Personalized transcranial alternating current stimulation improves sleep quality: Initial findings.

Insufficient sleep is a major health issue. Inadequate sleep is associated with an array of poor health outcomes, including cardiovascular disease, diabetes, obesity, certain forms of cancer, Alzheimer's disease, depression, anxiety, and suicidality. Given concerns with typical sedative hypnotic drugs for treating sleep difficulties, there is a compelling need for alternative interventions. Here, we report results of a non-invasive electrical brain stimulation approach to optimizing sleep involving transcranial alternating current stimulation (tACS). A total of 25 participants (mean age: 46.3, S.D. ± 12.4, 15 females) were recruited for a null-stimulation controlled (Control condition), within subjects, randomized crossed design, that included two variants of an active condition involving 15 min pre-sleep tACS stimulation. To evaluate the impact on sleep quality, the two active tACS stimulation conditions were designed to modulate sleep-dependent neural activity in the theta/alpha frequency bands, with both stimulation types applied to all subjects in separate sessions. The first tACS condition used a fixed stimulation pattern across all participants, a pattern composed of stimulation at 5 and 10 Hz. The second tACS condition used a personalized stimulation approach with the stimulation frequencies determined by each individual's peak EEG frequencies in the 4-6 Hz and 9-11 Hz bands. Personalized tACS stimulation increased sleep quantity (duration) by 22 min compared to a Control condition (p = 0.04), and 19 min compared to Fixed tACS stimulation (p = 0.03). Fixed stimulation did not significantly increase sleep duration compared to Control (mean: 3 min; p = 0.75). For sleep onset, the Personalized tACS stimulation resulted in reducing the onset by 28% compared to the Fixed tACS stimulation (6 min faster, p = 0.02). For a Poor Sleep sub-group (n = 13) categorized with Clinical Insomnia and a high insomnia severity, Personalized tACS stimulation improved sleep duration by 33 min compared to Fixed stimulation (p = 0.02), and 30 min compared to Control condition (p < 0.1). Together, these results suggest that Personalized stimulation improves sleep quantity and time taken to fall asleep relative to Control and Fixed stimulation providing motivation for larger-scale trials for Personalized tACS as a sleep therapeutic, including for those with insomnia.

Roles of ventral versus dorsal pathways in language production: An awake language mapping study.

Human language is organized along two main processing streams connecting posterior temporal cortex and inferior frontal cortex in the left hemisphere, travelling dorsal and ventral to the Sylvian fissure. Some views propose a dorsal motor versus ventral semantic division. Others propose division by combinatorial mechanism, with the dorsal stream responsible for combining elements into a sequence and the ventral stream for forming semantic dependencies independent of sequential order. We acquired data from direct cortical stimulation in the left hemisphere in 17 neurosurgical patients and subcortical resection in a subset of 10 patients as part of awake language mapping. Two language tasks were employed: a sentence generation (SG) task tested the ability to form sequential and semantic dependencies, and a picture-word interference (PWI) task manipulated semantic interference. Results show increased error rates in the SG versus PWI task during subcortical testing in the dorsal stream territory, and high error rates in both tasks in the ventral stream territory. Connectivity maps derived from diffusion imaging and seeded in the tumor sites show that patients with more errors in the SG than in the PWI task had tumor locations associated with a dorsal stream connectivity pattern. Patients with the opposite pattern of results had tumor locations associated with a more ventral stream connectivity pattern. These findings provide initial evidence using fiber tract disruption with electrical stimulation that the dorsal pathways are critical for organizing words in a sequence necessary for sentence generation, and the ventral pathways are critical for processing semantic dependencies.

Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study.

Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon.

Specifying the role of the left prefrontal cortex in word selection.

Word selection allows us to choose words during language production. This is often viewed as a competitive process wherein a lexical representation is retrieved among semantically-related alternatives. The left prefrontal cortex (LPFC) is thought to help overcome competition for word selection through top-down control. However, whether the LPFC is always necessary for word selection remains unclear. We tested 6 LPFC-injured patients and controls in two picture naming paradigms varying in terms of item repetition. Both paradigms elicited the expected semantic interference effects (SIE), reflecting interference caused by semantically-related representations in word selection. However, LPFC patients as a group showed a larger SIE than controls only in the paradigm involving item repetition. We argue that item repetition increases interference caused by semantically-related alternatives, resulting in increased LPFC-dependent cognitive control demands. The remaining network of brain regions associated with word selection appears to be sufficient when items are not repeated.

Double dissociation of the roles of the left and right prefrontal cortices in anticipatory regulation of action.

