QALMRIQ Written Assignments Purpose of the QALMRIQ Writing QALMRIQs will help you comprehend the empirical papers that you read on a weekly basis. Empirical papers contain a lot of information and it requires practice to extract the central important questions that are being asked, and the main findings that are being reported. QALMRIQ is an acronym. It stands for the following components of empirical papers: What are the broad and specific questions?, what were the alternative hypotheses, what was the logic of the design, what was the method, what were the results, what inferences about the specific and broad question can be made from the results, what’s the next question? QALMRIQ is a guide to focus your reading so that you can identify these aspects of the articles you read. If you can clearly identify all of these aspects of a journal article, then you are on your way to comprehending the research you read about. The best way to ensure your comprehension is complete is to write it out. Assignment Writing a QALMRI for any research paper is simply writing short answers to each of these questions using clear and concise language. It is a condensed, short-form, version of the research. You should think of this as an efficient way to summarize the paper. If someone hadn’t read the paper, they should be able to get the gist of the paper from your QALMRIQ. You should not copy and paste any sections of the article- these summaries must be entirely in your own words to reflect your own understanding of the content in the article. To be even more specific, your task is to answer these questions for the paper that you read: Question: What was the broad question? What was the specific question? Alternative hypotheses: What were the hypotheses? Logic: If hypothesis #1 was true, what was the predicted outcome? What was the predicted outcome if hypothesis #2 was true? Method: What was the experimental design? Results: What was the pattern of data? What was the main finding? Inferences: What can be concluded about the hypotheses based on the data? What can be concluded about the specific and broad question? Question: What new questions arise from these results? What’s the next step in the research? What remains unknown with regard to the original broad/specific questions? How long is a QALMRIQ? Long enough to answer each question with clear and brief sentences. Should be about one-page (single-spaced). Making Memories: Brain Activity that Predicts How Well Visual Experience Will Be Remembered Brewer, J. B., Zhao, Z., Desmond, J. E., Glover, G. H., & Gabrieli, J. D. (1998). Making memories: brain activity that predicts how well visual experience will be remembered. Science, 281(5380), 1185–1187. Question What was the broad question being asked by this research project? • Why are some things remembered and some things forgotten? What was the specific question being asked by this research project? • What are the neural determinants of remembering/forgetting? Alternatives What was the author’s hypothesis? • H1: Activity in the medial temporal lobe (MTL) during encoding will predict later memory. What were the alternative hypotheses? • H2: Activity in the frontal lobes during encoding will predict remembering versus forgetting. Logic What was the logic of the hypotheses? If the author’s hypothesis is true, what should happen? • If H1, then there will be more activity in the MTL during memory encoding for items later remembered versus forgotten. That is, activity will be correlated with later memory. • If H2, then there will be more activity in the frontal lobes during memory encoding for items later remembered versus forgotten. That is, activity will be correlated with later memory. Methods What were the methods? 6 subjects participated in the fMRI study. In the scanner participants were shown pictures and asked to judge whether each picture depicted an indoor or outdoor scene (memory encoding 2 phase). After scanning, they were given a surprise recognition test. They were shown 96 old and 32 new images and judged whether they had seen the image before. If judged as previously seen, they were also asked whether the judgment was based on a distinct recollection (“remember”) or a less certain feeling of familiarity (“know”). The encoding data was sorted based on performance on the recognition test to compare subsequently remembered, familiar, and forgotten trials. Results What were the important results? There was greater activity in the left and right parahippocampal cortex and right dorsolateral prefrontal cortex (DLPFC) during the memory encoding phase for images later remembered as compared to images later forgotten. That is, activity in both these brain regions were correlated with later memory for images. Inferences What inferences about the hypotheses and questions can be made based on the results? The results of the experiment are partially consistent with both hypotheses. The results showed regions in both the frontal lobes and medial temporal lobe were correlated with later memory for images. However, more specifically the left and right parahippocampal cortex (in the MTL) and only the right DLPFC showed higher activation. This suggests that these brain regions may interact to form memories during encoding. Furthermore, the lateralized activity (right DLPFC) may be specific to visuospatial images. Questions Thinking critically: If the right DLPFC is activated during successful memory encoding of images (visual stimuli), would we expect the left DLPFC would correlate with later memory for verbal materials? Nutrition 21 (2005) 878 – 882 www.elsevier.com/locate/nut Ethics Scientific misconduct and unethical human experimentation: historic parallels and moral implications Alan T. Lefor, M.D., M.P.H.a,b,c,* b a Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA c Center for Graduate Medical Education, Jichi Medical School, Tochigi, Japan Manuscript received June 23, 2004; accepted October 8, 2004. Abstract Although a great deal of human experimentation has been performed to elucidate information otherwise not obtainable, there are many recorded instances of unethical human experimentation. There is also a history of crimes that were committed and disguised as human experiments, best exemplified by the activities of some physicians in Nazi Germany from 1933 until 1945. As a direct result of these activities, a war-crimes trial after World War II resulted in the creation of the Nuremberg Code, to guide future human experimentation. Despite this, unethical experiments were conducted at major academic institutions in the United States in the years after World War II by otherwise normal physicians