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Trauma Link to Psychosis Is Strengthened

25 June 2005. Does exposure to psychological trauma in childhood—war, natural disasters, child abuse—cause schizophrenia? A new study that assessed childhood trauma, then prospectively measured the appearance of psychotic symptoms, doesn’t answer that question directly, but it suggests that for at least a subset of schizophrenia symptoms, the answer is yes. The work, from Jim van Os at the University of Maastricht, the Netherlands, with Roselind Lieb and Hans-Ulrich Wittchen at Max Planck Institute, Munich, showed a dose-response relationship between the severity of self-reported childhood trauma and later psychoses in a large group of young Germans. The effect of trauma was enhanced in subjects who measured high on a scale of psychotic proneness at the beginning of the study. The results, appearing in the June issue of the British Journal of Psychiatry, support the idea that childhood trauma can promote psychosis later in life, and in particular may bring out or exacerbate symptoms in a subset of susceptible people.

While psychological trauma is clearly associated with depression and other symptoms of post-traumatic stress disorder, a link to psychosis has been unclear. Many previous studies have surveyed populations with existing mental illness and found a high incidence of a history of childhood physical or sexual abuse. To prospectively look for an association between self-reported traumatic experiences and the risk of psychosis, first author Janneke Spauwen and colleagues interviewed 3,021 subjects between 14 and 24 years old at entry to determine their experience of traumatic events. Showing a list of nine horrors ranging from war experience, abuse, rape, and natural catastrophe to a serious accident, the interviewers elicited histories from the subjects. The presence of psychosis or a proneness to psychosis was assessed with a checklist of psychosocial effects, including scales for hallucinations, delusions, paranoia, and psychoticism. Subjects were reassessed an average of 3.5 years later.

The data, based on follow-up of 2,524 men and women, showed that exposure to any trauma at all increased the risk of psychosis, and the effect was strongest for the most stringent definition of psychosis (three or more psychotic symptoms reported vs. zero, one, or two). The odds ratio (adjusted for confounding factors and psychosis proneness at the beginning of the study) was 1.89 (95 percent confidence interval 1.16-3.08) for exposure to any trauma and the occurrence of at least three psychotic symptoms. Beyond the broad categories of trauma, the study did not measure the type of trauma in great detail, except to distinguish severe trauma—engendering feelings of intense fear, helplessness, or horror—which was more strongly associated with later psychosis. The association was the same whether the trauma occurred before age 13 or later in life.

A dose response effect supported the idea that trauma played a causal role in the psychotic symptoms. The odds ratio for psychosis increased with an increasing number of trauma events. The effect of trauma appeared specific for psychosis, as the researchers found no association between self-reported trauma and the occurrence of bipolar disorder or major depression.

Experiencing traumatic events was significantly more likely to produce psychoses in people who scored in the top quartile on tests of psychosis proneness, compared to those in the lower three quarters. The effect size for trauma in those without psychosis proneness was 1.8 percent, while in those with proneness, it was 7 percent. The difference was statistically significant, and showed a synergistic rather than additive effect of childhood trauma on later psychoses in this susceptible group. Of course, the authors concede, childhood abuse itself could affect psychosis proneness, and they did detect a weak interaction between reported trauma at baseline and signs of psychosis proneness.

The results are entirely consistent with many previous retrospective studies showing high levels of childhood abuse and trauma among schizophrenia patients. By relaxing the outcome criteria from a diagnosis of schizophrenia to the presence of any of a broad category of symptoms, the researchers were able in this study to prospectively and convincingly link trauma to a later psychotic state. A handful of other studies have recently used similar designs and along with this report, the results are starting to show a consistent pattern between trauma and psychosis, particularly hallucinations (reviewed in Read et al., 2005). It remains to be seen, however, if the association between trauma and psychotic symptoms also applies to psychotic disorders, including schizophrenia.

