both have been shown to exacerbate depression, such that these ag

both have been shown to exacerbate depression, such that these agents which are effective in

the primary comorbid condition would not. appear to have utility in patients with bipolar disorder. Animal models of biphasic mood alterations While there are a number of useful models for acute antidepressant and antimanic efficacy, the field suffers from a lack of models representing biphasic alterations in mood and behavior, and the inherent cyclicity or mood phase reversal and recurrence of the disorder. One of the few exceptions to this is Antelman’s model of intermittent stressors or cocaine Inhibitors,research,lifescience,medical administration, which appears to be associated with inductions of alterations in hyperactive and inhibited behavior.62 Interestingly, in this model, inositol appears to improve and stabilize both the behavioral and Inhibitors,research,lifescience,medical neurochemical alterations evident, in this model. Examination of the efficacy of inositol in acute depression has led to equivocal results and perhaps deserves further exploration as a potential longterm therapeutic tool.63,64 Inhibitors,research,lifescience,medical One of the more intriguing features of bipolar illness is its potential for recurrence and behavioral oscillation to opposite poles at almost any frequency from intermittent and infrequent, episodic recurrences to more rapid, ultrarapid, and even ultradian cycling,

wherein mood can fluctuate numerous times within a single 24-hour period. Thus, examination of mechanisms

involved in this extraordinarily wide range Inhibitors,research,lifescience,medical of temporal manifestations of opposing mood and behavior in bipolar disorders would be a. fruitful avenue of investigation beyond the phenomena that show regular and invariant cyclicity in a given time Inhibitors,research,lifescience,medical domain. Thus, studies of diurnal alterations in circadian rhythms have been a primary focus of theoretical and empirical inquiry directed at. therapeutics of bipolar disorder, but may not, be adequate to deal with the extraordinary variability and aperiodicity that can be manifest in the illness. The Thalidomide dihydropyridine L-type calcium channel blocker nimodipine has shown preliminary success in some patients with ultrafast (ultradian) mood switches,65 and this class of compounds deserves further exploration, even SCH900776 though a new dihydropyridine did not differ from placebo. Overview There are obviously a. multiplicity of novel potential approaches to the therapeutics of bipolar illness, as briefly outlined here. While each requires much further exploration in order to validate its potential utility, such exploration is also likely to yield many surprises, and some approaches will be developed much more rapidly than we can currently anticipate and envision. We have only preliminarily dealt with the issue of psychotherapy in conjunction with other approaches, but emphasize that there is a.

130 These data suggest that the right subgenual PFC facilitates e

130 These data suggest that the right subgenual PFC facilitates expression of visceral responses during emotional processing, while the left subgenual PFC inhibits or modulates such responses.130 It is thus noteworthy that

the gray matter reduction in this region in MDD and BD was lateralized to the left side, suggesting that it may contribute to disinhibition of neuroendocrine and autonomic function in depression.127,131,132 The ventral ACC also appears to participate in processing of behavioral incentive and motivated behavior. These areas send efferent projections to the VTA and substantia nigra, and receive dense dopaminergic innervation Inhibitors,research,lifescience,medical from VTA.124 In rats, electrical or glutamatergic stimulation of medial PFC areas that include prelimbic cortex elicits burst firing patterns from dopamine (DA) cells in the VTA and increases DA release in the accumbens.113 These phasic, burst firing patterns of DA neurons appear to encode information

regarding stimuli that Inhibitors,research,lifescience,medical predict, reward and deviations between such predictions and actual occurrence of reward.133 Ventral ACC dysfunction may thus conceivably contribute to disturbances of motivated behavior and hedonic perception in mood disorders. Inhibitors,research,lifescience,medical Dorsomedial/dorsal anterolateral PFC Metabolism and CBF arc abnormally GSK1349572 decreased in the dorsolateral and dorsomedial Inhibitors,research,lifescience,medical PFC in MDD.1 The dorsomedial PFC region includes the dorsal ACC92 and an area rostral to the dorsal ACC involving cortex on the medial and lateral surface of the superior frontal gyrus (approximately corresponding to BA9 and BA32).8,19,91 Postmortem studies

