"Hard-To-Cook"

In a recent publication, Medeiros Coelho and colleagues (2007) reported that altered levels of phytate contribute to the "hard-to-cook" phenomenon that can occur after storage of common beans at extreme temperature conditions. Why do they become "hard-to-cook"?

In countries such as Brazil and Mexico, common beans are an important part of the human diet because they are the primary source of daily proteins and minerals.[1][2] ...when the grains are subjected to improper post-harvest storage conditions, such as high temperature (30-40 °C) and high humidity (>75%), the grains can be altered in their color, texture, flavor and time required for cooking.[3-5] These alterations have been associated with the 'hard-to-cook' phenomenon (HTC) and a reduction in the quality of the grains.[3]

Adapted from Figure 2 of Medeiros Coelho et al. (2007). Phytate content of the bean genotypes Peruano and Paraiso stored at 29 °C (C) and at 5 °C ( D), both at 75% relative humidity (RH) for 135 days.

Why the post on beans? Threats to fellow bloggers who comply with fair use of material published in scientific journals are "hard-to-swallow" and don't amount to a hill of beans¹.



¹ For a fascinating look at bean biopiracy, read Danielle Goldberg's excellent report, JACK AND THE ENOLA BEAN, which describes how an American bean industry executive patented a yellow bean originally obtained from Mexico.



Reference

Cileide Maria Medeiros Coelho, Cláudia de Mattos Bellato, Julio Cesar Pires Santos, Edwin Moises Marcos Ortega, Siu Mui Tsai (2007). Effect of phytate and storage conditions on the development of the 'hard-to-cook' phenomenon in common beans. Journal of the Science of Food and Agriculture 87:1237-1243.

Tops Down

In Bottoms Up, we learned that "bottom-up" attention -- useful for detecting "pop-out" stimuli in the visual field -- is bottom-up (parietal neurons respond first, then prefrontal neurons), and that "top-down" attention required for effortful visual search is top-down (prefrontal, then parietal) [and that this merited publication in Science (Buschman & Miller, 2007).]


The timing of events in the lateral interparietal area (LIP), lateral prefrontal cortex (LPFC), and frontal eye fields (FEF) was as follows:

figure from Yantis (2003)

LIP, LPFC, and FEF neurons began finding the target 170 ms, 120 ms, and 35 ms before saccade, respectively' [pop-out] ...target location information reached significance in the FEF and LPFC at 50 and 40 ms before the saccade, respectively, followed by LIP at 32 ms after the saccade. [visual search]¹

It's nice to get the onset information all in one experiment, but did we need single-unit recording in awake behaving monkeys to tell us this? Unique opportunities to record intracranially in awake behaving humans occur clinically in the neurosurgical arena, to monitor for seizures in patients with intractable epilepsy (Dubeau & McLachlan, 2000). In a series of such experiments in the mid-90's, Halgren and colleagues recorded local field potentials from over two thousand cortical and subcortical sites while the patients performed an "oddball" task (reviewed in Halgren et al., 1998; see the three original papers for a full view of this tour de force).

In the oddball task, a series of simple auditory or visual or somatosensory stimuli are presented. Participants attend to rare target stimuli embedded in a train of standard stimuli, and press a button when a target is detected. A brain wave called the P300 (or P3b) can be recorded from the scalp at approximately 300 msec after target presentation. Rare, task-irrelevant distractor stimuli can also be presented, and these elicit the P3a component. Most germane here is the P3a, because it's often thought to be part of the automatic orienting response (Halgren et al., 1998):

The P3a is evoked by rare stimuli, regardless of whether they are targets or non-targets, overtly attended or unattended, auditory or visual. It is generated in a frontoparietocingulate system that has been associated with the orientation of attention... It is associated with an electrodermal response and represents the cortical component of the orienting response.

Employing a task with pure tone stimuli, Halgren et al. plotted the peak latencies of P3a at different recording sites, and demonstrated that frontal locations had earlier peaks than posterior locations. In essence, here we have evidence for "top-down" attentional mechanisms in a "bottom-up" situation.


from Halgren et al. (1998): The P3a has a significantly shorter latency in frontal sites (including anterior cingulate gyrus, aCg, and Brodman’s area 46 in the dorsolateral prefrontal cortex, a46), than in parietal sites (including posterior cingulate gyrus, pCg, and supramarginal gyrus, sMg), or temporal sites (including parahippocampal gyrus, pHg). At all sites, the depth P3a is earlier than the scalp P3.

