Human prefrontal and sensory cortical activity during divided attention tasks

In our natural environment, the ability to divide attention is essential since we attend simultaneously to a number of sensory modalities, e.g., to visual and auditory stimuli. In this study, functional magnetic resonance imaging (fMRI) was used to study brain activation while a divided attention task was performed. Brain activation was also assessed under selective attention. Fourteen healthy male subjects aged between 19 and 28 years underwent fMRI studies using gradient EPI sequences. Cingulate activation was evident in all attention tasks. Focusing attention on one modality (visual or auditory) increased the activity in the corresponding primary and secondary sensory area. When attention is divided between both modalities, the activation in the sensory areas is decreased, possibly due to a limited capacity of the system for controlled processing. Left prefrontal activation, however, was evident selectively during the divided attention task. The present results suggest that this area may be important in the execution of controlled processing when attention is divided between two sources of information. These results support the view that the prefrontal cortex is involved in the central executive system and controls attention and information flow.     

Dysfunctional prefrontal cortical network activity and interactions following cannabinoid receptor activation

Coordinated activity spanning anatomically distributed neuronal networks underpins cognition and mediates limbic-cortical interactions during learning, memory, and decision-making. We used CP55940, a potent agonist of brain cannabinoid receptors known to disrupt coordinated activity in hippocampus, to investigate the roles of network oscillations during hippocampal and medial prefrontal cortical (mPFC) interactions in rats. During quiet wakefulness and rest, CP55940 dose-dependently reduced 0.1-30 Hz local field potential power in CA1 of the hippocampus while concurrently decreasing 30-100 Hz power in mPFC; these contrasting population-level effects were paralleled by differential effects on underlying single-unit activity in the two structures. During decision-making phases of a spatial working memory task, CP5540-induced deficits in hippocampal theta and prefrontal gamma oscillations were observed alongside disrupted theta-frequency coherence between the two structures. These changes in coordinated limbic-cortical network activities correlated with (1) reduced accuracy of task performance, (2) impaired phase-locking of prefrontal single-unit spiking to the local gamma and hippocampal theta rhythms, and (3) impaired task-dependent activity in a subset of mPFC units. In addition to highlighting the importance of CA1-mPFC network oscillations for cognition, these results implicate disrupted theta-frequency coordination of CA1-mPFC activity in the cognitive deficits caused by exogenous activation of brain cannabinoid receptors.     

Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.

BACKGROUND: Psychiatric disorders such as schizophrenia are believed to emerge from an interaction of several factors. Thus, a genetic predisposition can lead to developmental compromises that may leave the system more susceptible to deficits induced by subsequent environmental variables such as stress. METHODS: The impact of neurodevelopmental interruption induced by exposure of rats prenatally to a compound methylazoxymethanol acetate (MAM) that disrupts neuronal proliferation was investigated using in vivo electrophysiologic recordings from the prefrontal cortex of adult rats. RESULTS: Prenatal exposure to MAM resulted in alterations in the medial prefrontal cortex indicative of a compromise in information processing. Specifically, we observed a disruption in activity patterns consistent with deficits in neuronal synchronization and abnormal augmentation of synaptic plasticity that was more severely disrupted by stress exposure than in normal animals. Furthermore, these deficits could be reversed by manipulating the mesocortical dopamine system. CONCLUSIONS: These results suggest that disruption of early cortical development causes impairments in medial prefrontal cortical function at adulthood that are more vulnerable to disruptive influences, despite the presence of only subtle structural alterations in the brain.     

The influence of memory load upon delay-interval activity in a working-memory task: an event-related functional MRI study