of MDD and BD found abnormal reductions in the size of neurons and/or the density of glia in this portion of BA9,18,20,134 which may account Inhibitors,research,lifescience,medical for the reduction in metabolism in this region in MDD, and for the failure of antidepressant drug treatment, to correct metabolism in these areas.8,19 Nevertheless, currently remitted MDD subjects who experience depressive relapse during tryptophan depletion show increased metabolic activity within these areas in the depressed versus the remitted conditions,93 similar to other structures where histopathological and gray matter volume changes exist, in MDD. Flow normally increases in the vicinity of this GPX6 dorsomedial/dorsal anterolateral PFC in healthy humans as they perform tasks that elicit emotional responses or require emotional evaluations.1 In healthy humans, CBF increases in this region during anxious anticipation of an electrical shock to an extent that correlates inversely with changes in anxiety ratings and heart rate, suggesting that this region functions to attenuate emotional expression.

2010) In order to reconcile these contradictory findings, it has

2010). In order to reconcile these contradictory findings, it has been proposed that the effects

of dopaminergic drugs depend on task demands as well as the residual level of endogenous dopamine in nigrostriatal and ventral tegmental area (VTA) PFC circuits (“dopamine overdose hypothesis”) (Cools 2006; Kehagia et al. 2010; de la Fuente-Fernandez 2012). Previous evidence also showed that the relation between dopaminergic neurotransmission and PFC Inhibitors,research,lifescience,medical function follows an inverted-U-shaped model (Williams and Goldman-Rakic 1995; Arnsten and Goldman-Rakic 1998). In other words, a drug that restores the function of a dopamine-depleted circuit might simultaneously overdose, and thus impair the function of a different network with a less severe dopaminergic deficit (Cools 2006; Kehagia

et al. 2010). Nonetheless, the complex relation between Inhibitors,research,lifescience,medical dopaminergic drugs and cognition in PD is far from being fully characterized and several questions remain open. For example, it is still unclear how Inhibitors,research,lifescience,medical dopamine agonists impact on cognition in PD and whether the brain responses associated with specific neuropsychological functions might be influenced by individual levels of nigrostriatal degeneration. This study investigated the effects of apomorphine, a potent and fast-acting dopamine agonist, on neural activity during working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed by dopamine-transporter (DAT) imaging. Previous research in animal models of PD combined radio-isotopic Inhibitors,research,lifescience,medical and functional magnetic resonance imaging (fMRI) to investigate the relations between dopaminergic damage (tracked via DAT scan), D2 receptor sensitivity (measured with raclopride, a dopamine agonist), and blood oxygenation level–dependant (BOLD) response after infusion of apomorphine (Nguyen et al. 2000; Zhang et al. 2000, 2001, 2006).

These studies demonstrated that dopaminergic Inhibitors,research,lifescience,medical damage (i.e., reduced DAT levels) was associated with PI3K inhibitor enhanced striatal BOLD response to apomorphine (Nguyen et al. 2000; Zhang et al. 2000, 2001, 2006) and increased D2 receptor sensitivity Cediranib (AZD2171) (i.e., enhanced raclopride binding; Nguyen et al. 2000). Apomorphine is a nonselective dopamine agonist, although it exhibits a very high affinity for the D2 receptor family, and particularly the D4 receptor (Millan et al. 2002). At low doses (i.e., ~0.004 mg/kg), apomorphine reduces the dopamine release within the striatum via the inhibitory D2 receptors located presynaptically (i.e., on the nigrostriatal terminals) (Montoya et al. 2008; Schellekens et al. 2010). In contrast, at the higher (10-fold) doses used for PD treatment (i.e., ~0.04 mg/kg), apomorphine mainly stimulates the postsynaptic D2 receptors expressed by striatal neurons (Bowron 2004; LeWitt 2004).

This has been studied at several institutions in a phase II setti

This has been studied at several institutions in a phase II setting (18)-(22). Our group has completed two gemcitabine based chemoradiation trials in patients

with potentially resectable pancreatic cancer (18),(21). In the 176 patients from both trials (Gem-XRT and Gem-Cis-XRT) isolated tumor progression at the time of preoperative restaging was rare with the rate of local tumor progression precluding surgery 0.6% (1 of 176 patients). We have used a similar preoperative strategy for borderline resectable pancreatic cancer Inhibitors,research,lifescience,medical with the exception that therpay lasts longer prior to planned PD (the original dataset of 176 patients did not include any patients with MDACC criteria for borderline resectability). Since patients with borderline resectable pancreatic cancer (type