Recent actions can benefit or disrupt our current actions and the prefrontal cortex (PFC) is thought to play a major role in the regulation of these actions before they occur. The left PFC has been associated with overcoming interference from past events in the context of language production and working memory. The right PFC, and especially the right IFG, has been associated with preparatory inhibition processes. But damage to the right PFC has also been associated with impairment in sustaining actions in motor intentional disorders. Moreover, bilateral dorsolateral PFC has been associated with the ability to maintain task-sets, and improve the performance of current actions based on previous experience. However, potential hemispheric asymmetries in anticipatory regulation of action have not yet been delineated. In the present study, patients with left (n=7) vs. right (n=6) PFC damage due to stroke and 14 aged- and education-matched controls performed a picture naming and a verbal Simon task (participants had to say "right" or "left" depending on the color of the picture while ignoring its position). In both tasks, performance depended on the nature of the preceding trial, but in different ways. In the naming task, performance decreased if previous pictures were from the same rather than from different semantic categories (i.e., semantic interference effect). In the Simon task, performance was better for both compatible (i.e., response matching the position of the stimulus) and incompatible trials when preceded by a trial of the same compatibility (i.e. Gratton effect) relative to sequential trials of different compatibility. Left PFC patients were selectively impaired in picture naming; they had an increased semantic interference effect compared to both right PFC patients and aged-matched controls. Conversely, right PFC patients were selectively impaired in the Simon task compared to controls or left PFC patients; they showed no benefit when sequential trials were compatible (cC vs. iC trials) or a decreased Gratton effect. These results provide evidence for a double dissociation between left and right PFC in the anticipatory regulation of action. Our results are in agreement with a preponderant role of the left PFC in overcoming proactive interference from competing memory representations and provide evidence that the right PFC, plays a role in sustaining goal-directed actions consistent with clinical data in right PFC patients with motor intentional disorders.

Treatment plan complexity metrics for predicting IMRT pre-treatment quality assurance results.

The planning of IMRT treatments requires a compromise between dose conformity (complexity) and deliverability. This study investigates established and novel treatment complexity metrics for 122 IMRT beams from prostate treatment plans. The Treatment and Dose Assessor software was used to extract the necessary data from exported treatment plan files and calculate the metrics. For most of the metrics, there was strong overlap between the calculated values for plans that passed and failed their quality assurance (QA) tests. However, statistically significant variation between plans that passed and failed QA measurements was found for the established modulation index and for a novel metric describing the proportion of small apertures in each beam. The 'small aperture score' provided threshold values which successfully distinguished deliverable treatment plans from plans that did not pass QA, with a low false negative rate.

A practical and theoretical definition of very small field size for radiotherapy output factor measurements.

PURPOSE: This work introduces the concept of very small field size. Output factor (OPF) measurements at these field sizes require extremely careful experimental methodology including the measurement of dosimetric field size at the same time as each OPF measurement. Two quantifiable scientific definitions of the threshold of very small field size are presented. METHODS: A practical definition was established by quantifying the effect that a 1 mm error in field size or detector position had on OPFs and setting acceptable uncertainties on OPF at 1%. Alternatively, for a theoretical definition of very small field size, the OPFs were separated into additional factors to investigate the specific effects of lateral electronic disequilibrium, photon scatter in the phantom, and source occlusion. The dominant effect was established and formed the basis of a theoretical definition of very small fields. Each factor was obtained using Monte Carlo simulations of a Varian iX linear accelerator for various square field sizes of side length from 4 to 100 mm, using a nominal photon energy of 6 MV. RESULTS: According to the practical definition established in this project, field sizes ≤ 15 mm were considered to be very small for 6 MV beams for maximal field size uncertainties of 1 mm. If the acceptable uncertainty in the OPF was increased from 1.0% to 2.0%, or field size uncertainties are 0.5 mm, field sizes ≤ 12 mm were considered to be very small. Lateral electronic disequilibrium in the phantom was the dominant cause of change in OPF at very small field sizes. Thus the theoretical definition of very small field size coincided to the field size at which lateral electronic disequilibrium clearly caused a greater change in OPF than any other effects. This was found to occur at field sizes ≤ 12 mm. Source occlusion also caused a large change in OPF for field sizes ≤ 8 mm. Based on the results of this study, field sizes ≤ 12 mm were considered to be theoretically very small for 6 MV beams. CONCLUSIONS: Extremely careful experimental methodology including the measurement of dosimetric field size at the same time as output factor measurement for each field size setting and also very precise detector alignment is required at field sizes at least ≤ 12 mm and more conservatively ≤ 15 mm for 6 MV beams. These recommendations should be applied in addition to all the usual considerations for small field dosimetry, including careful detector selection.