Plus [for starters], there's some evidence for reverse hierarchies in the visual system (Hochstein & Ahissar, 2002)...

...we suggest a reversal of the way of understanding conscious perception and its relationship to cortical mechanisms. Based on results from feature search, vision at a glance and vision with scrutiny have been viewed as reflecting, respectively, low-level and high-level cortical representations. Thus, effortless simple feature detection has been seen as reflecting mechanisms operating at lower levels. Subsequent studies finding that the pop-out phenomenon also occurs for complex features challenged this view, while accumulating evidence for global precedence was viewed as an oddity.

We propose instead that vision at a glance reflects high-level mechanisms, while vision with scrutiny reflects a return to low-level representations. ... Thus, early spread attention reflects the large receptive fields found in high-level areas, and focused attention reflects localized low-level representations. High-level spread attention subserves our initial, crude global percept of the gist of the scene. Pop-out is but one aspect of this crude initial assessment. Associating early conscious perception with high cortical level mechanisms has implications for attentional phenomena as well.

...but that's a topic for another post!

References

Buschman TJ, Miller EK (2007). Top-Down Versus Bottom-Up Control of Attention in the Prefrontal and Posterior Parietal Cortices. Science 315: 1860-1862.

Dubeau F, McLachlan RS. (2000). Invasive electrographic recording techniques in temporal lobe epilepsy. Can J Neurol Sci 27 Suppl 1:S29-34.

Halgren E, Marinkovic K, Chauvel P. (1998). Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr Clin Neurophysiol 106:156-64.

Hochstein S, Ahissar M. (2002). View from the top: hierarchies and reverse hierarchies in the visual system. Neuron 36:791-804.

Yantis S (2003). To see is to attend. Science 299:54-56.


Footnote

¹ When the trials were time-locked to stimulus onset rather than response onset, the results were as follows:

For the pop-out condition, while the distribution was more variable due to the variability in reaction time, LIP showed selectivity for the target location approximately 50 ms after array onset, followed by LPFC and then FEF (after 120 and 220 ms, respectively). All these differences were also significant ... When aligning search trials on visual array onset, LPFC and FEF carried significant information at 250 ms after array onset, significantly preceding selectivity in LIP, which began at 320 ms after onset...

Bottoms Up

Attention (everyone knows what that¹ is) is often described as having "bottom-up" and "top-down" components (referring to the direction of information flow from sensory to high-order cortical regions, and vice versa).

ThinkGeek (bottoms up!)

In a recent study appearing in Science, Buschman and Miller (2007) recorded simultaneously from a number of neurons in both frontal and parietal cortices to examine the onset and location of responses to the two types of attention, as summarized below.

Attention and Information Flow

Cortical neurons modulate their activity with shifts in attention, but the source and flow of attention signals are unclear. Buschman et al. (p. 1860) used 50 electrodes to record simultaneously the activity from three cortical regions thought to be critical for attention. Bottom-up shifts of attention were first reflected in the parietal cortex, whereas top-down shifts of attention were reflected first in the frontal cortex. Thus, external control of visual attention originates in parietal cortex, but internal control of visual attention is directed from the frontal cortex.

The authors defined bottom-up attention as pop-out (or visual salience, an "automatic" process) and top-down attention as visual search (a "controlled" process). Thus, the flow of information was initially defined by task, not by physiology (Treisman & Gelade, 1980; pdf)


from Buschman & Miller (2007)

Buschman TJ, Miller EK (2007). Top-Down Versus Bottom-Up Control of Attention in the Prefrontal and Posterior Parietal Cortices. Science 315: 1860-1862.

Attention can be focused volitionally by "top-down" signals derived from task demands and automatically by "bottom-up" signals from salient stimuli. The frontal and parietal cortices are involved, but their neural activity has not been directly compared. Therefore, we recorded from them simultaneously in monkeys. Prefrontal neurons reflected the target location first during top-down attention, whereas parietal neurons signaled it earlier during bottom-up attention. Synchrony between frontal and parietal areas was stronger in lower frequencies during top-down attention and in higher frequencies during bottom-up attention. This result indicates that top-down and bottom-up signals arise from the frontal and sensory cortex, respectively, and different modes of attention may emphasize synchrony at different frequencies.

