Response to Beretich and Beretich

no abstract availabl

Episodic memory for personally relevant information, evidence from aging, divided attention at retrieval and positron emission tomography

grantor: University of TorontoThree components of episodic memory are retrieval content, retrieval success, and retrieval experience. These components, as they relate to episodic memory for personally relevant information, were investigated in two behavioral experiments and in a positron emission tomography (PET) experiment; the PET study investigated the neural correlates of the three components with particular attention paid to changes in frontal activity. In each experiment retrieval content was investigated by comparing the retrieval of adjectives that were processed in one of four ways: in terms of the self, another person, social desirability, or phonological structure. Retrieval success was investigated by comparing recognition performance across the four conditions and/or between groups. Retrieval experience was investigated by using a "remember/know" (R/K) recognition procedure; R responses index retrieval that is accompanied by a "re-experiencing" of aspects of the encoding episode whereas K responses index retrieval based on a feeling of familiarity. The retrieval content results suggest that the retrieval of category specific information engages anterior cortical areas when the category is personally or socially relevant. The retrieval success results support previous suggestions of right frontal involvement. The retrieval experience results suggest that increases in frontal activity are more correlated with K responses than R responses. Additional frontal regions may be recruited for K responses to verify and monitor the output, and to engage additional strategic search processes to try to change K responses to R responses. R responses primarily engaged limbic regions and anatomically related structures that may deliver their output to right frontal regions or be "switched on" by them. The PET results converge with the results of the two behavioral studies. Relative to young adults under full attention, the R scores of old adults were smaller in only the self-reference and social desirability conditions, and young adults who divided their attention at retrieval performed similarly to old adults; previous studies have suggested that divided attention and aging affect frontal function. The present series of experiments shed light on the neuro-cognitive system that mediates the retrieval of self-referential information. The experiments revealed different components of episodic memory that contribute to the cognitive processes and patterns of neural activity associated with episodic memory for personally relevant information.Ph.D