Network dynamics predict improvement in working memory performance following donepezil administration in healthy young adults.

Attentional selection in the context of goal-directed behavior involves top-down modulation to enhance the contrast between relevant and irrelevant stimuli via enhancement and suppression of sensory cortical activity. Acetylcholine (ACh) is believed to be involved mechanistically in such attention processes. The objective of the current study was to examine the effects of donepezil, a cholinesterase inhibitor that increases synaptic levels of ACh, on the relationship between performance and network dynamics during a visual working memory (WM) task involving relevant and irrelevant stimuli. Electroencephalogram (EEG) activity was recorded in 14 healthy young adults while they performed a selective face/scene working memory task. Each participant received either placebo or donepezil (5mg, orally) on two different visits in a double-blinded study. To investigate the effects of donepezil on brain network dynamics we utilized a novel EEG-based Brain Network Activation (BNA) analysis method that isolates location-time-frequency interrelations among event-related potential (ERP) peaks and extracts condition-specific networks. The activation level of the network modulated by donepezil, reflected in terms of the degree of its dynamical organization, was positively correlated with WM performance. Further analyses revealed that the frontal-posterior theta-alpha sub-network comprised the critical regions whose activation level correlated with beneficial effects on cognitive performance. These results indicate that condition-specific EEG network analysis could potentially serve to predict beneficial effects of therapeutic treatment in working memory.

Monte Carlo-based diode design for correction-less small field dosimetry.

Due to their small collecting volume, diodes are commonly used in small field dosimetry. However, the relative sensitivity of a diode increases with decreasing small field size. Conversely, small air gaps have been shown to cause a significant decrease in the sensitivity of a detector as the field size is decreased. Therefore, this study uses Monte Carlo simulations to look at introducing air upstream to diodes such that they measure with a constant sensitivity across all field sizes in small field dosimetry. Varying thicknesses of air were introduced onto the upstream end of two commercial diodes (PTW 60016 photon diode and PTW 60017 electron diode), as well as a theoretical unenclosed silicon chip using field sizes as small as 5 mm × 5 mm. The metric D(w,Q)/D(Det,Q) used in this study represents the ratio of the dose to a point of water to the dose to the diode active volume, for a particular field size and location. The optimal thickness of air required to provide a constant sensitivity across all small field sizes was found by plotting D(w,Q)/D(Det,Q) as a function of introduced air gap size for various field sizes, and finding the intersection point of these plots. That is, the point at which D(w,Q)/D(Det,Q) was constant for all field sizes was found. The optimal thickness of air was calculated to be 3.3, 1.15 and 0.10 mm for the photon diode, electron diode and unenclosed silicon chip, respectively. The variation in these results was due to the different design of each detector. When calculated with the new diode design incorporating the upstream air gap, k(f(clin),f(msr))(Q(clin),Q(msr)) was equal to unity to within statistical uncertainty (0.5%) for all three diodes. Cross-axis profile measurements were also improved with the new detector design. The upstream air gap could be implanted on the commercial diodes via a cap consisting of the air cavity surrounded by water equivalent material. The results for the unclosed silicon chip show that an ideal small field dosimetry diode could be created by using a silicon chip with a small amount of air above it.

The effect of very small air gaps on small field dosimetry.

The purpose of this study was to investigate the effect of very small air gaps (less than 1 mm) on the dosimetry of small photon fields used for stereotactic treatments. Measurements were performed with optically stimulated luminescent dosimeters (OSLDs) for 6 MV photons on a Varian 21iX linear accelerator with a Brainlab µMLC attachment for square field sizes down to 6 mm × 6 mm. Monte Carlo simulations were performed using EGSnrc C++ user code cavity. It was found that the Monte Carlo model used in this study accurately simulated the OSLD measurements on the linear accelerator. For the 6 mm field size, the 0.5 mm air gap upstream to the active area of the OSLD caused a 5.3% dose reduction relative to a Monte Carlo simulation with no air gap. A hypothetical 0.2 mm air gap caused a dose reduction >2%, emphasizing the fact that even the tiniest air gaps can cause a large reduction in measured dose. The negligible effect on an 18 mm field size illustrated that the electronic disequilibrium caused by such small air gaps only affects the dosimetry of the very small fields. When performing small field dosimetry, care must be taken to avoid any air gaps, as can be often present when inserting detectors into solid phantoms. It is recommended that very small field dosimetry is performed in liquid water. When using small photon fields, sub-millimetre air gaps can also affect patient dosimetry if they cannot be spatially resolved on a CT scan. However the effect on the patient is debatable as the dose reduction caused by a 1 mm air gap, starting out at 19% in the first 0.1 mm behind the air gap, decreases to <5% after just 2 mm, and electronic equilibrium is fully re-established after just 5 mm.