So we see what was expected: top-down attention is top-down, and bottom-up attention is bottom-up. Have we learned anything we don't already know? What's novel about this study? Well, the technical feat of simultaneously recording from multiple single neurons in 3 different cortical regions is impressive, as are the detailed statistical analyses described in the 27 page supplement.

In the press, the authors stretched their point a bit to state the study's relevance to ADD:

Neuroscientists find different brain regions fuel attention

. . .

ADD involves being overly sensitive to the automatic attention-grabbers and less able to willfully sustain attention. "Our work suggests that we should target different parts of the brain to try to fix different types of attention deficits," Miller said.

"The downside of most psychiatic drugs is they are too broad," he continued. "It's like hitting the problem with a sledgehammer; you get the benefits but also many unintended consequences. Our work suggests that we may one day be able to figure out what is the exact problem with each individual and specifically target those shortcomings. And that is the ultimate goal in psychiatric intervention."

In addition to charting the activity of single neurons, the authors recorded local field potentials (e.g., see Kreiman et al., 2006 among many others) and determined the frequency bands that showed coherence (neural synchrony) between frontal and parietal regions, observing

a greater increase in middle-frequency (22 to 34 Hz) coherence between LIP and frontal cortex during top-down search than during bottom-up pop-out. By contrast, the increase in upper-frequency (35 to 55 Hz) coherence was greater during pop-out than during search. Thus, bottom-up and top-down attention may rely on different frequency bands of coherence between the frontal and parietal cortex.

What about EEG studies in humans? Intracranial recordings in epilepsy patients? What have these methodologies revealed about bottom-up and top-down attention? [And were any of those papers published in Science?] Stay tuned...

Footnote

¹ Everyone knows what attention is. It is the taking possession by the mind in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought...It implies withdrawal from some things in order to deal effectively with others.

-- William James
Principles of Psychology (1890)

Requiem

When the last living thing
has died on account of us,
how poetical it would be
if Earth could say,
in a voice floating up
perhaps
from the floor
of the Grand Canyon,
"It is done."
People did not like it here.

-- Kurt Vonnegut (1922-2007), Requiem

This is the last page, but the Author's Note, of A Man Without A Country, (c) 2005

Trolls Wanted For Research Study

image credit: mosquito25
Racername: TrollKiller

TROLLS WANTED!

The NIMH seeks participants for a new neuroimaging study on neurodevelopmental abnormalities in the brains of blog trolls. Objective: measuring the quantity of gray matter lost by repeatedly browsing MindFreedom's web site.

It's been hard to find enrollees, so far, because those who qualify tend to sneer and shrug it off with, "NIMH? They're just pharma shills. Neuroscience is a sham, man." Subjects also have difficulty filling out the application form, claiming to be named God, giving a Yahoo newsgroup as an address, and pasting long rants about Zyprexa into the spaces provided for "birthdate" and "sex". The lone participant the NIMH has managed to recruit thus far is apparently getting along fine by screaming "pseudoscience fuckwits! ha-ha, I'll prove you all wrong!" at the lab technicians while they good-naturedly jam him into an MRI tube where a piece of rotting fish is hidden.

Via Omni Brain.

Encephalon #20!! Plus More on Neuroantomical Differences in Schizophrenia!

A fabulous new edition of Encephalon has arrived at Neurontic (not to be confused with The Neurocritic).

The sequel to my post included there, Differences in Auditory Cortex Neurons and Prefrontal microRNA Expression in Schizophrenia, begins below with a figure illustrating a striking amount of gray matter loss in early-onset schizophrenia (Thompson et al., 2001).


from Thompson et al. 2001: MRI image of an averaged profile of brain tissue loss from a group of patients with early-onset schizophrenia. These brain maps depict striking anatomical characteristics of accelerated gray matter loss and unsuspected patterns of brain structure defects. Red and pink indicate the regions with the fastest gray matter loss, green colors slower loss, and blue colors no loss.

The comparison group was a set of individuals who were matched for age, IQ, and medication.

Medication-Matched Subjects. To address the possibility that neuroleptic exposure and/or lower IQ could have determined differential gray matter loss in the schizophrenics, we mapped 10 serially imaged subjects referred to the childhood schizophrenia study who did not meet diagnostic criteria for schizophrenia [labeled psychosis NOS, in DSM terms]. These subjects received medication identical to that of the patients in this study through adolescence, primarily for control of aggressive outbursts, and at follow-up, none had progressed to schizophrenia but all continued to exhibit chronic mood and behavior disturbance.