More work will be necessary to sort out the mechanisms by which trauma increases the risk of psychosis, but several likely hypotheses exist. Childhood stress affects early brain development, and changes the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. This could contribute to the dopamine abnormalities seen in psychosis. It is also possible that traumatic experiences early in life could directly affect dopamine pathways.

In any case, the study reveals childhood trauma as an often-hidden factor that could explain much of the burden of psychosis that occurs outside of major mental disorders. But what about the psychosis of schizophrenia? As van Os and colleagues have written (Read et al., 2005), the practice of classifying psychotic symptoms as PTSD whenever there is clear evidence of trauma may have led clinicians astray and hindered studies on the possible role of trauma in raising the risk of schizophrenia-like disorders. The current work bolsters the case for taking a symptom-centric view of stress-related mental illnesses, especially in light of the fact that different diagnoses, including post-traumatic stress disorder and schizophrenia, involve common psychotic hallmarks like hallucinations and paranoia.—Pat McCaffrey.

Reference:
Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

Comments on News and Primary Papers
Comment by:  Margaret Almeida
Submitted 28 June 2006
Posted 30 June 2006
  I recommend the Primary Papers

This article supported absolutely what our research clinic is anecdotally experiencing. On more than several occasions we have conducted a Structured Clinical Interview for DSM-IV Axis I disorders (SCID) to find a diagnosis of schizophrenia or schizoaffective disorder. However, in contrast, the clinical chart is describing psychotic symptoms, but the clinical diagnosis is post-traumatic stress disorder alone or perhaps along with borderline personality disorder with depression. All of these cases involved younger clients (18-25 years old), either just beginning mental health services or certainly without a long history of mental health care to reflect on. They also had histories (according to primary care providers) of severe childhood abuse and trauma.

View all comments by Margaret AlmeidaComment by:  Craig Morgan
Submitted 30 July 2006
Posted 31 July 2006
  I recommend the Primary Papers

This is a fascinating study investigating the relationship between psychological trauma and the development of psychotic symptoms using data from the Early Developmental Stages of Psychopathology (EDSP) study conducted in Munich, Germany.

There are a number of interesting findings: 1) Self-reported trauma (any) was associated with experiencing one (OR 1.40; 95 percent CI 1.09, 1.78), two (OR 1.88; 95 percent CI 1.35-2.62) and three or more (OR 2.60; 95 percent CI 1.66-4.09) psychotic symptoms during the follow-up period. While these odds ratios increase linearly with number of psychotic symptoms, when potential confounders, such as urbanicity and psychosis proneness, were controlled for, only the association with three or more psychotic symptoms remained significant (Adj. OR 1.89, 95 percent CI 1.16-3.08); 2) Most specific categories of trauma showed positive associations with psychotic symptoms, particularly at the level of three or more, though only physical threat, natural catastrophe and terrible event to other reached statistical significance (though this may be largely an issue of statistical power); and 3) There was evidence that the association between trauma and psychotic symptoms varied by psychosis proneness. That is, the association between trauma and psychosis was strongest in those with pre-existing vulnerability to psychosis.

There has been recent controversy, at least in the U.K., about the role of trauma in the etiology of psychosis, largely as a consequence of a review paper published by John Read and colleagues which concluded that child abuse is a cause of schizophrenia (Read et al., 2005). Does the study by Spauwen et al. provide support for this conclusion? The findings allow interpretation both ways.

On the one hand, there is a robust association between any traumatic event and subsequent development of three or more psychotic symptoms. There are also indications that this may be a dose-response relationship. Further, this study has a number of methodological advantages over much of what has gone before. The prospective design overcomes many of the concerns regarding potential recall bias and direction of causation, as does the inclusion of a measure of psychosis proneness. The sample was large, and the analyses sophisticated.

