Drug Trials in 'At Risk' Youth

Is it ethical to medicate healthy teenagers "at risk" of developing psychosis to prevent a symptom that may not occur? One such clinical trial in Australia was recently stopped before it could even begin:

Drug trial scrapped amid outcry

Jill Stark
August 21, 2011

FORMER Australian of the Year Patrick McGorry has aborted a controversial trial of antipsychotic drugs on children as young as 15 who are "at risk" of psychosis, amid complaints the study was unethical.

The Sunday Age can reveal 13 local and international experts lodged a formal complaint calling for the trial not to go ahead due to concerns children who had not yet been diagnosed with a psychotic illness would be unnecessarily given drugs with potentially dangerous side effects.

Quetiapine, sold as Seroquel, has been linked to weight gain and its manufacturer AstraZeneca, which was to fund the trial, last month paid $US647 million ($A623 million) to settle a lawsuit in the US, alleging there was insufficient warning the drug may cause diabetes.

Dr. McGorry works at Orygen Youth Health in Parkville (near Melbourne) and is a proponent of early interventions for treating mental illness and substance abuse (McGorry et al., 2011). In discussing psychotic disorders, these authors say:

The importance of timely treatment initiation has been further underscored by new data from the Treatment and Intervention in Psychosis (TIPS) project showing that early treatment had positive effects on clinical and functional status at 2-year and 5-year follow-up in first episode psychosis. These studies showed that reducing the duration of untreated psychosis has longer-term effects on the course of negative symptoms, depressive symptoms, cognitive symptoms and social functioning, suggesting the possibility of secondary prevention of these pathologies in first-episode schizophrenia.

But how about prevention, as opposed to early intervention? Are researchers and clinicians able to predict (with reasonable accuracy) who will develop schizophrenia? The scrapped clinical trial intended to see whether quetiapine would decrease or delay the risk to 15-40 yr old participants who showed "early signs" of developing a psychotic disorder. What are these early signs and prodromal symptoms (Mechelli et al., 2011)?

...a gradual deterioration of global and social functioning and the emergence of attenuated psychotic symptoms. However, not all people with these features progress to develop a full-blown psychotic disorder; 20% to 50% develop psychosis, usually within 24 months, but the remainder do not. Individuals first seen with this clinical syndrome are, thus, said to be at ultra-high risk (UHR) for psychosis.

So anywhere from 50% to 80% of those showing prodromal symptoms and labeled ultra-high risk do not develop a psychotic disorder such as schizophrenia. Can neuroimaging improve this crude level of prediction? Ultimately, disordered thinking, delusions, and hallucinations arise from the brain -- right? -- so we should be able to see some abnormality on an MRI scan. A multi-site study enrolled 182 individuals at UHR for psychosis and 167 healthy controls. Voxel-based morphometry was used to quantify whole brain gray matter volumes, as well as 3 specific regions of interest (ROIs): the left parahippocampal gyrus in the medial temporal lobe (important for memory), the right inferior frontal gyrus (important for attention and cognitive control), and the left superior temporal gyrus (which may be implicated in auditory verbal hallucinations). Two years later, 48 UHR participants (26%) developed psychosis and the others did not.

Compared to controls, all subjects in the UHR group showed gray matter reductions in medial frontal regions, so this result was not predictive of whether full-blown psychosis would occur. Within the UHR group, however, a tiny region in the left anterior parahippocampal gyrus (6 voxels) differed in the UHR who later developed psychosis and those who did not. There were no volume reductions in the other two ROIs.

Figure 2 (adapted from Mechelli et al., 2011). Differences between ultra-high-risk (UHR) individuals who did (UHR-T) and did not (UHR-NT) develop psychosis. The UHR-T individuals had less gray matter volume than did the UHR-NT individuals in the left parahippocampal gyrus, bordering the uncus (MNI [Montreal Neurological Institute] coordinates x, y, and z: –21, 6, and –27, respectively). For visualization purposes, effects are displayed at P < .05 uncorrected.

So basically, only 6 voxels in the entire brain were capable of predicting whether or not a patient at ultra-high risk for psychosis will indeed be one of the 26% to progress to a clinically significant psychotic disorder. To examine the actual diagnostic accuracy, the authors then took gray matter volumes from the peak voxel, performed cross-validation analyses using a predictive linear model, and determined that the average predictive accuracy was only 62% (sensitivity = 61% and specificity = 65%). This means the single voxel measure incorrectly predicted that 39% of healthy UHR would become psychotic, while it missed a diagnosis in 35% who would later develop psychosis.