Thus, the gray matter changes can be attributed to the illness, rather than to typical or atypical antipsychotic treatment.

Now let's go one step further and examine what differences (if any) might occur in the brains of individuals with schizophrenia who are relatively drug-naive. These folks have been treated with antipsychotic medication for only a short duration [it's not particularly ethical to scan floridly psychotic patients before stabilizing them, so complete drug-naivety is not usually observed]. For example, structural MRI morphometric studies have demonstrated reduced volumes in the thalamus (Crespo-Facorro et al., 2007), in the left planum temporale (Takahashi et al., 2007) showing an inverse correlation with the duration of untreated psychosis, and in the left middle and inferior temporal gyri (Lappin et al., 2006), also showing an inverse correlation with the duration of untreated psychosis. A SPECT study in completely drug-naive patients showed abnormal dopaminergic D2 receptor binding (Corripio et al., 2006). Finally, increases in gray matter volume (along with improvements in clinical symptoms) have been obseved after treatment with atypical antipsychotics (Garver et al., 2005).

Caveats? Yes, there are caveats. Although genetic and neurodevelopmental factors influence brain structure and function, as I said before,

Certainly, one's environment, social circumstances, upbringing, stress levels, etc. do play a role in the expression of various mental illnesses...

Plus, it's not as if the literature presents a neat and consistent picture (e.g., for volumes of the caudate nucleus; see Tauscher-Wisniewski, 2005). Nevertheless, the evidence for brain changes in early-onset schizophrenia (and in individuals who are relatively drug-naive, with long durations of untreated psychosis), compared to proper control groups, is compelling.

References

Crespo-Facorro B, Roiz-Santianez R, Maria Pelayo-Teran J, Manuel Rodriguez-Sanchez J, Perez-Iglesias R, Gonzalez-Blanch C, Tordesillas-Gutierrez D, Gonzalez-Mandly A, Diez C, Magnotta VA, Andreasen NC, Luis Vazquez-Barquero J. (2007). Reduced thalamic volume in first-episode non-affective psychosis: Correlations with clinical variables, symptomatology and cognitive functioning. Neuroimage Feb 13; [Epub ahead of print] .

Corripio I, Perez V, Catafau AM, Mena E, Carrio I, Alvarez E. (2006). Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis. Neuroimage 29:662-6.

Garver DL, Holcomb JA, Christensen JD. (2005). Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biol Psychiatry 58:62-6.

Lappin JM, Morgan K, Morgan C, Hutchison G, Chitnis X, Suckling J, Fearon P, McGuire PK, Jones PB, Leff J, Murray RM, Dazzan P. (2006). Gray matter abnormalities associated with duration of untreated psychosis. Schizophr Res. 83:145-53.

Takahashi T, Suzuki M, Tanino R, Zhou SY, Hagino H, Niu L, Kawasaki Y, Seto H, Kurachi M. (2007). Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: A preliminary report. Psychiatry Res. 154:209-19.

Tauscher-Wisniewski S, Tauscher J, Christensen BK, Mikulis DJ, Zipursky RB. (2005). Volumetric MRI measurement of caudate nuclei in antipsychotic-naive patients suffering from a first episode of psychosis. J Psychiatr Res. 39:365-70.

Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL. (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci 98:11650-5.

THE MAGIC OF CONSCIOUSNESS SYMPOSIUM

This year's ASSOCIATION FOR THE SCIENTIFIC STUDY OF CONSCIOUSNESS (ASSC) annual meeting in

LAS VEGAS: THE CONSCIOUSNESS CAPITAL OF THE WORLD

promises to draw your attention and command your awareness!

DO NOT MISS the first scientific event to bring in WORLD FAMOUS magicians: Teller, from Penn & Teller, The Amazing Randi, The Great Tomsoni, Mac King, and Apollo Robbins, Professional Thief and Pickpocket, to share their deep insights into the covert manipulation of attention and
awareness! This event promises to astound you, to delight you, and to make you take magic seriously as an important experimental tool in the study of consciousness.

