Sylvain Houle

Age-Related Differences in Neural Activity during Memory Encoding and Retrieval: A Positron Emission Tomography Study

Positron emission tomography (PET) was used to compare regional cerebral blood flow (rCBF) in young (mean 26 years) and old (mean 70 years) subjects while they were encoding, recognizing, and recalling word pairs. A multivariate partial-least-squares (PLS) analysis of the data was used to identify age-related neural changes associated with (1) encoding versus retrieval and (2) recognition versus recall. Young subjects showed higher activation than old subjects (1) in left prefrontal and occipito-temporal regions during encoding and (2) in right prefrontal and parietal regions during retrieval. Old subjects showed relatively higher activation than young subjects in several regions, including insular regions during encoding, cuneus/precuneus regions during recognition, and left prefrontal regions during recall. Frontal activity in young subjects was left-lateralized during encoding and right-lateralized during recall [hemispheric encoding/retrieval asymmetry (HERA)], whereas old adults showed little frontal activity during encoding and a more bilateral pattern of frontal activation during retrieval. In young subjects, activation in recall was higher than that in recognition in cerebellar and cingulate regions, whereas recognition showed higher activity in right temporal and parietal regions. In old subjects, the differences in blood flow between recall and recognition were smaller in these regions, yet more pronounced in other regions. Taken together, the results indicate that advanced age is associated with neural changes in the brain systems underlying encoding, recognition, and recall. These changes take two forms: (1) age-related decreases in local regional activity, which may signal less efficient processing by the old, and (2) age-related increases in activity, which may signal functional compensation.

Functional brain maps of retrieval mode and recovery of episodic information.

Positron emission tomography (PET) was used to identify brain regions associated with two component processes of episodic retrieval; those related to thinking back in subjective time (retrieval mode) and those related to actual recovery of stored information (ecphory). Healthy young subjects recognized words that had been encoded with respect to meaning or the speakers voice. Regardless of how the information had been encoded, recognition was associated with increased activation in regions in right prefrontal cortex, left anterior cingulate, and cerebellum. These activations reflect retrieval mode. Recognition following meaning encoding was specifically associated with increased activation in left temporal cortex, and recognition following voice encoding involved regions in right orbital frontal and parahippocampal cortex. These activations reflect ecphory of differentially encoded information.

Functional role of the prefrontal cortex in retrieval of memories: a PET study.

Retrieval of information from episodic memory involves the processes invoked by the attempt to remember (retrieval attempt) as well as processes associated with the successful retrieval of stored information (ecphory). Previous PET studies of memory have shown an activation of the prefrontal cortex in memory retrieval tasks, and we hypothesised that this activation represents retreival attempt, not ecphory. This hypothesis was directly directed using [15O]H2 PET imaging in 19 healthy subjects who performed three matched tasks which involved different levels of retrieval attempt and ecphory. The results showed that retrieval attempt was associated with activation of the prefrontal cortex, right greater than left, while ecphory involved the posterior cortical regions. These findings illuminate the functional role of the different neuroanatomical regions involved in episodic remembering.

Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

IMPORTANCE The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation. OBJECTIVE To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers. MAIN OUTCOMES AND MEASURES Values of TSPO VT in the prefrontal cortex, ACC, and insula. RESULTS In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 [P = .001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 [P = .005]). CONCLUSIONS AND RELEVANCE This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.

Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of (11)C-Labeled 2-(Phenylthio)araalkylamines.

A series of four 2-(phenylthio)araalkylamines have been radiolabeled with 11C and evaluated as potential radiotracers for imaging the serotonin transporter (SERT) by positron emission tomography (PET). All four candidates display high affinity for SERT and low affinity for the dopamine or norepinephrine transporters using in vitro binding assays. Biodistribution studies in rats demonstrated that tail-vein injection of the 11C-labeled radiotracers resulted in high brain uptake of radioactivity with a preferential distribution in brain regions known to be rich in SERT such as hypothalamus and thalamus. The most promising candidate, 16, had hypothalamus-to-cerebellum ratios of 9:1, 1 h postinjection, an indication of high specific to nonspecific binding. Ex vivo pharmacological studies demonstrated that uptake in SERT-rich brain regions was both saturable and selective for SERT. Two of the tested radiotracers, 15 and 16, have highly favorable properties for imaging SERT and will be used in pilot human PET im...

The seats of reason? An imaging study of deductive and inductive reasoning

WE carried out a neuroimaging study to test the neuro-physiological predictions made by different cognitive models of reasoning. Ten normal volunteers performed deductive and inductive reasoning tasks while their regional cerebral blood flow pattern was recorded using [15O]H2O PET imaging. In the control condition subjects semantically comprehended sets of three sentences. In the deductive reasoning condition subjects determined whether the third sentence was entailed by the first two sentences. In the inductive reasoning condition subjects reported whether the third sentence was plausible given the first two sentences. The deduction condition resulted in activation of the left inferior frontal gyrus (Brodmann areas 45, 47). The induction condition resulted in activation of a large area comprised of the left medial frontal gyrus, the left cingulate gyrus, and the left superior frontal gyrus (Brodmann areas 8, 9, 24, 32). Induction was distinguished from deduction by the involvement of the medial aspect of the left superior frontal gyrus (Brodmann areas 8, 9). These results are consistent with cognitive models of reasoning that postulate different mechanisms for inductive and deductive reasoning and view deduction as a formal rule-based process.

Functional neuroanatomy of recall and recognition: A pet study of episodic memory

The purpose of this study was to directly compare the brain regions involved in episodic-memory recall and recognition. Changes in regional cerebral blood flow were measured by positron emission tomography while young healthy test persons were either recognizing or recalling previously studied word pairs. Reading of previously nonstudied pairs served as a reference task for subtractive comparisons. Compared to reading, both recall and recognition were associated with higher blood flow (activation) at identical sites in the right prefrontal cortex (areas 47, 45, and 10) and the anterior cingulate. Compared to recognition, recall was associated with higher activation in the anterior cingulate, globus pallidus, thalamus, and cerebellum, suggesting that these components of the cerebello-frontal pathway play a role in recall processes that they do not in recognition. Compared to recall, recognition was associated with higher activation in the right inferior parietal cortex (areas 39, 40, and 19), suggesting a larger perceptual component in recognition than in recall. Contrary to the expectations based on lesion data, the activations of the frontal regions were indistinguishable in recall and recognition. This finding is consistent with the notion that frontal activations in explicit memory tasks are related to the general episodic retrieval mode or retrieval attempt, rather than to specific mechanisms of ecphory (recovery of stored information).

Lower dopamine transporter binding potential in striatum during depression.

Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [11C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.

Positron emission tomography quantification of [11C]-DASB binding to the human serotonin transporter : Modeling strategies

[11C]-DASB, namely [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [11C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k3 and k4 were estimated with poor precision. Only the ratio k3/k4 was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k3/k4 estimates was 80 minutes. For routine use of [11C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [11C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.

Brain Regions Differentially Involved in Remembering What and When: a PET Study

Recollecting a past episode involves remembering not only what happened but also when it happened. We used positron emission tomography (PET) to directly contrast the neural correlates of item and temporalorder memory. Subjects studied a list of words and were then scanned while retrieving information about what words were in the list or when they occurred within the list. Item retrieval was related to increased neural activity in medial temporal and basal forebrain regions, whereas temporal-order retrieval was associated with activations in dorsal prefrontal, cuneus/precuneus, and right posterior parietal regions. The dissociation between temporal and frontal lobe regions confirms and extends previous lesion data. The results show that temporal-order retrieval involves a network of frontal and posterior brain regions.