On the basis of these results would you recommend MRI scans of the left parahippocampal gyrus to refine the cohort given Seroquel to reduce or delay the risk of psychosis? I would say no, especially not if you're Australian (Dazzan et al., 2011). Another paper by many of the same authors reported that of 102 UHR Australians, 28 converted to a psychotic disorder, and these individuals showed volume reductions in frontal [and other] regions, relative to the UHR subgroup who remained healthy (Dazzan et al., 2011). Left parahippocampal gyrus was nowhere to be found. In fact, none of the 3 ROIs from Mechelli et al. were selected as ROIs by Dazzan et al. Furthermore, neither of these papers cited the other, despite the fact that they shared 8 authors in common.

In my view, the results thus far seem disappointing to those looking for the neuroanatomical correlates of psychiatric disorders. What does this mean for future structural MRI studies searching for changes that will predict the onset of psychosis?


References

Dazzan P, Soulsby B, Mechelli A, Wood SJ, Velakoulis D, Phillips LJ, Yung AR, Chitnis X, Lin A, Murray RM, McGorry PD, McGuire PK, Pantelis C. (2011). Volumetric Abnormalities Predating the Onset of Schizophrenia and Affective Psychoses: An MRI Study in Subjects at Ultrahigh Risk of Psychosis. Schizophr Bull. Apr 25. [Epub ahead of print]

McGorry PD, Purcell R, Goldstone S, Amminger GP. (2011). Age of onset and timing of treatment for mental and substance use disorders: implications for preventive intervention strategies and models of care. Curr Opin Psychiatry 24:301-6.

Mechelli, A., Riecher-Rossler, A., Meisenzahl, E., Tognin, S., Wood, S., Borgwardt, S., Koutsouleris, N., Yung, A., Stone, J., Phillips, L., McGorry, P., Valli, I., Velakoulis, D., Woolley, J., Pantelis, C., & McGuire, P. (2011). Neuroanatomical Abnormalities That Predate the Onset of Psychosis: A Multicenter Study. Archives of General Psychiatry, 68 (5), 489-495 DOI: 10.1001/archgenpsychiatry.2011.42

Polka-Dotted Brainbow

...because you know that polka dots are a Fall 2011 Fashion Trend!


No, it's not the Brainbow neuroimaging technique that uses fluorescent proteins to visualize individual neurons (Livet et al., 2007), it's Brains and Bows on Etsy, the e-commerce site that features handmade crafts. This fine polka-dotted brainbow (featuring an anatomically incorrect brain) is on sale for only $3.00:

This is a hand sewn high quality fabric bow! Approzx size: 3 inch x 2 1/2 inch. This bow comes in polk dot fabric that is hand sewn into bow with the cutest-creepiest little PINK brain ever! The bow has an a double prong alligator clip in back. These are limited edition and sure to sell out fast!!!

Other anatomically incorrect handmade crafts include this Crocheted Life Size Brain Plush:



You'll have to shell out $55 for this beauty, however.

This brain is the perfect snack, or a huggable anatomy plush toy, depending on your preference. Or perhaps you know a scarecrow, or a neurology major - but the main reason to get this is because it looks totally cool, especially when sitting non-chalantly on a shelf or coffee table.

Each brain is made to order and will take two weeks to complete, in addition to shipping. Your new brain will have a circumference of about 23 inches (measuring long ways), and about 18 inches around, making it a nice sized plush, or a small pillow.

I don't think this one will make it into the The Museum of Scientifically Accurate Fabric Brain Art....


And just in case the Etsy parody site regretsy wants to start a new category for WTF Brain items for sale (to join the infamous Vaginas), I nominate the truly horrifying Zombie Girl Eating a Bowl full of brains and guts. It's a Cigarette Id Case Business Card Holder Wallet, too!

This is an awesome D.I.Y. business card, ID, or cigarette case that is handmade by me and brand new-- you won't find this design anywhere but here because this is a SHS original!

[It's somehow comforting to know they're not mass produced in Japan...]

...although I do think SweetHeartSinner's Zombie Pinup Pillbox for Birth Control would make a fun gift for that special someone in your life!


Reference

Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450:56-62.

A New Sexual Femunculus?