Differences in Auditory Cortex Neurons and Prefrontal microRNA Expression in Schizophrenia

Two new studies demonstrate differences between the brains of people with schizophrenia and those without. In the first, anatomical abnormalities were noted in neurons located in the primary auditory cortex (Sweet et al., 2007). This is an important finding, because one characteristic feature of schizophrenia is auditory hallucinations (Frith, 1996), or hearing voices that are not actually present. This is not the first time such a neuronal abnormality has been observed by this lab (Sweet et al., 2003, 2004), and the current study characterized the density of axon terminals in Brodmann areas 41 and 42. They did this by examining post-mortem tissue from 15 schizophrenia brains and 15 control brains, which were processed immunohistochemically with an agent (synaptophysin) to visualize axon terminals in different cortical layers.


Figure 1 (Sweet et al., 2007). Schematic diagram of feedforward and feedback pathways in the auditory core (area 41) and lateral belt cortices of primate. Auditory sensory processing is primarily initiated via projections (red) from the ventral subdivision of the medial geniculate nucleus of the thalamus to layers 4 and 3c of the core. Excitation spreads to supragranular layers via ascending projections from spiny stellate cells (black) and via ascending collaterals from layer 3 pyramidal cells (thin green). Feedforward projections (thick green) arise predominantly from layer 3 pyramidal cells in core and project to deep layer 3 and layer 4 of the lateral belt. Feedback projections (blue) arise predominantly from layer 5 in lateral belt and terminate in layer 1 of core.

The importance of comparing the pattern of synaptophysin staining in different cortical layers is to determine whether feedforward pathways (which convey information from auditory relay centers in the medial geniculate forward to auditory cortex) or feedback pathways (which send information from higher-order areas back to primary auditory cortex) are more affected. This difference may have some significance for different theories of the origins of auditory hallucinations in schizophrenia [although there won't be an easy answer to that one...].

In short, the study demonstrated that axon terminal densities are reduced in feedforward but not feedback auditory pathways.

Sweet RA, Bergen SE, Sun Z, Marcsisin MJ, Sampson AR, Lewis DA. (2007). Anatomical evidence of impaired feedforward auditory processing in schizophrenia. Biol Psychiatry 61:854-64.

BACKGROUND: Somal volumes of pyramidal cells are reduced within feedforward but not feedback circuits in areas 41 and 42 of the auditory cortex of subjects with schizophrenia. Because neuronal somal volume depends on both the number of axonal terminations onto and furnished by the neuron, we hypothesized that axon terminal densities are reduced in feedforward but not feedback auditory pathways in subjects with schizophrenia. METHODS: We used stereologic methods to quantify the density of a marker of axon terminals, synaptophysin-immunoreactive (SY-IR) puncta, in areas 41 and 42 of 15 subjects with schizophrenia and matched normal comparison subjects. The effect of long-term haloperidol exposure on density of SY-IR puncta was similarly evaluated in nonhuman primates. RESULTS: Synaptophysin-immunoreactive puncta density was 13.6% lower in deep layer 3 of area 41 in the schizophrenia subjects but was not changed in layer 1 of area 41 or in deep layer 3 of area 42. Density of SY-IR puncta did not differ between haloperidol-exposed and control monkeys. CONCLUSIONS: Reduction of SY-IR puncta density is selective for feedforward circuits within primary auditory cortex of subjects with schizophrenia. This deficit may contribute to impairments in auditory sensory processing in this disorder.

The authors speculate on the significance of their findings for impairments in auditory processing in schizophrenia [although they do not speculate about the origin of auditory hallucinations...]:

If our findings do reflect a lower number of excitatory feedforward thalamocortical and intrinsic axon terminals, then these abnormalities might underlie the deficits in auditory processing observed in subjects with schizophrenia. Individuals with schizophrenia demonstrate impaired pure tone discrimination (Rabinowicz et al. 2000). Though the precise intracortical mechanisms of this impairment are not known, this deficit is correlated with reductions in mismatch negativity (MMN), an evoked response potential arising in response to auditory stimuli that deviate in one characteristic (e.g., pitch) from a repetitive stimulus (Javitt et al. 2000).

But can't these neuroanatomical differences be produced by antipsychotic drugs? Thirteen of the brains were obtained from individuals treated with medications, and only two without. So "merely a by-product of drug treatment" is a valid objection, but the investigators considered this in a control experiment. Four monkeys were treated with haloperidol (a typical antipsychotic) for 9-12 months, then their brains were examined and compared to those of control monkeys. No significant differences were observed in the primary auditory cortices of the two groups. In addition, the brains from the individuals off medications at the time of their deaths did not differ from those obtained from medicated individuals (although the authors acknowledged the lack of statistical power in this comparison).