who did not feel that the Nuremberg Code applied to them personally. There are several possible explanations for such activities, but the desire for personal advancement is prominent among these. Episodes of scientific misconduct such as falsification of experimental data or of personal qualifications seem to be more commonly reported recently and have also been described in the popular press. This activity may also be motivated by desire for personal advancement, giving it a parallel to the conduct of unethical human experimentation. Education may be the best way to prevent these activities that may have similar motivating factors. © 2005 Elsevier Inc. All rights reserved. Until quite recently, the conduct of human experiments was left to individual investigators with little intervention from outside regulators. The risks associated with a laissezfaire attitude toward human experimentation are perhaps best illustrated by the nature and scope of “experiments” performed by Nazi physicians who used concentrationcamp inmates as their subjects. Although the vast majority of this work was of little value because it was poorly designed and lacked properly designed controls, it is natural to wonder what motivated these otherwise seemingly normal physicians to commit unspeakable acts of cruelty disguised as scientific experiments. In a separate category of improper activity, there have been numerous reports in recent times of investigators reporting the results of experiments that have been altered to yield a desired result, which is commonly referred to as “scientific misconduct.” There are examples of such activity * Corresponding author. Tel.: ⫹310-423-5874. E-mail address: alan.lefor@cshs.org (A. Lefor). 0899-9007/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2004.10.011 from the laboratories of highly respected investigators. By examining some events that occurred through history, this report seeks to understand the motivation for such seemingly disparate activities as scientific misconduct and unethical human experimentation and attempts to demonstrate that the motivation of the investigators may be similar. We all must guard against this vigilantly; only through understanding and education can we prevent its recurrence. In reviewing the history of human experimentation, an event sometimes referred to as the first recorded prospective trial, although not designed as a scientific experiment, is described in the Bible, in chapter 1 of the book of Daniel. Daniel’s people eat one kind of food and the king’s men eat another type. After 10 d, the appearance of the study participants was noted, and Daniel’s people “appeared fatter in flesh than did the king’s men.” As a result of this “prospective nutrition trial,” Daniel and his people were permitted to continue to eat their own food rather than be forced to eat the king’s food. Perhaps no chapter in the history of human experimentation evokes the emotion associated with that done under A.T. Lefor / Nutrition 21 (2005) 878 – 882 the auspices of the Nazi regime from 1933 until 1945. Much of this was carried out by German citizens in occupied countries such as Poland. The Nazi government successfully applied a medical metaphor to much of its murderous activity. Physicians used their professional knowledge to advance political goals without regard for their victims. When asked how he could reconcile the use of gas chambers to execute millions of civilians with being a medical doctor, one physician-perpetrator responded “when a body has a gangrenous appendix it must be removed” [1]. The undesirable civilians were simply seen as a diseased organ that had to be excised to allow the healthy development of society. The “experiments” carried out by these physicians can be broadly divided into two categories. The first included experiments that were designed to yield information applicable to military and political goals: cold-water survival, optimal methods of mass sterilization, optimal methods of killing (i.e., thanatology), low-pressure survival, infectious disease studies, etc. Advances in these areas may have been of potential political or military benefit, possibly resulting in rewards to the investigator. One case in point is the cold-water experiments conducted at the Dachau concentration camp, a suburb of Munich, and recently discussed in the literature [2]. These results were discussed at a conference in 1943, and published in the prestigious Zeitschrift für Chirugie in 1943 by Gohrbrandt, where they were portrayed as true scientific experiments [3]. The second group of experiments performed during the Nazi regime can be referred to as “ad hoc” experiments, where the investigator was acting out of self interest to further his private agenda. Perhaps the most famous such investigator was Dr. Joseph Mengele, not even named as a defendant in absentia at the Nuremberg trial, who died in South America in 1979 apparently as a result of drowning after many years living as a fugitive. Dr. Mengele carried out a great deal of work on twins and dwarves, including the establishment of a personal skeleton collection. These experiments were not part of the national agenda, and yet they were reviewed and funded by the Reichsforschungsrat, one member of which was the famous thoracic surgeon, Dr. Sauerbruch. Documents have revealed that Mengele carried out much of his work for his own academic advancement, as partial fulfillment of the requirement for the Habilitation, an advanced academic credential in Germany [4]. Another such ad hoc investigator was Dr. Hermann Voss. Dr. Voss became quite well known after the war as a professor of anatomy at the University of Jena. His VossHerrlinger handbook was a constant white-coat companion of most medical students [5]. Yet during the war Dr. Voss carried out research on the blood content of the spleen by using specimens from the Gestapo guillotine in Posen, in occupied Poland. The Gestapo guillotine was very active against the Polish resistance and supplied Dr. Voss with countless spleens. The bodies were then cremated anonymously. Dr. Voss reflected on the crematorium in his diary: “Yesterday I looked at the furnace in the crematorium. Now 879 it serves to incinerate executed Poles. Looking into such a furnace makes me feel calm and comfortable. How nice it would be to chase the whole Polish population through such furnaces. Then the German people would finally get some rest.” He followed by writing: “I wrote to professor Schoen and asked him to remember me when the chair for anatomy at the University becomes vacant.” This writing of Dr. Voss illustrates the total lack of concern for human life so obvious