We conducted two fMRI studies to investigate the sensitivity of delay-period activity to changes in memory load during a delayed-recognition task for faces. In Experiment 1, each trial began with the presentation of a memory array consisting of one, two, or three faces that lasted for 3 sec. A 15-sec delay period followed during which no stimuli were present. The delay interval concluded with a one-face probe to which subjects made a button press response indicating whether this face was part of the memory array. Experiment 2 was similar in design except that the delay period was lengthened to 24 sec, and the memory array consisted of only one or three faces. We hypothesized that memory maintenance processes that spanned the delay interval would be revealed by their sensitivity to memory load. Long delay intervals were employed to temporally dissociate phasic activity engendered by the memory array from sustained activity reflecting maintenance. Regions of interest (ROIs) were defined anatomically for the superior frontal gyri (SFG), middle frontal gyri (MFG), and inferior frontal gyri (IFG), intraparietal sulci (IPS), and fusiform gyri (FFG) on a subject-by-subject basis. The mean time course of activity was determined for all voxels within these regions and for that subset of voxels within each ROI that correlated significantly with an empirically determined reference waveform. In both experiments, memory load significantly influenced activation 6--9 sec following the onset of the memory array with larger amplitude responses for higher load levels. Responses were greatest within MFG, IPS, and FFG. In both experiments, however, these load-sensitive differences declined over successive time intervals and were no longer significant at the end of the delay interval. Although insensitive to our load manipulation, sustained activation was present at the conclusion of the delay interval within MFG and other prefrontal regions. IPS delay activity returned to prestimulus baseline levels prior to the end of the delay period in Experiment 2, but not in Experiment 1. Within FFG, delay activity returned to prestimulus baseline levels prior to the conclusion of the delay interval in both experiments. Thus, while phasic processes engendered by the memory array were strongly affected by memory load, no evidence for load-sensitive delay-spanning maintenance processes was obtained.     

The influence of encoding strategy on episodic memory and cortical activity in schizophrenia.

BACKGROUND: Recent work suggests that episodic memory deficits in schizophrenia may be related to disturbances of encoding or retrieval. Schizophrenia patients appear to benefit from instruction in episodic memory strategies. We tested the hypothesis that providing effective encoding strategies to schizophrenia patients enhances encoding-related brain activity and recognition performance. METHODS: Seventeen schizophrenia patients and 26 healthy comparison subjects underwent functional magnetic resonance imaging scans while performing incidental encoding tasks of words and faces. Subjects were required to make either deep (abstract/concrete) or shallow (alphabetization) judgments for words and deep (gender) judgments for faces, followed by subsequent recognition tests. RESULTS: Schizophrenia and comparison subjects recognized significantly more words encoded deeply than shallowly, activated regions in inferior frontal cortex (Brodmann area 45/47) typically associated with deep and successful encoding of words, and showed greater left frontal activation for the processing of words compared with faces. However, during deep encoding and material-specific processing (words vs. faces), participants with schizophrenia activated regions not activated by control subjects, including several in prefrontal cortex. CONCLUSIONS: Our findings suggest that a deficit in use of effective strategies influences episodic memory performance in schizophrenia and that abnormalities in functional brain activation persist even when such strategies are applied.     

The influence of working memory load on phase specific patterns of cortical activity

This study investigated patterns of cortical activity associated with the temporally separated encoding, maintenance and retrieval phases of a working memory (WM) task. Eighteen healthy subjects completed a variable load version of the Sternberg Item Recognition Task. Brain regions showing activity on average across load were determined for each task phase. In addition, brain regions showing activity that increased linearly with load were determined for encoding and retrieval. Although previous fMRI studies have used event-related designs to isolate phase specific activity, this study differed in that design and analysis methods were optimized to ensure low multicollinearity between the conditions of interest: the duration of the intermediate phase (maintenance) was varied and load was selectively modeled for the encoding and retrieval phases. The brain areas showing activity on average across load for each phase combine to encompass regions identified in previous studies that have not attempted to separate phase specific activity. Encoding is associated with extensive load dependent activity, with the most robust activity in bilateral occipital and posterior parietal regions. Retrieval is associated with more selective load dependent activity, primarily in the anterior supplementary motor region and the right posterior cerebellum. The analysis strategies employed in this study could be used to further delineate the phases of WM that are most severely compromised in clinical populations with WM disturbances.     