Figure 3A (adapted from Komisaruk et al., 2011). Group-based composite view of the clitoral, vaginal, and cervical activation sites, all in the medial paracentral lobule, but regionally differentiated. We interpret this as due to the differential sensory innervation of these genital structures, i.e., clitoris: pudendal nerve, vagina: pelvic nerve,¹ and cervix: hypogastric and vagus nerves.


"Femunulus" is a neologism for "female homuculus"

The neuroanatomical definition of homunculus is a "distorted" representation of the sensorimotor body map (and its respective parts) overlaid upon primary somatosensory and primary motor cortices. The figure below illustrates the sensory homunculus, where each body part is placed onto the region of cortex that represents it, and the size of the body part is proportional to its cortical representation (and sensitivity). It's rare to see the genitals represented at all. And if they are present, they are inevitably male genitals.


Homunculus image from Reinhard Blutner.

See the G-Rated [i.e., genital-less] flash explanation of homunculus.


A New Clitoral Homunculus?

To remedy this puritanical and androcentric situation, Swiss scientists at University Hospital in Zurich conducted a highly stimulating study in 15 healthy women to map the somatosensory representation of the clitoris (Michels et al., 2009).

Michels and colleagues began by reviewing the work of Wilder Penfield et al.:

During the last 70 years the description of the sensory homunculus has been virtually a standard reference for various somatotopical studies (Penfield and Boldrey 1937; PDF). This map consists of a detailed description of the functional cortical representation of different body parts obtained via electrical stimulation during open brain surgery. In their findings they relied on reported sensations of different body parts after electrical stimulation of the cortex. Assessment of the exact location was generally difficult and sometimes led to conflicting results. The genital region was especially hard to assess due to difficulties with sense of shame.

In contrast to electrical stimulation of the brain, modern mapping studies have used sensory stimulation to map the penis with fMRI (e.g., Kell et al., 2005). But as of 2009, there were no comparable fMRI studies of female genitalia. So how is such a study conducted, methodologically speaking? Electrical stimulation of the dorsal clitoral nerve was compared to electrical stimulation of the hallux (big toe). It was all very clinical, no sexual arousal involved. Here's the experimental protocol (Michels et al., 2009):

Prior to the imaging session, two self-attaching surface disc electrodes (1 × 1 cm) were placed bilaterally next to the clitoris of the subjects so that we were able to stimulate the fibers of the dorsal clitoral nerve. Before the start of the experiment, electrical test stimulation was performed to ensure that subjects could feel the stimulation directly at the clitoris. In addition, the strength of electrical stimulation was adjusted to a subject-specific level, i.e. that stimulation was neither felt [as] painful nor elicited – in case of clitoris stimulation – any sexual arousal. Functional imaging was performed in a block design with alternating rest and stimulation conditions, starting with a rest condition. ... In addition to the clitoris stimulation, we performed in eight of the recorded subjects a second experimental session, in which we applied electrical stimulation of the right hallux using the same type of electrodes, stimulation and scan paradigm.

Their neuroimaging results revealed no evidence of clitoral representation on the medial wall (i.e., the paracentral lobule, as shown above in Komisaruk et al.'s Figure 3A and the male homunculus). Instead, electrical stimulation produced significant activations predominantly in bilateral prefrontal areas and the precentral, parietal and postcentral gyri, including S1 and S2. Click here to see Fig. 3 of Michels et al., 2009.

However, that experiment involved electrical stimulation of the dorsal clitoral nerve, which was not sexually arousing. What if the stimulation occurred in a more naturalistic fashion?


Even newer clitoral, vaginal, cervical and nipple homunculi?

Now, Komisaruk et al., (2011) have expanded the somatosensory map of female sexual organs by having the participants engage in self-stimulation of the clitoris, vagina, cervix, and nipple while laying in a 3T scanner. For comparison, the investigators stimulated the thumb and the big toe. Should we be concerned about differential movement artifact (of the head, hand, arm, pelvis) in these varied stimulation conditions? We'll leave that question aside for the moment and examine the experimental protocol, which consisted of 30 sec of rest and 30 sec of the various stimulation modalities, each followed by 30 sec rest (in 5 min blocks):

...Control trials consisted of an experimenter rhythmically tapping a participant's thumb or toe in separate trials to establish reference points on the sensory cortex. Experimental mapping trials consisted of participants self-stimulating, by hand or personal device, using “comfortable” intensity, the clitoris, anterior wall of the vagina, the cervix, or the nipple, in separate, randomized-sequence trials. Clitoral self-stimulation was applied using rhythmical tapping with the right hand. Vaginal self-stimulation (of the anterior wall) was applied using the participant's own stimulator (typically a 15 mm-diameter S-shaped acrylic rounded-top cylinder). Cervical self-stimulation was applied using a similar-diameter, glass or acrylic straight rounded-tip cylinder brought to the study by each participant. Nipple self-stimulation was applied using the right hand to tap the left nipple rhythmically...