in this time and his desire to simply use the material at his disposal for his own personal academic advancement. Medicine under the Nazi regime has again been criticized with revelations about an atlas of anatomy drawn by Professor Pernkopf [6]. Although the quality of this reference is excellent, it is possible that some of the anatomic material used to make these drawings came from concentration-camp victims. Older editions of this book still readily available show the swastika symbol embedded in the signature of one of the artists (Mr. Lepier) on many plates in the book, whereas newer editions have that symbol “airbrushed” out of appearance. The publishers have decided to continue the publication of this work and include a statement about the controversy regarding the sources of material used within. Some of the perpetrators of these experiments were tried at Nuremberg (the “doctors’ trial”) and punished after the war ended. Of the 23 physicians who stood trial, seven were executed by hanging. The remaining physicians were imprisoned for different periods, and many resumed the practice of medicine after their release. At the end of the Nuremberg trial, a landmark document was produced, which is referred to as the Nuremberg Code (Table 1). This list of 10 items attempts to specify basic requirements for the conduct of human experimentation. It was by no means the first such attempt to codify this important subject. A British physician, Thomas Percival, developed a fairly similar code in 1803. In 1833 the American physician William Beaumont developed a list of requirements for human research after he had spent 11 y studying his famous patient, Alexis St. Martin, much of it performed while Beaumont cared for St. Martin in his own home. The French physiologist Claude Bernard also developed a code in the late 19th century. What was special about the Nuremberg Code is that it was adopted by many countries, including the United States, as a basic standard of conduct. This was further developed and adopted as the Helsinki Declaration. A pivotal article in the annals of human experimentation appeared in 1966 by Dr. Henry Beecher [7]. In this article, Beecher cited 22 cases of human experimentation carried out largely at university centers in the United States in the years after World War II. These experiments included testicular irradiation, injection of live tumor cells into people, withholding of known effective therapies, and others. It is clear that these subjects had no clear idea of what was being done to them. Many were institutionalized because of retardation or incarcerated prisoners who lacked an opportu- 880 A.T. Lefor / Nutrition 21 (2005) 878 – 882 Table 1 The Nuremberg Code 1. The voluntary consent of the human subject is absolutely essential. 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not be random and unnecessary in nature. 3. The experiment should be so designed and based on the results of animal experimentation and knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. 4. The experiment should be so conducted to avoid all unnecessary physical and mental suffering and injury. 5. No experiment should be conducted when there is an a priori reason to believe that death or disabling injury will occur, except perhaps in those experiments in which the experimental physicians also serve as subjects. 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. 7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment. 9. During the course of the experiment, the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. 10. During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, with the exercise of the good faith, superior skill, and careful judgment required of him, that continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. nity not to participate. Beecher attempted to understand what motivated these American physicians to conduct these experiments, particularly after the exposure of the Nazi activities during World War II. Some American physicians saw the Nuremberg Code as applying to “them” and not “us.” It has been asserted that “the prevailing view was that the Nuremberg medical defendants were Nazis first and last; by definition nothing they did, and no code drawn up in response to them, was relevant to the United States” [8]. The summation by Katz offers a similar response: “It was a good code for barbarians but an unnecessary code for ordinary physicians” [9]. In the United States between 1948 and 1960, even popular magazines had stories about “human guinea pigs” and referred to these subjects as “volunteers” [8]. These articles tended to be non-critical of the work done and portrayed the participants as willing subjects. Thus, a review of “experiments” done by Nazi physicians during World War II on concentration-camp inmates and experiments done in the United States on retarded and incarcerated citizens after World War II and the revelations of the Nuremberg trials demonstrates a possibly similar motive for the investigators, that being the desire for personal advancement, whether political or academic. In a landmark review of science in the Nazi era, Alexander (psychiatric counsel for the prosecution at the Nuremberg Doctors’ trial) explains that “science under dictatorship becomes subordinated to the guiding philosophy of the dictatorship” [10]. In this paper, he suggests that some of these criminal activities were undertaken by the “investigators” to gain acceptance in the Nazi party and the Schutzstaffel. Some of these people were suspected of disloyalty and, as occurs in many criminal organizations, by participating in a crime they become irrevocably tied to that organization. Similar activities are reported regularly today in reference to street gangs in the United States. Alexander concludes that “fear and cowardice, especially fear of punishment or of ostracism by the group are often more important motives than simple ferocity or aggressiveness.” The defining moment for a change in the attitudes toward human experimentation in the United States came in July 1972, when the scope of a non-therapeutic experiment of syphilis became a headline in a Washington, D.C., newspaper. In 1932, 399 black men who had serum positive for syphilis were entered into a trial that consisted of observation only, commonly referred to as the Tuskegee Experiment (named after the town in Alabama where many participants lived). Even after the development of penicillin, these men were not treated, sometimes necessitating significant intervention by governmental agencies. These men were never told of the nature of their disease, nor of the scope of the study. The study was