Anterior cingulate cortex and cognitive control: neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex.

Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring.

Executive functions after orbital or lateral prefrontal lesions: neuropsychological profiles and self-reported executive functions in everyday living.

OBJECTIVE: This study examined the effects of chronic focal lesions to the lateral prefrontal cortex (LPFC) or orbitofrontal cortex (OFC) on neuropsychological test performance and self-reported executive functioning in everyday living. METHODS: Fourteen adults with OFC lesions were compared to 10 patients with LPFC injuries and 21 healthy controls. Neuropsychological tests with emphasis on measures of cognitive executive function were administered along with the Behavior Rating Inventory of Executive Functions (BRIEF-A) and a psychiatric screening instrument. RESULTS: The LPFC group differed from healthy controls on neuropsychological tests of sustained mental effort, response inhibition, working memory and mental switching, while the BRIEF-A provided more clinically important information on deficits in everyday life in the OFC group compared to the LPFC group. Correlations between neuropsychological test results and BRIEF-A were weak, while the BRIEF-A correlated strongly with emotional distress. CONCLUSIONS: It was demonstrated that LPFC damage is particularly prone to cause cognitive executive deficit, while OFC injury is more strongly associated with self-reported dysexecutive symptoms in everyday living. The study illustrates the challenge of identifying executive deficit in individual patients and the lack of strong anatomical specificity of the currently employed methods. There is a need for an integrative methodological approach where standard testing batteries are supplemented with neuropsychiatric and frontal-specific rating scales.

Monte Carlo verification of gel dosimetry measurements for stereotactic radiotherapy.

The quality assurance of stereotactic radiotherapy and radiosurgery treatments requires the use of small-field dose measurements that can be experimentally challenging. This study used Monte Carlo simulations to establish that PAGAT dosimetry gel can be used to provide accurate, high-resolution, three-dimensional dose measurements of stereotactic radiotherapy fields. A small cylindrical container (4 cm height, 4.2 cm diameter) was filled with PAGAT gel, placed in the parietal region inside a CIRS head phantom and irradiated with a 12-field stereotactic radiotherapy plan. The resulting three-dimensional dose measurement was read out using an optical CT scanner and compared with the treatment planning prediction of the dose delivered to the gel during the treatment. A BEAMnrc/DOSXYZnrc simulation of this treatment was completed, to provide a standard against which the accuracy of the gel measurement could be gauged. The three-dimensional dose distributions obtained from Monte Carlo and from the gel measurement were found to be in better agreement with each other than with the dose distribution provided by the treatment planning system's pencil beam calculation. Both sets of data showed close agreement with the treatment planning system's dose distribution through the centre of the irradiated volume and substantial disagreement with the treatment planning system at the penumbrae. The Monte Carlo calculations and gel measurements both indicated that the treated volume was up to 3 mm narrower, with steeper penumbrae and more variable out-of-field dose, than predicted by the treatment planning system. The Monte Carlo simulations allowed the accuracy of the PAGAT gel dosimeter to be verified in this case, allowing PAGAT gel to be utilized in the measurement of dose from stereotactic and other radiotherapy treatments, with greater confidence in the future.

A dynamical pattern recognition model of γ activity in auditory cortex.

This paper describes a dynamical process which serves both as a model of temporal pattern recognition in the brain and as a forward model of neuroimaging data. This process is considered at two separate levels of analysis: the algorithmic and implementation levels. At an algorithmic level, recognition is based on the use of Occurrence Time features. Using a speech digit database we show that for noisy recognition environments, these features rival standard cepstral coefficient features. At an implementation level, the model is defined using a Weakly Coupled Oscillator (WCO) framework and uses a transient synchronization mechanism to signal a recognition event. In a second set of experiments, we use the strength of the synchronization event to predict the high gamma (75-150 Hz) activity produced by the brain in response to word versus non-word stimuli. Quantitative model fits allow us to make inferences about parameters governing pattern recognition dynamics in the brain.

Single trial discrimination of individual finger movements on one hand: a combined MEG and EEG study.