What's a "comfortable" intensity, and how are we sure the hand and the dildo applied rhythmic tapping of the same frequency and intensity? Looking at Figure 2 below, you'll see that large swaths of lateral sensorimotor cortex were activated on the side contralateral to hand use (i.e., L side of the brain activated by R hand).² These activations seem to cover most of the sensory and motor homunculi, not just the arm, hand, and finger areas.

Figure 2 (adapted from Komisaruk et al., 2011). Three-axis (coronal, sagittal, and transaxial) views of the group-based responses to participant self-applied (clitoris, vagina, or cervix) stimulation ... The arrows indicate the sensory cortical regions activated by the various stimulated body regions. Clitoral, vaginal, and cervical self-stimulation activated the medial paracentral lobule. Note that the perineal (groin) region just lateral to the midline in the paracentral lobule was also activated... There was marked hand-related activation in the postcentral gyrus, and continuation of activation into the supplementary motor area immediately rostral to the sensory cortical responses... The secondary sensory cortex (SII; at the base of the homunculus) was activated under all the stimulus conditions...

To me, it looks like all the midline activations [including the toe activation, not shown here] bleed into motor areas including supplementary motor cortex, which is involved in both planning and inhibiting movement. We aren't given MNI coordinates to precisely locate the activations in 3D space, but my guess is that the clitoral, vaginal, and cervical regions are more overlapping than Figure 3A would lead you to believe. In fact, there is visible overlap between the vaginal and cervical regions, and the authors say this is due to unavoidable cross-stimulation in the cervical condition. Given the amount of motion artifact that likely occurred, a 4-5 mm difference in the foci of activation may not be entirely reliable in this particular study.³

The most surprising finding was that nipple stimulation largely overlapped with the genital regions:

Unexpectedly, nipple/breast self-stimulation activated not only the (expected) thoracic sensory homuncular region, but also the region of the paracentral lobule that overlaps with the region activated by clitoral, vaginal, or cervical self-stimulation. This finding is consistent with many women's reports that nipple/breast stimulation is erotogenic and can elicit orgasms...

The infamous Stuart Brody ["unprotected penile-vaginal sex is the only mature and worthwhile form of sex"] was an author on this paper, and of course he'll use these results as support for his prejudicial and boring view of sex. In my view, this study says nothing about different types of female orgasms and how they might be represented in the brain. There was no explicit mention of whether the women found the self-stimulation arousing at all, but the concluding sentence implies it was perceived as "just pressure." I'd recommend reading Dr Petra as an antidote to Brody.


Footnote

¹ I'm not sure there is one "pelvic nerve" per se in the human female, as opposed to in rats.

² You'll notice that Figure 3A better illustrates the bilateral nature of the activation, however [which could suggest mirror movement on the L side].

³ I'm not familiar enough with the human peripheral nervous system to say whether separate nerves innervate different female sexual regions with no overlap.

References

Kell CA, von Kriegstein K, Rösler A, Kleinschmidt A, Laufs H. (2005). The sensory cortical representation of the human penis: revisiting somatotopy in the male homunculus. J Neurosci. 25:5984-7.

Komisaruk, B., Wise, N., Frangos, E., Liu, W., Allen, K., & Brody, S. (2011). Women's Clitoris, Vagina, and Cervix Mapped on the Sensory Cortex: fMRI Evidence. The Journal of Sexual Medicine DOI: 10.1111/j.1743-6109.2011.02388.x

Michels, L., Mehnert, U., Boy, S., Schurch, B., & Kollias, S. (2009). The somatosensory representation of the human clitoris: An fMRI study NeuroImage.

Body mapping on the brain - revised homunculus from New Scientist.

The Man Who Mistook a Harmonica for a Cash Register

One of the most famous books written by Oliver Sacks, popular author and beloved behavioral neurologist, is The Man Who Mistook His Wife for a Hat. One of the chapters describes the case of a patient with visual agnosia, or the inability to recognize objects.