On the other hand, it could be countered, the observed association between any trauma and psychotic symptoms was modest (Adj. OR 1.89) and much smaller than that found in other studies (e.g., Janssen et al. (2004) reported an adjusted odds ratio of 7.3 over a 2-year period). The evidence for a dose-response relationship was weak, and when confounders were adjusted for, only the association with the most severe level of psychotic symptoms remained significant. Furthermore, and issues of statistical power notwithstanding, it is important to note that only a small number of specific types of trauma were significantly associated with risk of developing psychotic symptoms, and these did not include sexual abuse. And there remains the ongoing issue of the relationship, if any, between psychotic-like symptoms reported in general population samples and the clinical syndromes of psychosis, particularly schizophrenia.

So, there are reasons to retain a healthy skepticism, particularly in relation to claims that child abuse causes schizophrenia. But equally, the emerging evidence suggests it would be wrong to reject a possible role for psychological trauma out of hand. Studies are becoming more methodologically robust, and that by Spauwen et al. is an example of this. There is, however, clearly a need for much more research. Until this is available, we should remain open-minded.

References:

Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

View all comments by Craig MorganComment by:  Ezra Susser, SRF Advisor
Submitted 9 August 2006
Posted 9 August 2006

I agree with most of the comments already posted by others on the very interesting paper by Spauwen et al on psychological trauma and psychotic symptoms. I'd like to raise just one additional point. This pertains to the specificity for psychotic symptoms. It appears that the study found no relation of these psychological traumas to depression or bipolar disorder, but it isn't clear whether there was any relation to depressive symptoms. It's worth considering this point in the interpretation of the results, because psychological traumas have been related to a number of other conditions in previous studies.

View all comments by Ezra SusserComment by:  Maurits Van den NoortPeggy Bosch
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

We read the paper by Spauwen et al. (2006) with great interest. Their findings suggest a specific relationship between psychological trauma and psychosis. Previous studies already showed that psychological trauma is clearly associated with depression and other symptoms of post-traumatic stress disorder, but the link between childhood trauma and psychosis was controversial. The current finding is very interesting and based on a study with a large data set and a good methodology. However, more research on this topic needs to be done. This research should measure the type of trauma in greater detail since this could give a better understanding of the exact link between trauma and psychosis. Moreover, the focus of future research should be more on the underlying neurological mechanisms by which childhood trauma increases the risk of psychosis. For instance, it would be interesting to conduct neuroimaging studies (Ni Bhriain et al., 2005), that focus on dopamine abnormalities (McGowan et al., 2004) in patients with traumatic experiences early in life.

References:

McGowan S, Lawrence AD, Sales T, Quested D, Grasby P. Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Arch Gen Psychiatry. 2004 Feb;61:134-142. Abstract

Ni Bhriain S, Clare AW, Lawlor BA. Neuroimaging: a new training issue in psychiatry? Psychiat Bull. 2005 May;29:189-192.

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

View all comments by Maurits Van den Noort
View all comments by Peggy BoschComment by:  James ScottJohn McGrath (SRF Advisor)
Submitted 10 August 2006
Posted 10 August 2006
  I recommend the Primary Papers

Spauwen and colleagues add further weight to research linking traumatic experiences and psychotic symptoms (Spauwen et al., 2006). There are now a number of studies showing an association between trauma and psychotic symptoms (Bebbington et al., 2004; Janssen et al., 2004; Sareen et al., 2005; Shevlin et al., 2006; Whitfield et al., 2005). There are also a number of large community-representative studies showing that psychotic symptoms are highly prevalent in community populations (Eaton et al., 1991; Scott et al., 2006; van Os et al., 2000).

Read and colleagues have argued that child abuse may be an etiological factor for schizophrenia in some individuals (Read et al., 2001; Read et al., 2005). In a clinical study of adolescent inpatients who hallucinated, we found using a structured questionnaire and structured clinical interview (K-SADS) that the hallucinations of schizophrenia and those of post-traumatic stress disorder (PTSD) were very similar in form and content (Scott et al., 2006, in press). Thus, clinicians and researchers need to remain mindful of the overlap of psychotic symptoms in these disorders.

