Most of you have probably heard about "Surviving Schizophrenia, 6th Edition: A Family Manual," by E. Fuller Torrey. It's a classic but, in my opinion, still worth reading.
I, and my family, are forever indebted to Chuck for his kindness and support. Chuck was chair at Case Western Reserve University Department of Psychiatry and brought me and my wife Leonie to America in 1992, thus changing our lives and giving us great opportunity. Chuck was a lifelong friend and mentor to me and I know to many other colleagues. He was always supportive and took great pleasure in advancing others as part of his commitment to move the profession of psychiatry and schizophrenia research forward. Chuck was fun to be with and always a gracious host, most notable in his co-leadership of the International Congress on Schizophrenia Research, itself a remarkable gift to the field from Chuck and his colleague and friend Carol.
I will sorely miss Chuck though I will always feel immensely grateful to have had the gift of his friendship and mentorship.
“A Dheis De Anam“
... an Irish farewell wish, which translates as ...
“May he rest at God’s right hand.”
Chuck Schultz was a wonderful person who gave creatively and generously to those of us involved in the care and understanding of persons with schizophrenia and to those who suffer from this and related disorders. My almost 40 years in the field with him have been an uninterrupted pleasure. Most of all I appreciate the gift to the field that he and Carol Tamminga have provided with the ICOSR. Will miss his gentle spirit, robust ideas, and smooth humor.
Chuck's passing leaves a void in the field of schizophrenia research. His was such a genuine and lasting love of studying schizophrenia, which I saw from the time that we met as clinical fellows at NIH until his last Congress meeting in 2017, where I had to call him with meeting updates! He never disengaged from doing schizophrenia care or research even though his life became busy with administrative responsibilities. Our collaboration around the International Congress on Schizophrenia Research generated a setting where he worked hard to provide a marvelous forum for the best, the newest and the most innovative research. It was always Chuck's favorite time, where he met, talked and planned with researchers from around the world. He was keen on every good idea, advantaged young investigators at every step, and had endless enthusiasm for the emerging science around schizophrenia. He leaves a legacy of care, commitment and contributions which I will always remember. And many good stories from the International Congress!
Place cells are neurons in the mammalian hippocampus that fire if the animal is in a specific place. The discovery of place cells in rats in the 1970s was awarded a Nobel Prize in 2014. Place cells have been the focus of intense study, because place cell dynamics may play a central role in mediating the important memory functions associated with the hippocampus, including spatial and episodic memory (O’Keefe, 2014).
Zaremba et al. used two-photon calcium imaging of hippocampal place cell firing in head-fixed mice performing a goal-location learning ("goal-oriented learning," GOL) task on a treadmill, to study the relationship between place cell dynamics and behavior in wild-type (WT) mice and in Df(16)A+/− mice, an animal model of human 22q11.2 deletion syndrome. This study has implications for our fundamental understanding of how place cell dynamics may mediate goal-directed learning. Moreover, 22q11.2 deletion is one of the strongest identified risk factors for schizophrenia (schizophrenia) in humans and associated with the development of schizophrenia in up to one third of all cases, although this mutation accounts for < 1% of all schizophrenia cases (Karayiorgou et al., 2010). Therefore, the changes in place cell dynamics and task performance in the Df(16)A+/− mice may have implications for our understanding of cognitive deficits, in particular memory deficits, in schizophrenia. Indeed, the authors propose that "impaired hippocampal ensemble dynamics may be a central component of cognitive memory dysfunctions emerging from the 22q11.2 DS [deletion syndrome] and schizophrenia in general." My comments will focus on two challenges in applying the findings of this study to neuro-cognitive deficits in schizophrenia.
First, it remains to be clarified how behavioral deficits on the GOL task relate to cognitive deficits in schizophrenia. The task was carefully chosen, so as to facilitate the combination of hippocampal two-photon imaging of place cell activity with behavioral testing of goal-location learning and memory. The authors suggest "that the memory deficit revealed by the GOL task is reminiscent of episodic memory deficits." However, episodic memory is the memory of unique events and assays of episodic-like memory in animal models are, therefore, based on one-trial learning (Morris, 2001). In contrast, the GOL task involves multi-trial learning across several days. In the Introduction of their paper, the authors point to "a central role of [the hippocampus] in the pathophysiology of cognitive memory deficits in schizophrenia." Their experiment using functional inhibition of the hippocampus by muscimol shows that aspects of the GOL task require the hippocampus and may, thus, be suitable to probe hippocampal dysfunction relevant to the memory deficits in schizophrenia. However, the part of the GOL task demonstrated to require the hippocampus (i.e., the initial learning of the goal location on the treadmill, as well as the expression of this memory) is actually not disrupted in Df(16)A+/− mice, and it remains to be demonstrated that those aspects of the GOL task that are impaired in Df(16)A+/− mice require hippocampal function.