An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression

Repetitive transcranial magnetic stimulation (rTMS) is currently undergoing active investigation for use in the treatment of major depression. Recent research has indicated that current methods used to localize the site of stimulation in dorsolateral prefrontal cortex (DLPFC) are significantly inaccurate. However, little information is available on which to base a choice of stimulation site. The aim of the current study was to systematically examine imaging studies in depression to attempt to identify whether there is a pattern of imaging results that suggests an optimal site of stimulation localization. We analysed all imaging studies published prior to 2005 that examined patients with major depression. Studies reporting activation in DLPFC were identified. The DLPFC regions identified in these studies were analysed using the Talairach and Rajkowska-Goldman-Rakic coordinate systems. In addition, we conducted a quantitative meta-analysis of resting studies and studies of serotonin reuptake inhibitor antidepressant treatment. There was considerable heterogeneity in the results between studies. Changes in Brodmann area 9 were relatively consistently identified in resting, cognitive activation and treatment studies included in the meta-analysis. However, there was little consistency in the direction of these changes or the hemisphere in which they were identified. At this stage, the results of imaging studies published to date have limited capacity to inform the choice of optimal prefrontal cortical region for the use in rTMS treatment studies.     

Rodent models of prefrontal cortical function

In this article, we consider whether studies in rats can provide useful information regarding the debate about the functions of the primate prefrontal cortex. At a superficial level, comparison of regional specializations within the prefrontal cortices of different species suggests functional correspondence. Unfortunately, the nature of functional specialization in primate prefrontal cortex is controversial, and data supporting the idea of homology between specific areas of rat and primate prefrontal cortex are weak. Nevertheless, we argue here that studies of the computational functions within the relatively undifferentiated prefrontal cortex of rats can shed light on processing in primate prefrontal cortex.     

Phase precession of medial prefrontal cortical activity relative to the hippocampal theta rhythm

Theta phase-locking and phase precession are two related phenomena reflecting coordination of hippocampal place cell firing with the local, ongoing theta rhythm. The mechanisms and functions of both the phenomena remain unclear, though the robust correlation between firing phase and location of the animal has lead to the suggestion that this phase relationship constitutes a temporal code for spatial information. Recent work has described theta phase-locking in the rat medial prefrontal cortex (mPFC), a structure with direct anatomical and functional links to the hippocampus. Here, we describe an initial characterization of phase precession in the mPFC relative to the CA1 theta rhythm. mPFC phase precession was most robust during behavioral epochs known to be associated with enhanced theta-frequency coordination of CA1 and mPFC activities. Precession was coherent across the mPFC population, with multiple neurons precessing in parallel as a function of location of the animal. The existence of phase precession beyond the hippocampus implies a more global role for this phenomenon during theta rhythm-mediated coordination of neural activity.     

Corticotropin‐releasing factor infusion into nucleus incertus suppresses medial prefrontal cortical activity and hippocampo‐medial prefrontal cortical long‐term potentiation

The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin‐releasing factor type 1 (CRF₁) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high‐frequency stimulation of the NI on plasticity in the hippocampo‐prelimbic medial prefrontal cortical (HP‐mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long‐term potentiation in the HP‐mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra‐pituitary functions of CRF and indicate that the NI may play a role in stress‐driven modulation of working memory and possibly other cognitive processes subserved by the mPFC.     

The dependence of span and delayed-response performance on prefrontal cortex.

Theoretical and empirical research on the cognitive functions of the prefrontal cortex have established that this region mediates what have been called 'executive' processes that can influence working and long-term memory. Despite the accumulation of such empirical evidence, the dependence of purely mnemonic portions of memory tasks on PFC remains unresolved. To address this issue, we performed an analysis of reports of performance on tests of working memory of patients with lesions of the dorsolateral prefrontal cortex, focusing on published reports in the literature of simple span and delayed-response tasks. We found that none of the eleven studies of forward verbal and spatial span in patients with prefrontal cortical lesions that we reviewed (reflecting the performance of 166 individual patients) demonstrated a statistically significant deficit relative to normal controls. In contrast, our review of the delayed-response literature indicated that there are conditions under which PFC lesions disrupt delayed-response performance. Based on the results of our review of the literature, we present testable hypotheses about the working memory functions of the PFC.     