In the second study, Perkins and colleagues (2007) identified a molecular mechanism that may contribute to the development of schizophrenia.

Brain tissue reveals possible genetic trigger for schizophrenia

. . .

In studying the postmortem brain tissue of adults who had been diagnosed with schizophrenia, the researchers found that levels of certain gene-regulating molecules called microRNAs were lower among schizophrenia patients than in persons who were free of psychiatric illness.

"In many genetic diseases, such as Huntington's disease or cystic fibrosis, the basis is a gene mutation that leads to a malformed protein. But with other complex genetic disorders – such as schizophrenia, many cancers, and diabetes – we find not mutated proteins, but correctly formed proteins in incorrect amounts," said study lead author and UNC professor of psychiatry Dr. Diana Perkins.

The reported differences were in prefrontal cortex, which has been repeatedly demonstrated to be altered in schizophrenia (e.g., Lewis et al., 2005; Rusch et al., 2007) [as have interactions between prefrontal and auditory areas (Lawrie et al., 2002]. Once again, the investigators did appropriate control studies (in haloperidol-treated and untreated rats this time) to demonstrate that the alterations were not due to medication effects in schizophrenia.

Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. (2007). microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 8(2):R27.

BACKGROUND: microRNAs (miRNAs) are small, noncoding RNA molecules that are now thought to regulate the expression of many mRNAs. They have been implicated in the etiology of a variety of complex diseases, including Tourette's syndrome, Fragile x syndrome, and several types of cancer. RESULTS: We hypothesized that schizophrenia might be associated with altered miRNA profiles. To investigate this possibility we compared the expression of 264 human miRNAs from postmortem prefrontal cortex tissue of individuals with schizophrenia (n = 13) or schizoaffective disorder (n = 2) to tissue of 21 psychiatrically unaffected individuals using a custom miRNA microarray. Allowing a 5% false discovery rate, we found that 16 miRNAs were differentially expressed in prefrontal cortex of patient subjects, with 15 expressed at lower levels (fold change 0.63 to 0.89) and 1 at a higher level (fold change 1.77) than in the psychiatrically unaffected comparison subjects. The expression levels of 12 selected miRNAs were also determined by quantitative RT-PCR in our lab. For the eight miRNAs distinguished by being expressed at lower microarray levels in schizophrenia samples versus comparison samples, seven were also expressed at lower levels with quantitative RT-PCR. CONCLUSION: This study is the first to find altered miRNA profiles in postmortem prefrontal cortex from schizophrenia patients.

Some people believe that there are no documented differences between the brains of people with and those without psychiatric disorders. That mental illnesses do not have biological causes. Certainly, one's environment, social circumstances, upbringing, stress levels, etc. do play a role in the expression of various mental illnesses, but so do genetics, brain structure, and brain function. The present studies provide yet another example of the latter.

References

Frith C. (1996). The role of the prefrontal cortex in self-consciousness: the case of auditory hallucinations. Philos Trans R Soc Lond B Biol Sci. 351:1505-12.

Javitt DC, Shelley AM, Ritter W (2000). Associated deficits in mismatch negativity generation and tone matching in schizophrenia. Clin Neurophysiol 111:1733–1737.

Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC. (2002). Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 51:1008-11.

Lewis DA, Hashimoto T, Volk DW. (2005). Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 6:312-24.

Rabinowicz EF, Silipo G, Goldman R, Javitt DC (2000). Auditory sensory dysfunction in schizophrenia: Imprecision or distractibility? Arch Gen Psychiatry 57:1149–1155.

Rusch N, Spoletini I, Wilke M, Bria P, Di Paola M, Di Iulio F, Martinotti G, Caltagirone C, Spalletta G. (2007). Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. Mar 23; [Epub ahead of print].

Sweet RA, Bergen SE, Sun Z, Sampson AR, Pierri JN, Lewis DA (2004). Pyramidal cell size reduction in schizophrenia: Evidence for involvement of auditory feedforward circuits. Biol Psychiatry 55:1128–1137.

Sweet RA, Pierri JN, Auh S, Sampson AR, Lewis DA. (2003). Reduced pyramidal cell somal volume in auditory association cortex of subjects with schizophrenia. Neuropsychopharmacology 28:599–609.