A possible explanation for the above is that psychotic symptoms are non-specific experiences. Perhaps they represent a final common pathway to a range of stressors including unemployment, social isolation, migration, substance use and trauma. From a different perspective in relation to trauma, psychotic symptoms may be part of a dissociative process (van der Kolk et al., 1996), and the positive psychotic symptoms in PTSD are phenomenologically difficult to distinguish from those of schizophrenia.

The association between trauma and psychotic symptoms is a fascinating one requiring further objective, open-minded research.

References:

Bebbington PE, Bhugra D, Brugha T, Singleton N, Farrell M, Jenkins R, Lewis G, Meltzer H. Psychosis, victimisation and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity. Br J Psychiatry. 2004 Sep;185:220-6. Abstract

Eaton WW, Romanoski A, Anthony JC, Nestadt G. Screening for psychosis in the general population with a self-report interview. J Nerv Ment Dis. 1991 Nov;179(11):689-93. Abstract

Janssen I, Krabbendam L, Bak M, Hanssen M, Vollebergh W, de Graaf R, van Os J. Childhood abuse as a risk factor for psychotic experiences. Acta Psychiatr Scand. 2004 Jan;109(1):38-45. Abstract

Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry. 2001 Winter;64(4):319-45. Review. Abstract

Read J, van Os J, Morrison AP, Ross CA. Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatr Scand. 2005 Nov;112(5):330-50. Review. Abstract

Sareen J, Cox BJ, Goodwin RD, J G Asmundson G. Co-occurrence of posttraumatic stress disorder with positive psychotic symptoms in a nationally representative sample. J Trauma Stress. 2005 Aug;18(4):313-22. Abstract

Scott J, Chant D, Andrews G, McGrath J. Psychotic-like experiences in the general community: the correlates of CIDI psychosis screen items in an Australian sample. Psychol Med. 2006 Feb;36(2):231-8. Epub 2005 Nov 23. Abstract

Scott J, Nurcombe B, Sheridan J, et al. (2006) Hallucinations in Adolescents with Post-traumatic Stress Disorder and Psychotic Disorder. Australasian Psychiatry, In press.

Shevlin M, Dorahy M, Adamson G. Childhood traumas and hallucinations: An analysis of the National Comorbidity Survey. J Psychiatr Res. 2006 Apr 24; [Epub ahead of print] Abstract

Spauwen J, Krabbendam L, Lieb R, Wittchen HU, van Os J. Impact of psychological trauma on the development of psychotic symptoms: relationship with psychosis proneness. Br J Psychiatry. 2006 Jun;188:527-33. Abstract

van der Kolk BA, Pelcovitz D, Roth S, Mandel FS, McFarlane A, Herman JL. Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry. 1996 Jul;153(7 Suppl):83-93. Review. Abstract

van Os J, Hanssen M, Bijl RV, Ravelli A. Strauss (1969) revisited: a psychosis continuum in the general population? Schizophr Res. 2000 Sep 29;45(1-2):11-20. Abstract

Whitfield CL, Dube SR, Felitti VJ, Anda RF. Adverse childhood experiences and hallucinations. Child Abuse Negl. 2005 Jul;29(7):797-810. Abstract

View all comments by James Scott
View all comments by John McGrathComment by:  Ella Matthews
Submitted 24 August 2006
Posted 27 August 2006

Spauwen and colleagues find that exposure to psychological trauma may increase the risk of psychotic symptoms in people vulnerable to psychoses. The experiences of war, natural disasters and child abuse cannot be good for anyone. Am I wrong to think that these add up to much more than psychological trauma or that such events would also tend to bring on and exacerbate the symptoms of myriad other conditions such as those relating to the heart, lungs and other bodily organs?

