Comment by Deborah Levy, Debra Titone, and Howard Eichenbaum.
It is easy to appreciate why relational memory organization is such a compelling topic in studies of psychotic conditions. Relational memory allows one to flexibly manipulate information to discern new relationships based on known facts. The memory representations that support implicit reasoning of this type emerge effortlessly when the medial temporal lobe functions normally, whether navigating from a detour in a usual route or extrapolating that which is common across a set of individual memory traces. Relational thinking gone awry is a fundamental component of psychotic thinking. Inferential reasoning, referential ideas, and delusional extrapolations all involve making connections between unrelated things. These unwarranted connections, in turn, lead to erroneous (and potentially unrealistic) conclusions.

The kind of relational memory studied by Ongur et al. (2006) involves transitive inference (TI), or the capacity [...continued] to use knowledge of how individual memory traces overlap, to correctly infer a new relationship that is predicated on already stored information. For example, it is straightforward to make the TI that Sally is taller than Peter if one knows the two related premises, Sally is taller than Frank and Frank is taller than Peter.

The study by Ongur et al. follows up on two studies initiated by Titone’s translation of Eichenbaum’s paradigm for testing TI in rodents. The first study established that schizophrenic patients show TI deficits compared with controls (Titone et al., 2004). Using a modification of the same TI paradigm adapted for use in the imaging environment, the second study assessed which brain regions were selectively activated when nonpsychiatric controls made TI relational judgments (relative to non-TI relational judgments). Of particular interest was whether the hippocampus (HP) would be one of the regions to show selective activation, since Eichenbaum’s work in rodents had demonstrated that animals with HP lesions or whose HPs have been disconnected from their subcortical and cortical connections lose the capacity for TI (Dusek and Eichenbaum, 1997; 1998). The imaging study showed a selective association between TI and activation of right HP, pre-supplementary motor area, left prefrontal cortex, left parietal cortex, and thalamus (Heckers et al., 2004; see also Preston et al., 2004). Having established the neural circuitry subserving TI in the healthy brain, the stage was set to compare the patterns of regional brain activation in schizophrenic and control subjects, the focus of the study by Ongur et al.

In addition to shedding some light on a potential relational memory impairment in schizophrenia, the Ongur et al. paper is useful for illustrating some of the complexities that arise in designing and interpreting the results of imaging studies generally and of transitive inference studies in particular. Below we discuss several of them and the many intriguing questions that call for resolution in future work.

One main source of complexity is that the key condition that demonstrates the capacity for TI is also the most difficult, especially for schizophrenic patients. Ongur et al. report that in controls, accuracy does not differ between the BD and non-BD sequential inference trials. However, the mean accuracy score of the controls is in the direction of the BD condition being less accurate. In addition, had response latencies been reported for those two conditions as well, it is very likely that correct response latencies for BD would have been longer than those for non-BD sequential inference trials in both groups. Thus, with these particular stimuli it is not straightforward to distinguish discrete effects of TI from the increased difficulty of TI judgments relative to non-TI judgments on performance or on regional brain activation. In other words, did schizophrenics perform more poorly on BD than controls because BD is more difficult than non-BD or because their capacity for TI is compromised? Was the increased activation bilaterally of inferior parietal cortex during BD (relative to non-BD) in controls a function of TI or of task difficulty? Was the increased activation of right inferior parietal cortex in schizophrenics during BD (relative to non-BD) a function of TI or of task difficulty? (See Stark and Squire, 2003.)

Schizophrenic patients performed the critical TI task (BD vs. non-BD) significantly worse than controls, which is to be expected given the previously mentioned increased task difficulty of the BD condition. Indeed, as a group they performed no better than chance. The groups also differed in pattern of regional brain activation. In the whole brain analysis, controls activated inferior parietal bilaterally, whereas schizophrenics activated right inferior parietal, inferior frontal, and premotor cortices. Neither group significantly activated HP. The only region to show a significant activation difference between the groups was right inferior parietal cortex. Because performance and activation are confounded, the pattern of results does not lend itself to a simple interpretation. That is, did these differences in regional activation occur because schizophrenics could not perform a task that depends on these regions, or did the poor performance occur because schizophrenics could not activate critical regions? The same confound affects the ability to interpret the results of the ROI analysis of HP. Was HP activation decreased during BD in schizophrenics because they were not performing a task that depends on HP, or was performance poor because patients were not able to activate HP?

Several aspects of these results make it difficult to characterize the role of the HP in the neural circuitry subserving TI in humans. First, in the whole brain analysis, controls activated HP only in the analysis of a general comparison of “TI versus non-TI” conditions. The specific critical TI comparison condition (BD vs. non-BD) did not activate HP in controls in the whole brain analysis, a finding that would have been expected based on Eichenbaum and colleagues’ rodent work (Dusek and Eichenbaum, 1997; 1998). Second, was the decreased activation of HP during BD in the patients related to excessively high basal levels of activation? Third, the one region that did show a difference between BD and non-BD in controls and that distinguished schizophrenics from controls was right inferior parietal cortex, not HP. Based on the results of the whole brain analysis, it would be interesting to see the results of an ROI analysis of inferior parietal, inferior frontal, premotor cortex, and anterior cingulate. Fourth, to what extent do sensitivity and power contribute to the difference between the results of the whole brain and ROI analyses and between the more general TI versus non-TI contrast and the specific BD versus non-BD contrast? Fifth, was the increased activation of inferior frontal regions during BD in schizophrenics an effort to compensate for under-recruitment of inferior parietal cortex bilaterally or HP (see Bonner-Jackson et al., 2005)?

Although the results of the Ongur et al. (2006) study are promising, to characterize the neural basis of relational memory deficits in schizophrenia, at least two additional challenges must be met. The first is to differentiate TI from task difficulty. Our recent modification of the TI paradigm that was used in the Titone et al. (2004), Heckers et al (2004), and Ongur et al. (2006) studies disambiguates TI deficits from difficulty effects. The preliminary results are quite promising in showing that schizophrenics show behavioral deficits in TI independent of difficulty. The second is to unconfound behavioral performance and neural activation. One way to do this is to match the comparison groups on behavioral performance. Another is to separately analyze imaging data from individuals with schizophrenia who can do TI at greater than chance levels and those who cannot.

References:

Bonner-Jackson A, Haut K, Csernansky JG, Barch DM. The influence of encoding strategy on episodic memory and cortical activity in schizophrenia. Biol Psychiatry. 2005 Jul 1;58(1):47-55. Abstract

Dusek JA, Eichenbaum H. The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):7109-14. Abstract

Dusek JA, Eichenbaum H. The hippocampus and transverse patterning guided by olfactory cues. Behav Neurosci. 1998 Aug;112(4):762-71. Abstract

Heckers S, Zalesak M, Weiss AP, Ditman T, Titone D. Hippocampal activation during transitive inference in humans. Hippocampus. 2004;14(2):153-62. Abstract

Ongur D, Cullen TJ, Wolf DH, Rohan M, Barreira P, Zalesak M, Heckers S. The neural basis of relational memory deficits in schizophrenia. Arch Gen Psychiatry. 2006 Apr;63(4):356-65. Abstract

Preston AR, Shrager Y, Dudukovic NM, Gabrieli JD. Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus. 2004;14(2):148-52. No abstract available. Abstract

Stark CE, Squire LR. Hippocampal damage equally impairs memory for single items and memory for conjunctions. Hippocampus. 2003;13(2):281-92. Abstract

Titone D, Ditman T, Holzman PS, Eichenbaum H, Levy DL. Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr Res. 2004 Jun 1;68(2-3):235-47. Abstract