The main impairment in Df(16)A+/− mice was evident following a change in the environmental context: a context change disrupted performance in the Df(16)A+/− mice, whereas it left WT mice largely unaffected (Fig. 1C, Condition II). This increased context sensitivity is not really in line with a deficit in episodic-like memory, i.e. the memory of specific events and their spatio-temporal context (Morris, 2001), which – if at all – would rather be reflected by decreased context sensitivity. It is also decreased, rather than increased, context sensitivity that has typically been associated with hippocampal dysfunction (e.g., Maren & Holt, 2000; Good et al., 2007).
An interesting possibility, raised by the authors in their Discussion, is that the increased context sensitivity reflects "a misattribution of salience to irrelevant cues." This may be relevant to the schizophrenia-related phenotype of Df(16)A+/− mice, given that impaired salience allocation/selective attention has been implicated in psychotic symptoms, and could be confirmed using dedicated assays of salience allocation/selective attention (e.g., latent inhibition or blocking paradigms) (Gray et al., 1991; Kapur, 2003; Fletch and Frith, 2009). In addition, the authors suggested that Df(16)A+/− mice were impaired in learning a new goal location on the treadmill when tested in the familiar context again. However, Df(16)A+/− mice actually learnt the new goal location at a similar rate to WT mice, it was just that they started from a lower baseline (Fig. 1C, Condition III), which may again reflect a disruption caused by the context change.
Second, it remains to be clarified how the abnormal hippocampal place cell dynamics relate to key neural biomarkers of hippocampal dysfunction in schizophrenia. More specifically, metabolic hippocampal overactivity at rest, alongside impaired hippocampal recruitment during tasks normally requiring hippocampal activation, has emerged as a key feature of schizophrenia pathophysiology; this may reflect a deficient hippocampal inhibitory GABA system, as suggested by abnormal post-mortem markers of GABA function (Heckers and Konradi, 2015; Bast et al., 2017). Interestingly, using electrophysiological recordings, the authors showed a "dysregulation of hippocampal excitability during periods of rest" in Df(16)A+/− mice, as reflected by increased rate and power of hippocampal sharp-wave ripples (SWR) activity. In addition, previous experiments suggest reduced activity of hippocampal inhibitory GABA interneurons in these mice (Drew et al., 2011). SWRs reflect synchronous burst firing of hippocampal neuron populations (Csicsvari et al., 2000) and reduced hippocampal GABA function increases hippocampal burst firing (McGarrity et al., 2017). Therefore, the increased hippocampal SWR activity in Df(16)A+/− mice points to increased hippocampal activity at rest due to impaired GABA function, reminiscent of hippocampal pathophysiology in schizophrenia (Heckers and Konradi, 2015; Bast et al., 2017).
As discussed by the authors, the abnormal place cell dynamics may be a consequence of the aberrant SWR activity, although this remains to be clarified. Another possibility that should be considered is that aspects of the abnormal place cell dynamics in Df(16)A+/− mice are a consequence (rather than a cause) of abnormal GOL task behaviour. For example, as discussed by Zaremba et al. and supported by their data from WT mice, goals and motivational factors can be reflected in place cell firing. Therefore, changed place cell dynamics in Df(16)A+/− mice during later testing stages of the GOL task (i.e., during Conditions II and III) may partly reflect that these mice were less focused on the goal locations or that they received less reward.
Overall, the neurophysiological studies by Zaremba et al. offer intriguing insights into the relation of hippocampal place cell dynamics and behavior, as well as into alterations of this relation in Df(16)A+/− mice, a genetic mouse model relevant to schizophrenia. However, the significance of these alterations for memory deficits in schizophrenia remains to be clarified. In this respect, a more detailed characterization of the behavioral phenotype of Df(16)A+/− mice, using translational assays of clinically relevant neuro-cognitive functions, would be useful.
Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition.
Bast T, Pezze M, McGarrity S
Br J Pharmacol. 2017 Oct; 174(19):3211-3225.
Ensemble patterns of hippocampal CA3-CA1 neurons during sharp wave-associated population events.
Csicsvari J, Hirase H, Mamiya A, Buzsáki G
Neuron. 2000 Nov; 28(2):585-94.
Evidence for altered hippocampal function in a mouse model of the human 22q11.2 microdeletion.
Drew LJ, Stark KL, Fénelon K, Karayiorgou M, MacDermott AB, Gogos JA
Mol Cell Neurosci. 2011 Aug; 47(4):293-305.
Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia.
Fletcher PC, Frith CD
Nat Rev Neurosci. 2009 Jan; 10(1):48-58.
Context- but not familiarity-dependent forms of object recognition are impaired following excitotoxic hippocampal lesions in rats.
Good MA, Barnes P, Staal V, McGregor A, Honey RC
Behav Neurosci. 2007 Feb; 121(1):218-23.
The neuropsychology of schizophrenia.
Gray JA, Feldon J, Rawlins JNP, Hemsley DR, Smith AD.
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GABAergic mechanisms of hippocampal hyperactivity in schizophrenia.
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Schizophr Res. 2015 Sep; 167(1-3):4-11.
Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.
Am J Psychiatry. 2003 Jan; 160(1):13-23.
22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia.