View all comments by Ella Matthews

Comments on Related News


Related News: Frontal Cortical Areas Differ in Response to Stress

Comment by:  Patricia Estani
Submitted 31 August 2006
Posted 31 August 2006
  I recommend the Primary Papers

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Andreas Meyer-Lindenberg
Submitted 8 February 2007
Posted 8 February 2007

This fascinating paper contributes to our mechanistic understanding of a fundamental nonlinearity governing the response of prefrontal neurons during working memory to dopaminergic stimulation: the “inverted U” response curve (Goldman-Rakic et al., 2000), which proposes that an optimum range of dopaminergic stimulation exists, and that either too little or too much dopamine impairs tuning, or the relationship between task-relevant (“signal”) and task-irrelevant (“noise”) firing of these neurons. On the level of behavior, this is predicted to result in impaired working memory performance outside the optimum middle range, and this has been confirmed in a variety of species. This is a topic of high relevance for schizophrenia where prefrontal dysfunction and related cognitive deficits, and dopaminergic dysregulation, have long been in the center of research interest (Weinberger et al., 2001), and may be linked (Meyer-Lindenberg et al., 2002). In particular, evidence for abnormally decreased dopamine levels in prefrontal cortex would predict that patients with schizophrenia are positioned to the left of the optimum. This line of thought has recently received impetus from genetic studies on COMT, the major enzyme catabolizing dopamine in prefrontal cortex (Tunbridge et al., 2004). Neuroimaging studies have shown that genetic variants with high COMT activity are positioned to the left, those with lower activity nearer the optimum of the inverted U curve, and that this position predicts nonlinear response to amphetamine stimulation (Mattay et al., 2003), as well as interactions between dopamine synthesis and prefrontal response (Meyer-Lindenberg et al., 2005). Variants with sub- (Egan et al., 2001; Nicodemus et al., 2007) or superoptimal (Gothelf et al., 2005) stimulation were associated with schizophrenia risk. Task-related and task-unrelated prefrontal function reacted in opposite ways to genetic variation in dopamine synthesis, suggesting a tuning mechanism (Meyer-Lindenberg et al., 2005). Recently, interacting genetic variants in COMT have also been found to affect prefrontal cortex function in an inverted U fashion (Meyer-Lindenberg et al., 2006).

A seminal contribution to the cellular mechanisms of the inverted U curve is the paper by Williams (one of the authors of the current study) and Goldman-Rakic in Nature 1995 (Williams and Goldman-Rakic, 1995). In this work, dopamine D1 receptor antagonists were used and shown to increase prefrontal cell activity in low levels, whereas high levels inhibited firing. This implicated a mechanism related to D1 receptors and suggested that the neurons studied were to the right of the optimum on the inverted U curve, that is, their dopamine stimulation was excessive. The present study, from Amy Arnsten’s lab at Yale, further defines the cellular mechanisms underlying the inverted U curve in recordings from PFC neurons of awake behaving monkeys exposed to various levels of stimulation by a dopamine 1 receptor agonist. A spatial working memory paradigm was used, enabling the determination of the degree to which the neurons were tuned by comparing the firing rate to stimuli in the preferred spatial stimulus direction (“signal”) to the firing rate to nonpreferred stimuli (“noise”). The authors recorded both from neurons that were highly tuned (supposedly receiving optimum stimulation) and neurons that were less tuned. As would be predicted from the model, highly tuned neurons did not improve, or worsened, during stimulation, while weakly tuned neurons became more focused in their activity profile. It is not quite clear to me why the previous paper (Williams and Goldman-Rakic, 1995) found neurons that were predominantly to the right of the optimum, while this work identified neurons using a similar paradigm that were either to the left or near the optimum. Perhaps it is because Williams and Goldman-Rakic (Williams and Goldman-Rakic, 1995) screened neurons for a response to the D1 antagonist first. In both studies, extracellular dopamine was not actually measured, meaning that the state of basal stimulation can only be inferred indirectly from the response to the iontophoresed agonist or antagonist. Importantly, the effect of D1 stimulation was always suppressive; effects on tuning were due to the fact that the reduction in response to the signal and the noise were different in extent, such that for weakly tuned neurons and low levels of D1 stimulation, the noise firing was more suppressed than that of the signal, resulting in increased signal to noise. In a second set of pharmacological experiments, which included validation in a rat working memory model, the authors show that these effects are cAMP, but not PKC-dependent, suggesting a preferential cellular mechanism through Gs-proteins, which might be useful for exploration of more specific drug targets.