finally terminated in 1972, after 40 y of no treatment. What was to have been a short-term study became a 40-y study simply to salvage scientific data [11]. Once again, now in the late 20th-century United States, the motivations of the researchers for publishing data became more important than the conduct of an ethical trial, thus totally ignoring the lessons of the Nuremberg trials held 26 y before the end of the Tuskegee Experiment. This demonstrates a frightening parallel to the “research” conducted by physicians under the Nazi regime. Further, this “study” continues to play a role in medical politics. The fallout from the Tuskegee Experiment currently hampers education efforts concerning the human immunodeficiency virus in African-American communities because of the distrust and suspicion generated [12]. There have been scientific studies published in prestigious journals that were later demonstrated to be partly or totally falsified. In 1986, Milanese et al. [13] published the discovery of a new cytokine, termed interluekin-4A, as a lead article in the journal Science. However, over the next year, several researchers tried to take advantage of interleukin-4A and, in attempting to repeat the work of Milanese, discovered that it could not be repeated. Eventu- A.T. Lefor / Nutrition 21 (2005) 878 – 882 ally, a public retraction was issued by Milanese that stated that the research was indeed falsified [14]. A related but slightly different form of scientific fabrication has more recently become discussed publicly, that of credentials misrepresentation. In an article that examined the professional credentials of applicants for gastroenterology fellowships, Sekas and Hutson [15] found that research activity could not be confirmed for 34% of applicants. These findings were widely discussed in the medical literature and in the lay press. This problem may be widespread but underappreciated and demonstrates yet another area where scientific dishonesty invades the academic enterprise. The public has more recently been made aware of a large-scale effort by at least one investigator to deliberately falsify data (which included maintenance of two sets of records, one true and the other false) collected for the National Surgical Adjuvant Breast and Bowel Project (NSABP) Study B-06 [16]. Although it is now known that eliminating this investigator’s data from the study had no effect on the validity of the conclusions regarding the therapy of small breast cancers, the motivation that caused this investigator to deliberately submit falsified reports is worth questioning. Other contributing centers have been rigorously audited, with the elimination of more data due to various inconsistencies. The data auditing process was made more rigorous after these events. Mueller also discusses the ethical dilemma caused by the duality of roles of the physician-investigator [16]. Although a physician is bound to care for the patient under one set of ethics, the scientist may view the subject with a different set of ethics. This dilemma may be at the root of other instances of scientific misconduct by physicians. What is the motivation for the submission of fabricated data by respected established investigators? The NSABP provides several rewards to its participants including financial support on a per capita basis for each patient accrued and the inclusion of the names of principal investigators from those centers that contribute the largest numbers of patients in published manuscripts. Once again, it appears that scientific misconduct is based in desire for personal and professional advancement. This investigator wished to be recognized as contributing many patients on “the right side” of the results, which resulted in the inclusion of his name on several publications. Because the public funds a large proportion of medical research, the press has recently increased its coverage of scientific misconduct. It is possible that more studies are based on falsified data. In some cases this has resulted in censure of the individuals involved, and probably in many cases there have been few repercussions because the perpetrators were never caught and their data have never been challenged and no attempts to repeat the experiment as was done in the interleukin-4A fraud published by Milanese. As members of the scientific and professional community, we must ask ourselves where this problem originates. Perhaps it results from a system built to reward those who 881 achieve, thus motivating them to achieve at any cost, even dishonesty. Perhaps the defect resides within each of us and we are ready to take control of our sensibilities to drive us ahead professionally. It may be a combination of these two possibilities. This was Beecher’s conclusion and he felt that young investigators, in their drive to win tenure, were “led to commit ethical errors” [17]. At the time of the publication of Beecher’s article, society was indeed not what it is today. There was less public discussion of ethical issues in research, and more concern with the utility of the research performed. As pointed out by Rothman, this was even more characteristic of U.S. medical research during World War II [17]. However, as discussed above, even after Beecher’s article and after revelations of the Tuskegee study, scientific misconduct continues to plague our research enterprise. One of the most important things we can do to combat this problem is to openly teach and discuss ethical issues in medicine and in science. Although one’s ethical approach begins with what is learned at home as a child, each of us as teachers must also discuss this in the course of formal education. Although misconduct and fraud are not common occurrences, we must guard against it and address the issue [18]. The defect in the individual that resulted in atrocities beyond description under the Nazi regime may be the same defect that results in dishonest reporting of scientific data. Dishonesty is not to be accepted in the medical profession or in the scientific community as a whole. The importance of teaching ethics cannot be underestimated. In a study of trainees who received formal training in ethics, whether or not trainees received the training, they all perceived that too much emphasis was placed on quantity of publications rather than on quality [19]. Interestingly, those trainees who received formal ethics training were more likely to seek input from others in ethical dilemmas. Perhaps we will have to realign incentives in the academic world to remove some of the motivation to perform such acts. Allowing dishonest science to be conducted is but one step along a continuum to the conduct of cruel experiments that are conducted to yield personal rewards. Although certainly conducting dishonest science does not inevitably lead to the conduct of unethical experiments, some of these historical examples do suggest that there may be a common thread, one of personal advancement. Only by policing ourselves and teaching others can we truly realize the admonition of the memorial stone at the Dachau concentration camp: Nie Wieder (Never Again). References [1] Lifton RJ. The Nazi doctors. New York: Basic Books; 1986. [2] Burger R. Nazi science—the Dachau hypothermia experiments. N Engl J Med 1990;322:1435– 40. [3] Gohrbrandt E. Auskühlung. Zentralbl Chir 1943;70:1553–7. [4] Barondess JA. Medicine against society: lessons from the Third Reich. JAMA 1996;276:1657– 61. 