A) are at a high risk for margin positive resection and poor survival, these patients are ideal candidates for a prolonged course of preoperative therapy. Treatment schema After reviewing the patient’s pancreas protocol CT scan in a multidisciplinary conference Inhibitors,research,lifescience,medical with radiologists and surgical, medical Inhibitors,research,lifescience,medical and radiation oncologists, patients’ cancers are categorized as borderline resectable types A, B, C or a combination of these. Most patients are candidates for initial gemcitabine based GDC-0941 purchase systemic therapy for 2-4 months. Patients with an ECOG PS of 0-1 are considered for combination chemotherapy, often Inhibitors,research,lifescience,medical with gemcitabine and a platinum agent. A restaging CT scan is reviewed after approximately 8 weeks of systemic therapy and patients with radiographic response or a biochemical response in the presence of stable disease are candidates for more systemic therapy followed by chemoradiation or may proceed to

chemoradiation. After a break of 4-6 weeks from their radiation therapy, patients who continue to show disease stability or response are candidates for surgery. Gemcitabine or capecitabine are the common radiation sensitizers used in this setting. After a break of 4-6 weeks from their radiation therapy, patients who continue to show disease stability or response are candidates for surgery. Given the high rate of systemic Inhibitors,research,lifescience,medical relapse in patients many with resected pancreatic cancer, the “best” systemic therapy available may be applicable in the neoadjuvant setting in selected patients. The recent phase 3 study published by Conroy and colleagues reports on FOLFIRINOX superiority over gemcitabine in the treatment of metastatic pancreatic cancer and has gathered interest (23). 342 patients with a PS of 0 or 1 were randomly assigned to receive FOLFIRINOX or gemcitabine. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.

The biochemical etiology is unknown” They also noted that: “The

The biochemical etiology is unknown”. They also noted that: “The mean age of death in women was 35 years, whereas the mean age of death in men

was 16 years. This pattern suggests X-linked dominant transmission, but autosomal dominant inheritance cannot be ruled out” (2). A feature that distinguished the vacuoles in Danon disease from typical lysosomes was that vacuolar membranes occasionally merged with indentations of the sarcolemma and stained with antibodies to sarcolemmal proteins, such as dystrophin and laminin (3, 4). Based on the shared lysosomal and plasma membrane features Inhibitors,research,lifescience,medical of the vacuoles and on the X-linked inheritance of the disease, in 2000, Nishino Inhibitors,research,lifescience,medical and coworkers sequenced a candidate gene on chromosome Xq24, LAMP-2, in ten unrelated patients with Danon disease, including one of the two boys described in the original paper. They found pathogenic mutations in all 10 patients and documented lack of LAMP-2 (lysosome-associated membrane protein 2) both by Western blot analysis and by immunohistochemistry

(5). Their findings were bolstered by data from LAMP-2 knockout mice, which also showed accumulation of autophagic Inhibitors,research,lifescience,medical vacuoles in all tissues, but predominantly in cardiac and skeletal muscle (6). LAMP-2 is a 410 amino acid protein consisting of a small cytoplasmic tail with a lysosomal membrane targeting signal, a transmembrane domain, and a large intraluminal head. The LAMP-2 open reading frame consists of 9 exons: the first 8 exons and part of the ninth

encode the luminal Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical domain, and what is left of exon 9 encodes both the transmembrane and the cytoplasmic domains. Human exon 9 exists in two forms, 9a and 9b, which are alternatively spliced, producing two isoforms, LAMP-2a and LAMP-2b. Nishino et al. provided evidence that Danon disease is mostly due to defects of the LAMP-2b isoform, which is predominantly expressed in heart, muscle, and brain, the three “target tissues” in Danon disease Org 27569 (5). The discovery of LAMP-2 deficiency in Danon disease ushered a new group of lysosomal diseases, those due to defects in lysosomal structural this website proteins rather than lysosomal enzymes. It also justified why Danon disease should not be included among the glycogenoses, glycogen being but one of many substrates that accumulate within abnormal autophagosomes. In 2002, Sugie et al. reviewed 38 genetically confirmed cases (20 men and 18 women) and provided a comprehensive description of the typical clinical and pathological features of Danon disease (7).