This work has interesting implications for our understanding of prefrontal function in schizophrenia. Since dopamine stimulation was found to be almost exclusively suppressive, cortical dopamine depletion in schizophrenia would be predicted to lead to relatively increased, but inefficient (untuned) cortical cognitive response, as has indeed been observed (Callicott et al., 2000). However, it is an open question precisely how cortical physiology assessed by imaging relates to these cellular events. The data by Arnsten suggest that each patch of prefrontal cortex will contain a population of neurons at various states of tuning that will respond differently to drug-induced or cognitively related changes in extracellular dopamine, with some improving, some decreasing their tuning. Depending on whether imaging signals and tasks are more sensitive to overall firing rate, or to specific signal-to-noise properties, the resulting blood flow change might be quite different. Perhaps this contributes to some of the puzzling discrepancies between hypo- and hyperactivation both being observed in comparable tasks and regions of prefrontal cortex in schizophrenia.

References:

1. Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301. Review. No abstract available. Abstract

2. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry. 2001 Dec 1;50(11):825-44. Review. Abstract

3. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002 Mar;5(3):267-71. Abstract

4. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. Abstract

5. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. Epub 2003 Apr 25. Abstract

6. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005 May;8(5):594-6. Epub 2005 Apr 10. Abstract

7. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22. Epub 2001 May 29. Abstract

8. Nicodemus KK, Kolachana BS, Vakkalanka R, Straub RE, Giegling I, Egan MF, Rujescu D, Weinberger DR. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet. 2007 Feb;120(6):889-906. Epub 2006 Sep 28. Abstract

9. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. Abstract

10. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry. 2006 Sep;11(9):867-77, 797. Epub 2006 Jun 20. Abstract

11. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995 Aug 17;376(6541):572-5. Abstract

12. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex. 2000 Nov;10(11):1078-92. Abstract

View all comments by Andreas Meyer-Lindenberg

Related News: The New "Inverted U”—Cellular Basis for Dopamine Response Pinpointed

Comment by:  Terry Goldberg
Submitted 6 April 2007
Posted 6 April 2007

In this landmark study, Arnsten and colleagues used a full dopamine agonist in awake behaving monkeys to make key points about the inverted U response at the cellular level and how this maps to the behavioral level. There were a number of surprises. The first was that stimulation of the D1 receptor had consistently suppressive effects on neuronal firing during delays in a working memory task. The second was that when responses were optimized, suppressive effects differentially affected non-preferred directional neurons, rather than preferred direction neurons. Thus, it appeared that noise was reduced rather than signal amplified. Too much D1 stimulation resulted in suppression of both classes of neurons.

The implications of this work are important because it suggests that there is a neurobiological algorithm at work that can reliably produce this unexpected physiological pattern (perhaps as the authors suggest on the basis of baseline activity). It remains to be elucidated whether the D1 receptor effects are mediated by glutamatergic neurons or GABA interneurons, or both. There is another layer of complexity to the story. As Arnsten and colleagues note, possible excitatory influences of D1 stimulation may not have been observed because endogenous dopamine had already triggered this process. It is unclear if D2 receptors in the cortex have a role in shaping or terminating this activity.

Last, it is tempting to speculate about the implications of these findings for other types of tasks that engage prefrontal cortex in humans. What does tuning mean in the context of tasks like the N Back which demands updating, the ID/ED test from the CANTAB, which involves suppression of salient distractors at early set shifting stages, or a task which demands heavy doses of cognitive control like the flanker task, all of which have been shown to be sensitive to manipulations of the dopamine system (Goldberg et al., 2003; Jazbec et al., 2007; Diaz-Asper et al., in press; Blasi et al., 2005)?

View all comments by Terry Goldberg