Research Article IN SEARCH OF THE SELF: A Positron Emission Tomography Study

Abstract-Previous work using positron emission tomography (PET) has shown that memory encoding processes are associated with preferential activation of left frontal regions of the brain, whereas retrieval processes are associated predominantly with right frontal activations. One possible reason for the asymmetry is that episodic retrieval necessarily involves reference to the self, and the self-concept may be represented (at least partially) in right frontal regions. Accordingly, the present study investigated the possibility that encoding of self-related material might also activate right frontal areas. Eight right-handed volunteers judged trait adjectives under four separate PET scan conditions: (a) relevance to self, (b) relevance to a well-known public figure, (c) social desirability, and (d) number of syllables. The results showed that self-related encoding yielded left frontal activations similar to those associated with other types of semantic encoding, but also specific activations in the right frontal lobe. It is concluded that the concept of self involves both general schematic structures and further specific components involved in episodic memory retrieval. It is well established that encoding and retrieval processes in episodic memory involve different regions in the frontal lobes of the cerebral cortex. Specifically, encoding processes differentially engage left prefrontal areas, whereas retrieval processes for the same materials predominantly involve right prefrontal areas. This observed difference was embodied in the hemispheric encoding/retrieval asymmetry model (HERA; Tulving, One question that can be asked is whether these asymmetrical cortical activations reflect the processes of memory encoding and retrieval as such, or whether they reflect the involvement of necessary constituents of encoding and retrieval, respectively. It is known, for example, that effective encoding processes typically involve deep, elaborate, semantic-processing operations What are the necessary constituents of memory retrieval? James (1890, Vol. I, p. 650) made the point that for a mental event to be experienced as a personal memory, the imagined event must, first, be referred to the past and, second, be associated with feelings of self; that is, it must be dated in the rememberer's own personal past. Recent work involving positron emission tomography (PET) has shown that the retrieval of episodic memories is associated with activation of the prefrontal cortex, predominantly on the right (for reviews, see One major purpose of the present study was to examine the possibility that the association of episodic memory retrieval with activation of the right prefrontal cortex is attributable (in part at least) to the representation of self in this area of the brain. This conjecture receives some support from studies of brain-damaged patients with disturbances of self-awareness; such disorders are often associated with lesions of the right frontal cortex A related purpose of the study was to gather evidence on the neural correlates of self-referential processing. It has been shown that words processed with reference to the self are very well remembered, usually even better than words processed in general semantic terms schematic cognitive structure, and that new information learned with reference to self is encoded in a rich and distinctive manner. Furthermore, the organized, interdependent nature of the self-schema facilitates the formation of organizational links among the events to be remembered Participants in the PET scanner made judgments about lists of personality trait adjectives. Four types of judgments were made (only one type during any one scan); in all cases, participants rated each word on a 4-point scale by pressing one of four response keys. The four types of judgments were (a) self ("How well does the adjective describe you?"), (b) other ("How well does the adjective describe Brian Mulroney?"-a former Canadian prime minister), (c) general ("How socially desirable is the trait described by the adjective?"), and (d) syllable ("How many syllables does the adjective contain?"). Processing words in terms of the number of syllables reflects a relatively shallow type of verbal processing with little involvement of meaning; activations from these scans formed the baseline for PET measurements. The other condition was included to see whether personal judgments not related to self would be associated with activations different from those associated with selfreferential and general semantic encoding. Behavioral studies have shown that subsequent memory for words judged with reference to another person depends on how well known the target person is to the participant. When the other in question is well known (e.g., parent, best friend), subsequent memory levels are almost as high as those associated with self judgments METHOD Participants Eight right-handed volunteers (4 men and 4 women) were recruited for participation in the present investigation. The volunteers were between the ages of 19 and 26 years (M = 22.8), and had a mean education of 15.5 years. All participants were screened for a history or current evidence of any serious medical, neurological, or psychological disorder; they were also screened for recreational drug abuse. Informed consent was obtained from all volunteers before they participated, and they received a $50 reimbursement for their participation. The study was approved by the local ethics committee of the University of Toronto. Task Design Relative regional cerebral blood flow (rCBF) was measured while participants performed one of four encoding tasks; each task was performed twice, for a total of eight relative rCBF measurements (i.e., scans). The four tasks were presented in an ABCDDCBA design (counterbalanced across participants) to minimize order effects. Each task involved making judgments about personality trait adjectives on a 4-point scale. Sixteen similar lists of 32 personality trait adjectives were constructed using the personality trait adjectives found in In one task, representing encoding of self-referential information (self task), participants were requested to judge how well they thought each trait adjective described them. To indicate their judgment, they were instructed to press one of the four keys on the keypad beneath their right fingers. More specifically, they were requested to press the key beneath their index, middle, ring, or little finger if they thought that the trait adjective almost never, rarely, sometimes, or almost always described them, respectively. In a second task, representing encoding of information about another person (other task), participants were requested to judge how well they thought each trait adjective described Brian Mulroney by responding in the same way as in the self task. In a third task, representing encoding of semantic information not specific to a person (general task), participants were requested to judge how socially desirable the trait described by each adjective was. They judged each trait as being almost never, rarely, sometimes, or almost always socially desirable by pressing designated keys. In a fourth task, representing the encoding of nonsemantic information (syllable task), participants were requested to judge the number of syllables in each trait adjective. They pressed one of four keys depending on whether the adjective had two, three, four, or five syllables. Each trial consisted of a 500-ms fixation point followed by an adjective with a maximum duration of 2,000 ms. If the participant made his or her judgment within the 2,000 ms, then the screen wen

Application of Bayesian methods to accelerate rare disease drug development: scopes and hurdles

Abstract Background Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes. Main text Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications. Conclusion The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting.http://deepblue.lib.umich.edu/bitstream/2027.42/173792/1/13023_2022_Article_2342.pd

The evolving role of medical geneticists in the era of gene therapy: an urgency to prepare

: By 2030, it is estimated that at least 30 non-oncology gene therapies will be approved in the United States alone. These therapies could be used to treat up to 50,000 patients annually and have the potential to result in major shifts in disease management pathways. Medical geneticists have well-established roles in the direct management of many rare genetic diseases and often provide support in the diagnosis and care of patients with such diseases. Because an increasing number of gene therapies are likely to become available over the next decade, there is a need to better define the role of medical geneticists within current and future gene therapy pathways and prepare for their expected role within the context of this new treatment paradigm. This commentary examines the current and potential future roles of medical geneticists in gene therapy and identifies specific needs that must be addressed for medical geneticists to assume an expanded leadership role in this area