” The “Thankless Man” (Character 17, μεμψιμοιρία) always sees the

” The “Thankless Man” (Character 17, μεμψιμοιρία) always sees the negative aspects and is incapable of enjoying life; he is presenting traits that might be qualified today as anhedonia, resentfulness,

and negativism. For instance, “when his sweetheart kisses him, he says ‘I wonder if you really do love me so in your heart’.” Theophrastus’ book exerted much influence in the 17th and 18th century in Western Europe, where it prompted much literature on #AP24534 keyword# character description. There is a well-known French translation by La Bruyere (Paris, 1688). Because of Theophrastus, European languages have adopted the term character. As suggested by the etymology of the Greek χαρακτήρ (instrument for marking or graving, impress, stamp), character refers to a permanent or long-standing mode of functioning that is inscribed in the fabric of the person, like a coin that has been stamped. Long before DSM-III, the permanence of traits Inhibitors,research,lifescience,medical has been part of the definition of a personality disorder, although

certain personality disorders may be acquired to some degree, and are amenable to change as a result of treatment. Besides “character,” other terms such as “temperament” and “personality” were well also defined by the 18th century. According to the Encyclopedic, the very influential French-language Inhibitors,research,lifescience,medical encyclopedia edited between 1751 and 1772 by Denis Inhibitors,research,lifescience,medical Diderot and Jean d’Alembert,4 temperament (temperament) originates from the natural constitution of the individual. The definition goes on to mention the four temperaments described by the GrecoRoman physician Galen, on the basis of the four humors of the Hippocratic school: phlegmatic, sanguine, melancholic, and Inhibitors,research,lifescience,medical choleric. This illustrates how humoral theories of personalities remained influential well into the 18th century. According to the Oxford English Dictionary, the term “personality” has been used since the 18th century to designate the distinctive

individual qualities of a person. Personality traits are a continuum, ranging from the normal to the pathological. However, in current usage, personality tends to refer to the traits or qualities that are strongly developed or strikingly displayed, rather than to usual features. This raises the issue of defining abnormality, a task complicated Org 27569 by the fact that the same terms are often used to designate both normal personality traits and psychiatric diagnoses. Personality and the birth of psychiatry Psychiatry, as a medical science, began to take shape toward the end of the 18th century. One very popular way of describing personality characteristics at that time was phrenology. Although this science is now discredited, it was a sincere attempt to describe personality on a neuroanatomical basis.

After creating scoring rules, Schnitker et al used the SAEM QIs

After creating scoring rules, Schnitker et al. used the SAEM QIs for cognitive assessment, in a geriatric ED population (N=277) and found that cognitive assessment and its documentation in medical records occurred in too few Doxorubicin patients such that scoring the majority of

the QIs was impracticable in this sample [32]. The aim of this project is to determine predictors of quality of care of geriatric patients Inhibitors,research,lifescience,medical in EDs, and to develop a suite of QIs, including structural, process and outcome measures, that are feasible with minimal collection cost, whilst being reflective of true levels of quality delivered, for use in ED-care of the elderly. This will include the potential to propose a sub-set of QIs focused on the special needs of 1) older ED patients with cognitive impairment 2) those residing in nursing homes presenting Inhibitors,research,lifescience,medical to EDs, 3) and older ED patients with palliative care needs. Methods/design To ensure that a suite of quality indicators for the care of older persons in the ED is developed using an evidence-based approach that reflects the diversity of ED systems in developed nations, a three-phase mixed methods study was designed (Figure 1). The project will consist of: 1) a review of the scientific literature and expert panel input for the development of a preliminary suite of indicators;

2) field study of preliminary indicators Inhibitors,research,lifescience,medical at 8 Australian emergency services; 3) a facilitated panel discussion among key experts in emergency and geriatric medicine followed by a formal voting process, resulting in a final QI suite. The results of each phase will inform subsequent phases. Figure 1 Schematic of the study design. Ethics Inhibitors,research,lifescience,medical Research ethics board approval was received for