882 A.T. Lefor / Nutrition 21 (2005) 878 – 882 [5] Pross C. Nazi doctors, German medicine, and historical truth. In: Annas GJ, Grodin MA, editors. The Nazi doctors and the Nuremberg Code. New York: Oxford University Press; 1992, p. 35–52. [6] Charatan FB. Anatomy textbook has Nazi origins. Br Med J 1966;313:1422. [7] Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354–60. [8] Faden RR, Lederer SE, Moreno JD. US Medical researchers the Nuremberg doctors trial and the Nuremberg Code. JAMA 1996;276:1667–71. [9] Katz J. The consent principle of the Nuremberg Code. In: Annas GJ, Grodin MA, editors. The Nazi doctors and the Nuremberg Code. New York: Oxford University Press; 1992, p. 227–39. [10] Alexander L. Medical science under dictatorship. N Engl J Med 1949;241:39 – 47. [11] Kampmeier RH. Final report in the “Tuskegee Syphilis Study.” South Med J 1974;67:1349 –53. [12] Thomas SB, Quinn SC. The Tuskegee Syphilis Study 1932 to 1972: implications for HIV education and AIDS risk education programs in the black community. Am J Public Health 1991;81:1498 –1504. [13] Milanese C, Richardson NE, Reinherz EL. Identification of a T helper cell-derived lymphokine that activates resting T lymphocytes. Science 1986;231:1118 –22. [14] Milanese C, Richardson NE, Reinherz EL. Retraction of data. Science 1986;234:1056. [15] Sekas G, Hutson WR. Misrepresentation of academic accomplishments by applicants for gastroenterology fellowships. Ann Intern Med 1995;123:38 – 41. [16] Mueller CB. The lumpectomy fraud: Poisson, the National Surgical Adjuvant Breast Project and a crisis of ethics. Arch Surg 1994;129: 1001–3. [17] Rothman DJ. Ethics and human experimentation: Henry Beecher revisited. N Engl J Med 1987;317:1195–9. [18] Ariyan S. Of mice and men: honesty and integrity in medicine. Ann Surg 1994;220:745–50. [19] Pollock RE, Curley SA, Lotzova E. Ethics of research training for NIH T32 surgical investigators. J Surg Res 1995;58:247–51. Psychiatry Research 127 (2004) 9–17 Transcranial magnetic stimulation for auditory hallucinations in schizophrenia Andrew M. McIntosh, David Semple, Katherine Tasker, Lesley K. Harrison, David G.C. Owens, Eve C. Johnstone, Klaus P. Ebmeier* Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Kennedy Tower, Morningside Park, Edinburgh EH10 5HF, UK Received 29 October 2003; received in revised form 13 February 2004; accepted 17 March 2004 Abstract It has been suggested that low frequency transcranial magnetic stimulation (TMS) over left temporo-parietal cortex may reduce the frequency and intensity of auditory hallucinations in schizophrenia. Sixteen patients with hallucinations, treatment-resistant for at least 2 months, were randomised into a placebo-controlled crossover study of TMS at 1 Hz and 80% of motor threshold over left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. Both patients and symptom raters were unaware of the treatment condition. Patients’ hallucination scores improved from baseline with both real and sham TMS, and there was no significant difference between real and sham treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. Previous positive studies could not be replicated with these parameters. TMS is safe if applied within the protocol used. 䊚 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Temporal lobe; Schizoaffective disorder; Auditory verbal learning test 1. Introduction Auditory hallucinations are a striking if not defining symptom of schizophrenia. Some patients continue to suffer from their voices, occasionally in spite of effective treatment of their other symptoms and signs. A recently proposed novel treatment specifically targeting voices is therefore of clinical interest and has attracted wide attention *Corresponding author. Tel.yfax: q44-131-5376505. E-mail address: k.ebmeier@ed.ac.uk (K.P. Ebmeier). (Hoffman et al., 1999, 2000) and attempts at replication (d’Alfonso et al., 2002). Transcranial magnetic stimulation (TMS) is based on Faraday’s law of electromagnetic induction: high intensity electric pulses cursing through an insulated coil are associated with a strong magnetic field (up to 2 T) that can penetrate without hindrance through scalp and scull. In underlying cerebral cortex layers, the magnetic field in turn can induce electric currents and the depolarisation of certain neuron populations. High frequency stimulation 0165-1781/04/$ – see front matter 䊚 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.03.005 10 A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 can result in spontaneous propagation of excitation and eventually seizure activity (Pascual-Leone et al., 1998; Wassermann, 1998), while low frequency stimulation at 1 Hz and less can reduce excitability in underlying cortex (Chen et al., 1997). There is limited evidence that during hallucinations there is increased abnormal activity in the left superior temporal gyrus as part of a distributed network including ‘auditory-linguistic association cortices, caudal and rostral limbicyparalimbic systems, prefrontal cortices, ventral striatum and (nonspecific projection and associative) thalamic nuclei’ (Musalek et al., 1989; Cleghorn et al., 1992; Silbersweig and Stern, 1996; Woodruff et al., 1997; Dierks et al., 1999; Lennox et al., 2000; Shergill et al., 2000a,b). There also seem to be volume reductions of left temporal structures (Levitan et al., 1999), although these are not necessarily associated with functional changes (Havermans et al., 1999). The present study was designed to replicate Hoffman and colleagues’ (Hoffman et al., 2000) experiment in 12 patients, which suggested that inhibitory (1-Hz) stimulation over left temporoparietal cortex can reduce intensity and frequency of auditory hallucinations. Based on Hoffman’s figure 1 (Hoffman et al., 2000), we computed that with a projected 16 patients, a hallucination score mean difference between treatments of approximately 3.75 and a standard deviation of the difference of 3.0 (effect size: 1.25), we should be able to get a significant (P-0.01, two-tailed) result with a power of approximately 0.95 (Dupont and Plummer, 1998). Effect sizes just smaller than 1 would be detectable with a power of 85%. 