Karayiorgou M, Simon TJ, Gogos JA
Nat Rev Neurosci. 2010 Jun; 11(6):402-16.
The hippocampus and contextual memory retrieval in Pavlovian conditioning.
Maren S, Holt W
Behav Brain Res. 2000 Jun 01; 110(1-2):97-108.
Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits.
McGarrity S, Mason R, Fone KC, Pezze M, Bast T
Cereb Cortex. 2016 Aug 22.
Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease.
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O´Keefe, J. (2014) Nobel Lecture: Spatial Cells in the Hippocampal Formation. Nobelprize.org. Nobel Media AB. Web. 12 Sep 2017.
An often replicated finding in psychology is that what we see and hear of the world around us is colored by what we expect to see and hear, such that the actual perception of an object or a sound is the combination of the sensory input and our stored memories and prior expectations. Another way of expressing this is to say that our perceptions are the sum of bottom-up sensory input and top-down cognitive modulations. In perceptual and cognitive psychology, the expectations that people carry with them and which shape their perceptions are called “priors,” which can be more or less salient. Perceptual errors, like visual illusions, may then be seen as a mismatch between the sensory input and these “priors,” for example, the illusion that the fishing rod is broken if it is dipped into the water.
In their study of hallucinations, Powers et al. found that strong “priors” can induce beliefs about perceptual experience in the absence of a corresponding sensory input. In other words, strong priors can induce a conviction that a perceptual experience has an external cause, although there is none, as when individuals are convinced that they “hear a voice” although there is no one speaking to them. This is an auditory hallucination, and one of the most debilitating symptoms in schizophrenia. The advent of modern brain imaging techniques, and especially functional magnetic resonance imaging (fMRI), made it possible to record blood flow in the brain when subjects solved various cognitive tasks, or when they were hallucinating (see Kompus et al., 2011; Hugdahl, 2015; Sommer et al., 2008). A typical brain activation pattern in the temporal lobe language area during auditory hallucinations is seen in Figure 1.
Although previous fMRI studies have shown how the brain is involved in hallucinations, it has not been known how the brain constructs such non-real percepts, and if they are caused by misinterpreted inner speech or by a perceptual mismatch between bottom-up perceptual and top-down cognitive influences.
The study by Powers et al. is, in this respect, an important contribution to a better understanding of the underlying mechanisms, with implications for more individualized treatments. The authors recruited four groups: patients with a diagnosis of psychosis who experienced “hearing voices”; patients who did not have such experiences; individuals without a diagnosis who “heard voices”; and individuals without a diagnosis who did not hear voices. In order to reveal the effect of priors on hallucinatory experiences, Powers et al. used an ingenious experimental paradigm based on Pavlovian, or classical, conditioning where they paired weak tones at sensory threshold concurrent on the presentation of a visual stimulus while they recorded blood flow changes in the brain with fMRI. Pairing the tones and the visual stimuli would then establish a conditioned, or learned, association between the two stimulus events. They then sometimes presented only the visual stimulus, and sometimes together with tones that were so weak that they could not be heard, and tested whether the subjects nevertheless believed that they had perceived a tone. If the subjects responded that they heard a tone and described how convinced they were, this constituted the foundation for the experience of an auditory hallucination (in the absence of a real perceptual stimulus).
The results showed that subjects in the groups that had previous experiences of auditory hallucinations, independent of a diagnosis, more often reported that they heard a tone, and were more convinced than the other two groups of their experience, and their brain responses also showed activation in networks that have previously been found in hallucinating individuals (see Figure 2 of Powers et al.). Thus, the results of the study by Powers et al. show how prior beliefs and expectations of a perceptual phenomenon, in this case an audio-visual association, can cause the experience of actually “hearing a voice” that does not exist. In this respect, the results also shed light on the ongoing discussion of theoretical models for auditory hallucinations, by providing strong arguments for the perceptual nature of the very strange phenomenon of being convinced of experiencing something that is simply not there.
I think both play a role in each phenotype, and we need to invest more in analyses that span all types of variants. As they both have roughly 80 percent heritability, there is clearly a lot to learn from GWAS in autism, but to date the sample sizes have been much smaller than in schizophrenia. Conversely, with autism cases usually being children and collected with parents, the trio study design that enables de novo mutation discovery has been more deeply explored in autism but clearly has some signal also in schizophrenia (though seemingly a bit less, perhaps because most schizophrenia collections may not include children who were earlier diagnosed with a neurodevelopmental disorder such as developmental/intellectual disability or autism). As GWAS grows in autism and trio sequencing in schizophrenia, I would expect more discoveries and a better opportunity to draw insights from considering common and rare variations together.
For different psychiatric diseases, should we focus more on de novo mutations/rare variants in autism and more on common variants in schizophrenia?
I was an early enthusiast for splitting based on clinical subtypes, but I think this has not been a very successful approach. When sample sizes are large enough―larger than we probably have so far for most disorders―some clinical subtypes may emerge, but I suspect that clinical symptoms are just too far removed from the genes to have a benefit that outweighs the loss of power from reduced sample size.
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