terms of the ‘dysfunctional’ interpretation. In essence, the English word ‘impairment’ (or ‘deficit’) is ambiguous, and researchers in this field often switch meanings in moving from actual findings to discussion of the implications of these findings.

One reason for avoiding use of the word “impairment” is to reduce the stigma attached to meth abuse, which is an important goal. To that end, it’s puzzling that the authors failed to cite some of the literature on recovery.

GREEN RED BLUE

One such paper (Salo et al., 2009) compared 38 recently-abstinent meth abusers (3 weeks to 6 months), 27 longer-abstinent meth abusers (at least 1 yr), and 33 controls on the Stroop Color-Word Interference Test. In this task, the participant is instructed to say the font color and ignore the word. It's much more automatic to read the word than to say the font color, so people are slower to respond when the two dimensions are in conflict ("Stroop effect"). Successful performance on this task requires cognitive control to overcome the routine behavior.

The results suggested that cognitive performance improved with persistent drug abstinence (Salo et al., 2009). The Stroop effect was significantly greater in the recent abstainers (186 msec) than in both the long-term abstainers (138 msec) and the controls (132 msec), who did not differ from each other. Furthermore, the increase in Stroop interference correlated with years of meth abuse, and any relative decrease correlated with the length of abstinence.

The long- and short-term abstainers were very well matched on years of use (13.9 vs. 13.4 yrs), age at first use, current age, and total years of education, yet they still differed from each other. One criticism of Hart et al. is that control groups are often not well-matched to the MA abusers for age and especially for education. The meth abusers typically have less education than controls (perhaps because they started using in their late teens), and this could present a problem in some tasks. In the current study, the same results persisted in an additional analysis that controlled for differences in education and an estimate of pre-meth-use IQ.

In my opinion, the review raises legitimate issues about how certain findings are interpreted, but then waves away all control data as invalid, therefore the addicted folks aren't impaired (in either sense of the term). A paper by Kim et al (2009) merited two paragraphs of critique because there are no published Korean norms for the Wisconsin Card Sorting Task (WCST). This was despite the fact that meth users performed significantly worse than controls (p<.01) on the three WCST measures listed. Then the lower education level of the meth abusers (10.5 yrs vs. 12.4 yrs in controls) was brought up as a confound, because it is "known" that education affects WCST performance. However, one of the cited papers did not demonstrate that at all, because the effects of education were no longer significant when the data were corrected for multiple comparisons.

At any rate, doesn't the fact that the meth abusers were high school dropouts tell you anything?? One suggestion for researchers in the field would be to relate their cognitive and brain findings to functional outcomes in daily life. The literature is rather extensive (and mostly unfamiliar to me), so there might be a raft of papers that have already done this, but went uncited in the review article.

Ending on a positive note, studies finding improvements in cognitive performance and normalization of brain function after quitting the drug offer hope for the future, as noted by Salo et al. (2009):

The understanding of how the human brain may recover or partially recover as a function of extended drug abstinence has important implications both for the neurobiology of addiction as well as substance abuse treatment. If cognitive improvements occur across extended periods of abstinence; this finding would be clinically salient. These cognitive improvements can then be applied in substance abuse treatment programs and utilized as predictors of treatment outcome in vulnerable difficult to treat populations (Streeter et al., 2008).

Footnote

¹ Also see The New Yorker, “HIGHER RISK: Crystal meth, the Internet, and dangerous choices about AIDS” {PDF}.


References

Baicy K, London ED. (2007). Corticolimbic dysregulation and chronic methamphetamine abuse. Addiction 102 Suppl 1:5-15.

Barr AM, Panenka WJ, MacEwan GW, Thornton AE, Lang DJ, Honer WG, Lecomte T. (2006). The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci. 31:301-13.

Hart, C., Marvin, C., Silver, R., & Smith, E. (2011). Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review. Neuropsychopharmacology DOI: 10.1038/npp.2011.276

Johanson CE, Frey KA, Lundahl LH, Keenan P, Lockhart N, Roll J, Galloway GP, Koeppe RA, Kilbourn MR, Robbins T, Schuster CR. (2006). Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers. Psychopharmacology 185: 327–338.

McCann UD, Kuwabara H, Kumar A, Palermo M, Abbey R, Brasic J, Ye W, Alexander M, Dannals RF, Wong DF, Ricaurte GA (2008). Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse 62: 91–100.

Salo, R., Nordahl, T., Galloway, G., Moore, C., Waters, C., & Leamon, M. (2009). Drug abstinence and cognitive control in methamphetamine-dependent individuals. Journal of Substance Abuse Treatment, 37 (3), 292-297 DOI: 10.1016/j.jsat.2009.03.004




...I am a glass human. I am a glass human disappearing in rain. I am standing among all of you waving my invisible arms and hands. I am shouting my invisible words. I am getting so weary. I am growing tired. I am waving to you from here. I am crawling around looking for the aperture of complete and final emptiness. I am vibrating in isolation among you. I am screaming but it comes out like pieces of clear ice. I am signalling that the volume of all this is too high. I am waving. I am waving my hands. I am disappearing. I am disappearing but not fast enough*

-David Wojnarowicz, Memories That Smell Like Gasoline (spiral)