Below is a conversation between Sacks and Dr. P, the patient with visual agnosia.

I showed him the cover [of a National Geographic Magazine], an unbroken expanse of Sahara dunes.

'What do you see here?' I asked.

'I see a river,' he said. 'And a little guest-house with its terrace on the water. People are dining out on the terrace. I see coloured parasols here and there.' He was looking, if it was 'looking', right off the cover into mid-air and confabulating nonexistent features, as if the absence of features in the actual picture had driven him to imagine the river and the terrace and the colored parasols.

I must have looked aghast, but he seemed to think he had done rather well. There was a hint of a smile on his face. He also appeared to have decided that the examination was over and started to look around for his hat He reached out his hand and took hold of his wife's head, tried to lift it off, to put it on. He had apparently mistaken his wife for a hat! His wife looked as if she was used to such things.

Visual agnosia is caused by an acquired brain injury to high-level object processing areas in lateral occipital and ventral temporal cortices. Primary and secondary visual regions are spared, meaning that basic visual responses are not compromised. Language and naming are intact, as is the ability to identify objects through other modalities (e.g., auditory, tactile).

A case study published in Neuron (Konen et al., 2011) describes a patient similar to Dr. P. Patient SM is a right-handed, 36 year old male who sustained a closed head injury in an automobile accident at the age of 18. He recovered after the accident but was left with visual agnosia and prosopagnosia, an impairment in recognizing faces. The damaged area of his brain was fairly circumscribed¹ and smaller in size than in many other patients with visual agnosia:

The lesion was situated within LOC, anterior to hV4 and dorsolateral to VO1/2, and was confined to a circumscribed region in the posterior part of the lateral fusiform gyrus in the RH [right hemisphere]. Typically, this region responds more to intact objects than scrambled objects and damage to this circumscribed area is likely the principle etiology of SM's object agnosia.

Figure 4 (modified from Konen et al., 2011). Lesion Site of SM in Anatomical Space. (C) Axial view of the lesion site marked in green. The slices were cut along the temporal poles for enlarged representation of occipitotemporal cortex.

In addition, detailed topographic mapping of visual cortex was conducted using fMRI in SM and controls. Responses in early cortical areas (prior to the lesioned fusiform gyrus in the feedforward processing stream) were intact in SM.

Figure 1 (Konen et al., 2011). Topographically Organized Areas and Lesion Site in SM (A) and Control Subject C1 (B). Flattened surface reconstructions of early and ventral visual cortex. The color code indicates the phase of the fMRI response and region of visual field to which underlying neurons responded best. Retinotopic mapping revealed regular patterns of phase reversals in both hemispheres of SM that were similar to healthy subjects such as C1. SM's lesion is shown in black, located anterior to hV4 and dorsolateral to VO1/2. LH = left hemisphere; RH = right hemisphere.

Conversely, the hemodynamic response to object presentation was reduced in the area surrounding the lesion, as expected. But the most remarkable and surprising aspect of the study is that reductions in object-related responses were also observed in the corresponding region of SM's intact left hemisphere. How might this be explained?

...while the RH lesion might be primary, this lesion has remote and widespread consequences, with functional inhibition of homologous regions in the structurally intact hemisphere. Such a pattern raises the question whether the observed brain-behavior correspondence serves as the neural underpinning of the impairment or whether reconceptualizing SM's agnosia in terms of disruption to an interconnected more distributed neural system might be a better characterization of SM's pattern and of agnosia more generally.

The authors discuss their findings in the video below, where Marlene Behrmann mentions that SM mistook a picture of a harmonica for a cash register.

Video Abstract (mp4)

Highlights

► Unilateral lesion of lateral fusiform gyrus in right hemisphere causes object agnosia ► Agnosic patient exhibits normal retinotopy and visual responsivity in visual cortex ► Object-responsive and object-selective responses are reduced in both hemispheres ► Cortical plasticity evident with reorganization of intermediate and higher-order areas


Footnote

¹ The Methods section notes additional damage in the corpus callosum and left basal ganglia.

Reference

Konen, C., Behrmann, M., Nishimura, M., & Kastner, S. (2011). The Functional Neuroanatomy of Object Agnosia: A Case Study. Neuron, 71 (1), 49-60 DOI: 10.1016/j.neuron.2011.05.030