It is crucial to understand what brain signals can be decoded from single trials with different recording techniques for the development of Brain-Machine Interfaces. A specific challenge for non-invasive recording methods are activations confined to small spatial areas on the cortex such as the finger representation of one hand. Here we study the information content of single trial brain activity in non-invasive MEG and EEG recordings elicited by finger movements of one hand. We investigate the feasibility of decoding which of four fingers of one hand performed a slight button press. With MEG we demonstrate reliable discrimination of single button presses performed with the thumb, the index, the middle or the little finger (average over all subjects and fingers 57%, best subject 70%, empirical guessing level: 25.1%). EEG decoding performance was less robust (average over all subjects and fingers 43%, best subject 54%, empirical guessing level 25.1%). Spatiotemporal patterns of amplitude variations in the time series provided best information for discriminating finger movements. Non-phase-locked changes of mu and beta oscillations were less predictive. Movement related high gamma oscillations were observed in average induced oscillation amplitudes in the MEG but did not provide sufficient information about the finger's identity in single trials. Importantly, pre-movement neuronal activity provided information about the preparation of the movement of a specific finger. Our study demonstrates the potential of non-invasive MEG to provide informative features for individual finger control in a Brain-Machine Interface neuroprosthesis.

Sub-centimeter language organization in the human temporal lobe.

The human temporal lobe is well known to be critical for language comprehension. Previous physiological research has focused mainly on non-invasive neuroimaging and electrophysiological techniques with each approach requiring averaging across many trials and subjects. The results of these studies have implicated extended anatomical regions in peri-sylvian cortex in speech perception. These non-invasive studies typically report a spatially homogenous functional pattern of activity across several centimeters of cortex. We examined the spatiotemporal dynamics of word processing using electrophysiological signals acquired from high-density electrode arrays (4mm spacing) placed directly on the human temporal lobe. Electrocorticographic (ECoG) activity revealed a rich mosaic of language activity, which was functionally distinct at four mm separation. Cortical sites responding specifically to word and not phoneme stimuli were surrounded by sites that responded to both words and phonemes. Other sub-regions of the temporal lobe responded robustly to self-produced speech and minimally to external stimuli while surrounding sites at 4mm distance exhibited an inverse pattern of activation. These data provide evidence for temporal lobe specificity to words as well as self-produced speech. Furthermore, the results provide evidence that cortical processing in the temporal lobe is not spatially homogenous over centimeters of cortex. Rather, language processing is supported by independent and spatially distinct functional sub-regions of cortex at a resolution of at least 4mm.

Adapting a generic BEAMnrc model of the BrainLAB m3 micro-multileaf collimator to simulate a local collimation device.

This work is focussed on developing a commissioning procedure so that a Monte Carlo model, which uses BEAMnrc's standard VARMLC component module, can be adapted to match a specific BrainLAB m3 micro-multileaf collimator (microMLC). A set of measurements are recommended, for use as a reference against which the model can be tested and optimized. These include radiochromic film measurements of dose from small and offset fields, as well as measurements of microMLC transmission and interleaf leakage. Simulations and measurements to obtain microMLC scatter factors are shown to be insensitive to relevant model parameters and are therefore not recommended, unless the output of the linear accelerator model is in doubt. Ultimately, this note provides detailed instructions for those intending to optimize a VARMLC model to match the dose delivered by their local BrainLAB m3 microMLC device.

Modeling a complex micro-multileaf collimator using the standard BEAMnrc distribution.

PURPOSE: The component modules in the standard BEAMnrc istribution may appear to be insufficient to model micro-multileaf collimators that have trifaceted leaf ends and complex leaf profiles. This note indicates, however, that accurate Monte Carlo simulations of radiotherapy beams defined by a complex collimation device can be completed using BEAMnrc's standard VARMLC component module. METHODS: That this simple collimator model can produce spatially and dosimetrically accurate microcollimated fields is illustrated using comparisons with ion chamber and film measurements of the dose deposited by square and irregular fields incident on planar, homogeneous water phantoms. RESULTS: Monte Carlo dose calculations for on-axis and off-axis fields are shown to produce good agreement with experimental values, even on close examination of the penumbrae. CONCLUSIONS: The use of a VARMLC model of the micro-multileaf collimator, along with a commissioned model of the associated linear accelerator, is therefore recommended as an alternative to the development or use of in-house or third-party component modules for simulating stereotactic radiotherapy and radiosurgery treatments. Simulation parameters for the VARMLC model are provided which should allow other researchers to adapt and use this model to study clinical stereotactic radiotherapy treatments.

High gamma power is phase-locked to theta oscillations in human neocortex.

We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.

The functional neuroanatomy of working memory: contributions of human brain lesion studies.

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.