the project from Metro South Human Research Ethics Committee (HREC/11/QPAH/628); Australian Capital Territory (ACT) Government Health Human Research Inhibitors,research,lifescience,medical Ethics Committee Low Risk Sub-committee (ETHLR.12.097); The University of Queensland Behavioural & Social Sciences Ethical Review Committee (2012000631); and Melbourne Health Human Research Ethics Committee (2012.010). Site Specific Governance approval PAK6 was received for this project from Metro South Centres for Health Research Governance (SSA/11/QPAH/628; SSA/12/QPAH/211); Metro North Health Service District Research, Ethics and Governance Unit (SSA/12/QPCH/76); West Moreton Health Service District Human Research Ethics Committee & Research Governance Office (SSA/12/QWMS/23); and Northern Health Research Governance Office (SSA/12/NH/4). For the field study, research nurses will obtain informed written consent from participating patients at each site. Phase 1: Review of the literature Objective The purpose of this phase is to develop a preliminary QI set through a process of evaluation of available scientific literature, analysis of data collected from a pilot study [32], and finally, expert panel input. There will be a focus on utilising structural, process and outcome measures.

There was no association between Bax expression and p53nac in eit

There was no association between Bax expression and p53nac in either patient group (data not shown). CRCs with negative or low Bax immunostaining were significantly

associated with CRCs that demonstrated frame-shift mutations at the Bax (G) 8 tract (20 of 23, 87%) as compared to CRCs without this mutation (25 of 60, 41%) (data not shown). In addition, most CRCs with poor differentiation had low Bax expression in the surgery-alone group (χ2, P= 0.0005) (Table 2). Figure 2 Examples of immunohistochemical expression of Bax, Bcl-2, and p53nac in colorectal adenocarcinomas Inhibitors,research,lifescience,medical and adjacent benign epithelium. Examples of immunostaining of the adjacent benign colorectal epithelium are presented for Bax expression Inhibitors,research,lifescience,medical (Panel-A, x20), … Table 2 Correlations between expression of Bax, Bcl-2 and p53nac and the characteristics of treated and untreated patients The median survival of the 5-FU treated group of patients with low Bax expression was 25 months relative to 5 months for surgery-alone patients with low Bax expression (Table 3). The median survival for 5-FU treated

patients with high Bax Inhibitors,research,lifescience,medical expression was 25 months relative to 56 months for surgery-alone patients with high Bax expression (Table 3). Kaplan-Meier analyses demonstrated a Rigosertib solubility dmso significant association between high Bax expression and better patient survival in the surgery-alone group (log rank P=0.006) (Fig 3A). Although there was no Inhibitors,research,lifescience,medical significant association between

Bax expression status and patient survival in the 5-FU treated group, patients with decreased Bax expression had improved survival (overall log rank P=0.211) (Fig 3B). Figure 3 Correlation of Bax and Bcl-2 expression with overall survival of colorectal cancer patients undergoing surgery alone or treated with 5-FU-based adjuvant therapy after surgery. The overall survival of patients with high Bax expression was compared Inhibitors,research,lifescience,medical to patients … Table 3 Median survival (in months) of patient groups based on the status of expression of Bax, Bcl-2, and p53nac Bcl-2 immunophenotypic expression analysis Immunoreactivity for Bcl-2 was localized in the cytoplasm; overall, the staining was homogenous. The staining in intra-tumoral lymphocytes was used as an internal control (Fig 2D-F). Of the patients, 46% had high Levetiracetam levels of Bcl-2 expression (27 5-FU-treated patients and 24 surgery-alone patients). There were no significant differences in the incidence of deaths due to CRCs in the Bcl-2 low and high expressors of among the 5-FU-treated or surgery-alone patients (Table 1). However, the median survival was higher (63.15 months) for surgery-alone patients with high levels of Bcl-2 expression as compared to those with low expression (17.61 months). There was no significant difference in the median survival of 5-FU treated patients with low or high Bcl-2 expression (Table 3).

Current consensus suggests, therefore, that smaller doses (up to

Current consensus suggests, therefore, that smaller doses (up to 0.5 mg) may be preferable to larger doses, and that treatment timing should be timed initially to phase advance if possible (to achieve immediate entrainment (Figure 6). 115 but if mistimed, may still eventually cause entrainment. Given melatonin’s soporific

properties, treatment should also be given close to the desired bedtime to ensure the alignment of the circadian and social day. Rigosertib mouse melatonin administration has also been explored for treatment of abnormal entrained phase disorders in the blind,117 Inhibitors,research,lifescience,medical as well as sighted populations,118 but appropriate timing may be even more important in these groups than non-24-hour Inhibitors,research,lifescience,medical sleep disorder.119 Figure