2. Methods 2.1. Patients Patients referred for TMS from the clinical teams in Lothian with a DSM-IV diagnosis of schizophrenia, schizoaffective or schizophreniform disorders (American Psychiatric Association, 1994) (verified by OPCRIT after inspection of all case notes) were interviewed with a view to obtain their written informed consent. All eligible patients were then referred for an electroencephalograph (EEG). Patients with EEG changes suggestive of an underlying predisposition to epilepsy were excluded. Patients with a history of seizures, head injury or current clozapine treatment were also excluded to minimise the risk of induced seizures. Patients were recruited until 16 had entered the study successfully. They were randomised into two groups of equal size using a computer-generated random sequence prepared before the start of the study. The randomisation code was held by a single researcher (A.M.) with no clinical responsibilities for the referred patients on his person or in a locked filing cabinet. 2.2. Stimulation protocol Eight patients received 1-Hz transcranial magnetic stimulation (TMS) over the left temporoparietal cortex; the remaining eight received the placebo condition ‘sham TMS’ over the same region. After 1 week, the patients randomised to real TMS received sham TMS, and vice versa. TMS was performed by two investigators (A.M. and K.P.E.) at the Royal Edinburgh Hospital. We obtained ethical approval for our study from the Lothian Research of Ethics Subcommittee for Psychiatry and Psychology. Patients, their clinicians and nursing staff were unaware of the group to which they had been randomised. The investigators rating treatment response were also blind to group allocation. 2.3. Real and sham TMS Subjects were seated comfortably with the right forearm supported horizontally with a pillow. They were instructed to keep their hand still but as relaxed as possible. An appropriately sized Lycra cap was placed on the head to enable marking of the TMS coil position. Motor evoked potentials (MEPs) were recorded from the abductor pollicis brevis (APB) muscle of the right hand. Electrodes located at the right APB muscle detected MEP signals via a bio-amplifier; signals were recorded using the Mac Lab TM (AD Instruments Ltd, UK) ‘Scope’ software for Apple Macintosh. We used a 70-mm figure-of-eight coil connected to a Dantec stimulator (Dantec Electronics Limited, Bristol). A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 The coil was systematically displaced (mapping) over the left primary motor cortex, until the largest consistent MEP response from the APB was recorded. Motor threshold (Tm) was then determined. This was defined as the minimum stimulus intensity to produce a MEP response of at least 50 mV from a minimum of five out of 10 consecutive stimuli. Once motor threshold had been determined, 1-Hz stimulation at 80% of threshold was given at a site halfway between the left temporal (T3) and left parietal (P3) electroencephalogram (EEG) electrode sites based on the international 10–20 electrode placement system, as suggested by Hoffman et al. (2000). Sham TMS was administered over the same point, tilting the coil to an angle of 458 away from the skull. Real, or ‘sham’, TMS was administered, following the Hoffman protocol, for 4 min on the first day, 8 min on the second, 12 min on the third and 16 min on the fourth day (Hoffman et al., 2000). A 15-s gap was allowed between each sequential minute of treatment to increase the compliance of patients and check coil position. At the beginning of the second week of treatment, motor threshold was redetermined as described above. 2.4. Outcome ratings Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS) at baseline, and at the end of weeks 1 and 2 (Kay et al., 1987, 1988). A change in the intensity of auditory hallucinations was also rated at the end of weeks 1 and 2 using a 10-point Likert scale where a rating of 10 indicated no change from baseline and a rating of zero indicated a complete remission of hallucinations (Hoffman et al., 2000). As TMS involves stimulation over the temporo-parietal cortex, an area involved in memory and language function, we measured memory using the auditory verbal learning test (AVLT; Rey, 1964 Rosenberg et al., 1984; Geffen et al., 1994). Handedness and pre-morbid IQ were recorded using the Annett Handedness Questionnaire (Annett, 1970; Briggs and Nebes, 1975) and the National Adult Reading Test (Nelson and Willison, 1991), respectively. 11 2.5. Data analysis Statistical analysis was conducted a priori for two main outcome measures, the hallucinations subscale of the PANSS (PANSS-hallucinations) and a patient-rated visual analogue scale of auditory hallucinations (VAS-hallucinations). Potential cognitive adverse effects were examined using the AVLT. Four other outcome measures were also considered (PANSS-positive symptoms, PANSSgeneral psychopathology, PANSS depression, and the PANSS negative symptom subscales). Most outcome measures were administered by the same investigator (D.S.) at baseline, and at the end of the first and second periods. Analyses were conducted using Stats Direct (version 1.9.15; 5 May 2002; www.statsdirect.com). Power analyses were computed with PS Power and Sample Size Calculations by Dupont and Plummer (1998). The distributions of scores on the AVLT and PANSS subscales were examined using a normal probability plot. Where data were normally distributed, parametric statistics were used. In cases where the outcome measure consisted of a count on a small number of scale items (e.g. PANSShallucinations or VAS-hallucinations), or where data were not normally distributed, non-parametric statistics were used. Each patient provided post-TMS and post-shamTMS scores for the period of treatment with real and sham TMS, respectively. The difference between each score was analyzed using a paired ttest for normally distributed data and the Wilcoxon matched pairs test when data were non-normal. Period effects and treatment-period interactions were investigated using the methods suggested by Altman, Pocock and Senn (Pocock, 1983; Altman, 1991; Senn, 2002). This involved comparing the between-period difference for the two treatment orders with an independent t-test for normally distributed data and a Mann–Whitney test for nonnormal data. The presence of a period-by-treatment interaction was examined