Tonic and phasic influence of basal forebrain unit activity on the cortical EEG

Changes in arousal levels are normally accompanied by modification of gross electrical activity (EEG) in the cortex, with low amplitude fast waves characterizing high levels and large slow waves low levels of arousal. These changes in cortical EEG patterns depend mainly on two factors: on the input from the thalamus and on the state of various membrane channels in the cortical pyramidal cells, which are both regulated by ascending modulatory systems. Several lines of evidence indicate that of the activating systems the cholinergic is the most effective in activating the cortex. Its blockade with atropine induces large slow waves in the EEG, while inhibition of other systems has no such profound effect. The effect of atropine can be mimicked by lesioning the basal forebrain. Neurons in this area show very close tonic and phasic correlation with the cortical EEG, further supporting the suggestion that projections of these neurons have a special role in the regulation of cortical activity. However, there is a discrepancy between the effects of excitotoxic and selective cholinotoxic lesions of the basal forebrain. The immunohistochemical diversity of the corticopetal basal forebrain projection and the electrophysiological heterogeneity of the neurons also indicate that, in addition to cholinergic cells, other types of neurons do also participate in the regulation of cortical activity from this area. To understand the intimate details the activity of identified basal forebrain neurons must be recorded and correlated with cortical events.     

Effects of dorsal or ventral medial prefrontal cortical lesions on five-choice serial reaction time performance in rats

Lesions of the rat medial prefrontal cortex (mPFC) produce behavioral impairments in the 5-choice serial reaction time (5CSRT) task, a widely used measure of sustained and selective visual attention. This experiment compared the effects of “dorsal” (centered on prelimbic and infralimbic cortices) and “ventral” (centered on dorsal peduncular cortex and tenia tecta) mPFC lesions on performance in a variant of the 5CSRT task. Because in some associative learning theories, the predictive validity of events determines the allocation of attention to them, we also examined the effects of cue validity in this task. Operant nosepoke responses to some briefly illuminated ports were consistently (100%) reinforced (CRF) with food, whereas for other ports, responding was reinforced on only 50% of the trials (partial reinforcement, PRF). Different patterns of impairment emerged depending on lesion location within the mPFC. Dorsal- and sham-lesioned rats responded more to CRF than to PRF cues, but ventral-lesioned rats responded similarly to CRF and PRF cues. Additionally, under some conditions of increased attentional demands, dorsal-lesioned rats failed to respond on many trials, whereas the impairment in ventral-lesioned rats was manifested as an increase in response errors. These results demonstrate separable roles for dorsal and ventral mPFC subregions in controlling attention.     

Chronic cold stress alters prefrontal cortical modulation of amygdala neuronal activity in rats.

BACKGROUND: Recent studies suggest that long-term exposure to stress can sensitize animals to subsequent novel or acute stressors. Stressors affect amygdala activity, and the prefrontal cortex has been implicated in the regulation of responses to stress. Little is known, however, about how the physiology of amygdala neurons is altered by chronic stressors or the role of the prefrontal cortex in these changes. METHODS: We used in vivo extracellular recordings from neurons in the rat central and basolateral amygdala nuclei to examine the effects of chronic stress on the basal firing and responses of amygdala neurons to a novel stressor. Additionally, prefrontal cortical afferents were severed to examine its role in the modulation of the response to stressors. RESULTS: Chronic exposure to cold enhanced the sensitivity of central amygdala neurons to footshock. A portion of this may be due to enhanced basolateral amygdala output. Furthermore, prefrontal cortical regulation of this response is weakened by chronic stress. CONCLUSIONS: The physiology of the amygdala is altered by chronic stress. Furthermore, the prefrontal cortical regulation of these responses may be weakened after chronic stress. This is a potential biological substrate for abnormal affect upon chronic stress and its effect on affective disorders.     

Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways

Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/- were also respectively more and less sensitive to D2 agonist- and antagonist-induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and CaMKKβ in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis.     

The effects of manipulations of attentional demand on cortical acetylcholine release.

In vivo microdialysis was used to measure acetylcholine (ACh) efflux in the frontoparietal cortex while rats performed in one of two operant tasks. One task was designed and validated to generate measures of sustained attention, while the other task was designed to minimize explicit demands on sustained attentional resources (low-demand task). Transferring animals from the baseline environment into the operant chambers robustly increased cortical ACh efflux regardless of subsequent task demands. Performance in the sustained attention task further increased frontoparietal ACh efflux, and these increases were not observed when animals were simply exposed to the operant chamber without task performance. Manipulations of the task parameters within a session, to either increase or decrease explicit demands on sustained attention, were not associated with fluctuations in ACh efflux. Unexpectedly, performance in the low-demand task was also associated with significant increases in ACh efflux that were similar to those observed during the sustained attention task. However, widespread depletions of cortical cholinergic inputs produced by intra-basalis infusions of 192 IgG-saporin failed to impair performance in the low-demand task, suggesting that cholinergic transmission is not necessary for performance in this task. The present results indicate that although a wider range of instrumental processes than previously hypothesized are associated with increases in cortical ACh release, the dependence of performance on the integrity of cortical cholinergic inputs may be limited to tasks with explicit attentional demands.     