6. Entrainment of circadian rhythms in the blind with melatonin. This Figure shows the double-plotted sleep timing (■) and urinary Cortisol peak times (○) for two totally blind men treated with 5 mg melatonin PO at 21:00 h for at least one … Conclusion The detrimental effects of loss of light perception, or loss of eyes, on circadian rhythm entrainment, and subsequently sleep and waking function, are often inadequately recognized by physicians, families, friends, and employers, making it difficult Inhibitors,research,lifescience,medical for blind people to obtain the treatment and support required to deal with this highly prevalent condition. Our data confirm the anecdotal accounts from subjects, who describe fighting to stay awake at work, having problems maintaining concentration and memory during the day, or being overwhelmed with a Inhibitors,research,lifescience,medical desire to sleep at inappropriate times. These circadian rhythm sleep disorders are chronic, unrelenting, and currently difficult to manage with conventional approaches. Simply treating the sleep-wake

symptoms, for example with a combination of daytime stimulants and night-time hypnotics, indicates an insufficient diagnosis and a failure to address the underlying cause of the condition. Correcting the underlying misalignment between circadian and sleep-wake Inhibitors,research,lifescience,medical cycles, for example using appropriatelytimed melatonin treatment as described above, is fundamental for the optimal treatment of circadian rhythm sleep disorders. Clinically, our data suggest that sleep disorders in visually impaired people with CYTH4 some degree of LP are not due to circadian desynchrony, and should therefore be investigated for other sleep disorders as in sighted subjects. Blind people with NPL who complain of sleep disorders, particularly episodic or cyclic insomnia and daytime sleepiness, should be studied longitudinally to confirm a circadian disorder diagnosis, using home-based sleep diary and urine assessments as described above.61,62 If non-24-hour rhythms are confirmed, then treatment with low-dose (0.

Executive control, rules, and the prefrontal cortex By definit

.. Executive control, rules, and the prefrontal cortex By definition, controlled thought and action are goal-directed and organized toward the completion of tasks. Consider a common cognitively demanding situation: navigating an airport. From the start, we know that we need a ticket, have to wait in line, board at the right

gate, etc. We are not born knowing this; we have to learn the rules. As such, the neural substrates for executive control need to have access to the wide range of information needed to identity potential goals and the rules that can achieve them. This no doubt Inhibitors,research,lifescience,medical depends on many different brain areas. However, one cortical region is particularly necessary (but not sufficient): the PFC. It is this cortical area that reaches the greatest relative size in the human brain and is thus thought to be the neural instantiation of the mental qualities that we think of as “intelligent.” The PFC is anatomically well situated to play a role as the brain’s executive. It receives information from, and sends projections to, forebrain systems that Inhibitors,research,lifescience,medical process information about the external world, motor system structures that produce voluntary movement, systems that consolidate long-term memories, and systems that process information about affect and motivational state.2-5 This anatomy has long suggested that the PFC may be Kinase Inhibitor Library important for synthesizing Inhibitors,research,lifescience,medical the external and internal information needed to produce complex behavior.

Neurophysiological studies suggest that this synthesis serves to form representations of task rules (for reviews see refs 6-8). This has been shown in studies that systematically vary task demands; subjects perform a different set of operations Inhibitors,research,lifescience,medical or make different decisions using the same set of sensory Inhibitors,research,lifescience,medical inputs and motor options. For example, in one trial the subject may have to choose one of two pictures that matches one

seen previously (a match rule); in another trial the subject has to choose the nonmatching picture (a nonmatch rule).9 These types of experiments have revealed that the PFC neural activity is highly sensitive to rule information. In fact, unlike sensory cortex, especially primary sensory cortex, it appears that task rules are more influential on how information is distributed across PFC neurons Oxygenase than bottom-up sensory information. More neurons reflect task demands than sensor information, indeed often at the expense of sensory information.10-11 Interestingly, cognitively demanding tasks engage a very large proportion of PFC neurons; after training, as many as 30% to 40% of randomly selected PFC neurons show task-related activity.9,12-15 So many PFC neurons (one third or more of the population) dedicated to a given rule might, at first blush, make it seem as if the PFC can only learn a few tasks. If the one third of PFC neurons represent the rules of one task, does that mean that only three tasks can be learned? In fact the opposite is true.