by comparing the mean period score for the two treatment orders using an independent-samples t-test for normally distributed data or a Mann–Whitney test when this was not the case. A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 12 Table 1 Patients’ age, age at presentation, sex, diagnosis (DSM-IV), total PANSS-score and medication at the time of the study Sex (Age at presentationyage) Diagnosis PANSS score Medication Female (23y37) Schizoaffective 67 Male (24y37)* Female (27y37)* Schizophrenia Schizoaffective 87 87 Male (25y41)* Schizophrenia 64 Female (20y26) Female (30y46)* Schizophrenia Schizoaffective 45 64 Female (19y22)* Schizoaffective 61 Male (21y44)* Schizophrenia 49 Male (41y65)* Male (25y31)** Schizophrenia Schizophrenia 42 79 Male (31y38)* Schizophrenia 76 Female (19y22) Schizophrenia 65 Female (20y39*) Schizophrenia 88 Female (18y38) Schizoaffective 78 Female (24y28)* Male (18y23)* Schizophrenia Schizophrenia 93 76 Thioridazine 450 mg – Sodium valproate 600 mg Thioridazine 650 mg Zuclopenthixol 600 mg weekly – Carbamazepine 400 mg – Fluoxetine 20 mg Zuclopenthixol 500 mg weekly – Olanzapine 10 mg – Fluoxetine 20 mg – Procyclidine 10 mg Olanzapine 20 mg Flupenthixol 40 mg 3 weekly – Amitriptyline 150 mg – Procyclidine 10 mg Carbamazepine 1200 mg – Pericyazine 150 mg – Clomipramine 75 mg – Zuclopenthixol 400 mg weekly Zuclopenthixol 500 mg weekly – Chlorpromazine 200 mg – Diazepam 4 mg – Temazepam 20 mg – Procyclidine 15 mg Carbamazepine 600 mg Trifluoperazine 15 mg – Procyclidine 15 mg – Imipramine 150 mg Flupenthixol decanoate 250 mg weekly – Olanzapine 20 mg – Paroxetine 50 mg Zuclopenthixol 400 mg 3 weekly – Procyclidine 10 mg Flupenthixol decanoate 40 mg weekly – Chlorpromazine 400 mg – Pericyazine 20 mg Lithium 600 mg – Pericyazine 120 mg – Amitriptyline 150 mg – Carbamazepine 600 mg – Diazepam 10 mg Fluphenazine 50 mg weekly Sulpiride 400 mg – Pericyazine 10 mg – Quetiapine 750 mg *Previously on clozapine; **started on clozapine after TMS trial. 3. Results 3.1. Descriptive data of patients Of 24 patients referred to the study over a period of 2 years, five did not meet the diagnostic criteria. Of the 19 eligible patients, three had EEG abnormalities precluding participation. The remaining 16 patients were randomised to equalsized groups to receive TMS or sham TMS first. No patient dropped out of the study, although many complained of headaches during the active treatment week. Table 1 gives medication status and clinical information for each patient. Table 2 shows the demographic descriptive data and bas- eline measures for memory performance and symptom scores. Although patients on clozapine were excluded from the protocol, we found that 11 of 16 patients had previously received clozapine (licensed in the UK for treatment-resistant illness). One further patient was started on clozapine after completing the course of TMS. Three of the 16 patients were left-handed with mean handedness scores of 19.9 (S.D. 4.3) for the right-handers and y17.7 (S.D. 4.9) for the left-handers. 3.2. Treatment effects No significant effects of TMS on symptom and memory measures were found. Mean or median A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 13 Table 2 Baseline characteristics of patients divided by randomisation group TMS First Ns8 TMS Second Ns8 All Ns16 PANSS General psychopathology wmean (S.D.)x Positive symptoms wmean (S.D.)x Negative symptoms wmedian (IQR)x* Hallucinations item wmedian (IQR)x 36 (6.8) 18.1 (4.3) 17.5 (9) 5.25 (1) 33.9 (8.4) 19.3 (6.2) 20 (15) 5 (2) 34.3 (7.7) 18.6 (4.9) 19.5 (10.5) 5 (1) IQ & AVLT NART(Verbal IQ) wmean (S.D.)x AVLT wmean (S.D.)x 99 (15.1) 35 (6.5) 104 (7.9) 32.4 (11.6) 100.9 (12.1) 33.8 (8.7) 35.3 (8.7) 23.9 (4.7)) 3 (37.5) 822 (823) 36.5 (13.4) 24.3 (7.5) 4 (50) 430 (221) 35.9 (10.9) 24.1 (6.0) 7 (43.7) 626 (616) 11.0 (6.1) 12.1 (8.7) 11.6 (7.3) Demographic and historical data Age wmean (S.D.)x Age at presentation wmean (S.D.)x Sex wnumber male (%)x Chlorpromazine equivalents (CPZ) wmean (S.D.)x (Bazire, 2001)a Illness duration from first presentation wmean (S.D.)x * a Median and interquartile range are given for non-normally distributed data. Additionally, assuming that olanzapine 10 mg;CPZ 100 mg; quetiapine 250 mg;CPZ 100 mg. improvement of all but the hallucination scores, however, consistently appeared somewhat better in patients when receiving TMS as opposed to sham TMS (Table 3). The Likert scale for hallucinations (Hoffman et al., 2000) and the PANSS-hallucination subscale scores were highly correlated after TMS (rs0.72, 95% CI: 0.34–0.89) and after sham treatment (rs0.72, 95% CI: 0.31–0.91) when two outliers with scores of zero on the Likert scale had been removed (a number of patients believed that the sham condition had been the active treatment). A trend for a period effect was found for the PANSS-auditory hallucination subscale. Patients improved more after the second than the first week Table 3 Outcome measures for baseline, TMS and TMS given with 458 angled coil (sham) Baseline* After TMS* After sham* TMSysham 33 (9.4) 17.6 (6.4) 34.7 (8.9) Mean difference (95% CI) y0.38 (y3.4 to 2.7) y1.1 (y2.8 to 0.5) 2.6 (y1.5 to 6.7) 19 (7) 4 (2.5)a 3.0 (2.5) 8 (4.75) Median difference (95% CI) y0.5 (y1.5 to 0.5) 0 (y0.5 to 0.5) 0 (y1 to 0) 0 (y0.5 to 1.5) Normally distributed PANSS general PANSS positive AVLT 34.3 (7.7) 18.6 (4.9) 33.8 (8.7) 32.6 (9.1) 16.4 (5.6)a 37.3 (10.4) Non-normal data PANSS negative PANSS hallucinations PANSS depression VAS hallucinations 19.5 (10.5) 5 (1) 3.0 (2.75) 10 (0) 18.5 (10.5) 4 (1.75)a 2.5 (2.75) 9 (5.75) * Means and standard deviations are shown for normally distributed interval data medians; and inter-quartile (IQR) ranges are shown otherwise. a Significantly smaller than baseline (d.f.s15, P-0.05), paired t-test for normally distributed data, Wilcoxon Signed Rank Test otherwise. A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 14 Table 4 Period difference (1sty2nd period) and ;average (by randomisation group). The comparison of group averages for between-period differences (two left columns) yields period effects; while period-by-treatment interactions can be computed from the period average scores of the two randomisation groups (two right columns; Altman, 1991; Pocock, 1983; Senn, 2002) Period difference Normally distributed Mean (S.D.) PANSS general PANSS positive AVLT Non-normal data Median (IQR) PANSS negative PANSS hallucinations* PANSS depression VAS hallucinations * Period average TMS 1st TMS 2nd TMS 1st TMS 2nd 1.0 (4.8) y0.4 (3.3) 0.9 (5.8) 1.8 (6.5) 1.9 (2.8) y4.1 (8.8) 33.3 (9.4) 16.1 (5.4) 35.6 (6.2) 32.4 (8.8) 17.9 (6.4) 36.4 (11.2) 0.5 (3.25) 0 (1) 0 (0.75) 0 (2) 1 (2.75) 0.5 (1) 0 (0.75) 0 (1) 19.25(10.5) 4.5 (2.25) 3 (3) 8.5 (4) 18.25 (11.25) 3.75 (1.875) 2.25 (2.5) 9.5 (5) Median period differences0.5, CIs0–1, d.f.s15, Ps0.05, two-tailed. (Table 4). No significant treatment-by-period interaction was found. In order to test for the presence of carry-over or priming effects, parallel group comparisons were made for the first and second periods of treatment separately. This post-hoc analysis was made on the grounds that if such effects existed, then the difference between real and sham TMS would be significant during the first period when no other treatment condition had been received, or the second if patients had acquired the experience to be able to differentiate between real and sham TMS. However, the between-group treatment differences in all outcome measures failed to reach statistical significance. Four of the 16 patients were medicated with carbamazepine; their median PANSS hallucination score difference after real TMS was y1, with a 95%-CI of y2 to 1, i.e. they lacked a treatment response similar to the whole group. There was no treatment-by-laterality interaction, suggesting that the left-handers did not have a significantly different response to TMS from that of the right-handers. 4. Discussion 4.1. Reasons for non-replication: patient characteristics We were thus not able to replicate Hoffman’s results (Hoffman et al., 2000) in a larger sample of patients and using a very similar method. A number of possible reasons have to be considered. If the actual effect size were in the small to medium range, our study would have been underpowered. However, for the effect size predicted by the Hoffman study, the chance of missing a significant result was less than 15%. Further, our patient sample could consist of different types of patients compared with the Hoffman sample. We required 2 years to collect the target number of 16 patients. This suggests that patients were not representative of admissions. Our criteria were possibly more inclusive than Hoffman’s in that patients had to suffer from hallucinations for only 2 months before admission to the trial, not 6 months. In all cases, however, auditory hallucinations were a feature of both the presenting illness and subsequent admissions to hospital. Between admissions, most patients also complained of persistent auditory hallucinations. Some patients described brief periods of remission over the many years of illness, although in all patients auditory hallucinations had in fact been present for at least 3 consecutive months before TMS was considered. The frequency of previous (and subsequent) treatment with clozapine (12 out of 16 patients) also suggests treatment resistance, as this is one of the two indications for this drug in the UK. It is, therefore, striking that symptom scores improved both after real and sham TMS in our study, while Hoffman’s A.M. McIntosh et al. / Psychiatry Research 127 (2004) 9–17 patients did not improve at all after sham TMS. This placebo phenomenon is not entirely new, as past treatment fads in schizophrenia have demonstrated (Carpenter et al., 1983; Wagemaker et al., 1984). 4.2. Reasons for non-replication: treatment parameters Both studies used 458 tilting of the coil as the sham condition to minimise magnetic field effects in the cortex. However, since planning the trials, it has been suggested that tilting of the coil can reduce the effective field by as little as 50% (Lisanby et al., 2001). Seeing that stimulation strength was 80% of motor threshold, however, we think it highly unlikely that hallucination scores improved in the sham condition due to specific TMS effects. This result is more likely due to placebo or time effects, consistent with the open trial result of d’Alfonso et al. (2002) and the single case report of Franck et al. (2003). Other possible explanations for the lack of a specific treatment response would be inadequate stimulation strength in the active condition (80% of motor threshold, which was, however, also used in the positive original study), duration of treatment wthis may be inferred from the recent report of successful treatment at 90% motor threshold over 9 days (Hoffman et al., 2003) (fig 3 ibid.)x and inaccurate positioning of the stimulation coil. In order to improve compliance with the protocol in seriously distressed psychiatric patients, we inserted a 15-s gap after each minute of stimulation. This allowed us to check the coil position at regular intervals, but may have interfered with the quenching effect of the stimulation. Coil position could be further improved by stereotactic positioning using the patient’s magnetic resonance scan or even functional scans that mark activity related to hallucinatory experiences. Similarly, visible temporal lobe atrophy or dystrophy (Levitan et al., 1999) with increased distance between coil and cortex could be compensated for by an appropriate increase of stimulation strength. A useful finding of the present study is that verbal memory measured at the end of each treatment week was not affected by real or sham TMS, thus adding information to the 15 safety profile of TMS (d’Alfonso et al., 2002; Hoffman et al., 2003). 4.3. Anatomy of hallucinations There is a great variability in subject responses to identical task conditions, as demonstrated by the modern methods of functional brain imaging, such as blood oxygen level dependent functional magnetic resonance imaging (fMRI). It is, moreover, far from certain that superior temporal activation is a necessary condition, and it is clear that it is not a sufficient condition for the experience of auditory hallucinations. Brain circuits involved in the production of auditory hallucinations are widespread and include basal ganglia (Busatto et al., 1995; Shergill et al., 2000b), cerebellum (Shergill et al., 2000b), inferior frontal cortex (Griffiths, 2000), anterior cingulate (Doris et al., 1995; Blakemore et al., 2000), planum temporale (Hunter et al., 2003), left superior temporal cortex (Musalek et al., 1989; Cleghorn et al., 1992; Silbersweig and Stern, 1996; Woodruff et al., 1997; Dierks et al., 1999; Lennox et al., 2000; Shergill et al., 2000a,b), and Wernicke’s area (Stephane et al., 2001). It is further possible that the pathological anatomy of hallucinations differs between subjects, as does in fact the phenomenology. The ideal paradigm to examine such variations would be the combination of fMRI to identify the locus of activation during the hallucination with stereotactically guided TMS. Acknowledgments We thank the Stanley Medical Research Institute for their generous support. 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