The activation of prefrontal cortical neurons in aggression--a double labeling study

Violence is associated with prefrontal deficits in humans, suggesting that this brain area inhibits aggressiveness. Its role, however, remains controversial, as certain subdivisions of the prefrontal cortex become activated by fights in rodents. Disparate human findings also show that this area is acutely activated by aggression under certain conditions. We explored prefrontal neuronal activation patterns in resident rats exposed to psychosocial (sensory contact with the intruder) and aggressive encounters. Both psychosocial and aggressive encounters increased c-Fos activation in the prelimbic (PrL), anterior cingular (Cg1), agranular insular (AI), ventral (VO) and lateral orbital (LO) cortices. The infralimbic (IL) and medial orbital (MO) cortices were activated significantly by aggressive encounters only. No other prefrontal regions were activated by psychosocial or aggressive encounters. The overwhelming majority of activated cells were pyramidal (glutamatergic) cells in the Cg1, IL, PrL, MO, and VO, whereas interneuron and pyramidal cell activation was similar in AI and LO. When rats showed violent aggression, the activation of GABAergic inhibitory cells decreased in these two, and two other areas (IL and MO). Notably, the latter two areas appeared to be specifically involved in aggressive behavior. The change occurred in a recently developed model of violent aggression. In this model, pyramidal cell activation in the above mentioned four areas (IL, MO, AI, and LO) predicted over 95% of variation in attack counts in general and violent attacks in particular. Based on these data, we present a tentative hypothesis on the involvement of the prefrontal cortex in the control of aggression.     

The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation

BackgroundThe use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC).HypothesisIt was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity.Methods29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis.ResultsIn females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males.ConclusionsThese preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.     

The cortical connectivity of the prefrontal cortex in the monkey brain

One dimension of understanding the functions of the prefrontal cortex is knowledge of cortical connectivity. We have surveyed three aspects of prefrontal cortical connections: local projections (within the frontal lobe), the termination patterns of long association (post-Rolandic) projections, and the trajectories of major fiber pathways. The local connections appear to be organized in relation to dorsal (hippocampal origin) and ventral (paleocortical origin) architectonic trends. According to the proposal of a dual origin of the cerebral cortex, cortical areas can be traced as originating from archicortex (hippocampus) on the one hand, and paleocortex, on the other hand, in a stepwise manner (e.g., Sanides, 1969; Pandya and Yeterian, 1985). Prefrontal areas within each trend are connected with less architectonically differentiated areas, and also with more differentiated areas. Such organization may allow for the systematic exchange of information within each architectonic trend. The long connections of the prefrontal cortex with post-Rolandic regions seem to be organized preferentially in relation to dorsal and ventral prefrontal architectonic trends. Prefrontal areas are connected with post-Rolandic auditory, visual and somatosensory association areas, and with multimodal and paralimbic regions. This long connectivity likely works in conjunction with local connections to serve prefrontal cortical functions. The afferent and efferent connections of the prefrontal cortex with post-Rolandic regions are conveyed by specific long association pathways. These pathways as well appear to be organized in relation to dorsal and ventral prefrontal architectonic trends. Finally, although prefrontal areas have preferential connections in relation to dual architectonic trends, it is clear that there are interconnections between and among areas in each trend, which may provide a substrate for the overall integrative function of the prefrontal cortex. Prefrontal corticocortical connectivity may help to elucidate both region-specific and integrative perspectives on the functions of the prefrontal cortex.     

Patterns of cortical activity and memory performance in Alzheimer's disease.

BACKGROUND: Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake. METHODS: Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres. RESULTS: Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided. CONCLUSIONS: Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.