Transcranial magnetic stimulation (TMS) applied to left dorsolateral prefrontal cortex disrupts verbal working memory performance in humans

Working memory refers to the temporary maintenance and processing of information and involves executive processes that manipulate the contents of the working memory. The role of the executive function in the human left dorsolateral prefrontal cortex (LDLPFC) was explored using transcranial magnetic stimulation (TMS) after confirming the LDLPFC activation using fMRI. We applied double-pulse TMS having a 100-ms inter-pulse interval to LDLPFC immediately after the subjects finished reading the sentences of the reading span test (RST) task, an efficient measure of verbal working memory, in which dual tasks that include both sentence comprehension and word maintenance are required. Using eight normal participants, we found a significant deterioration of performance, i.e., decreased number of correctly reported words, in RST due to TMS stimulation of LDLPFC. Evidence suggests that transient functional disruption of the LDLPFC impairs performance in the maintenance processing of the RST task.     

Reorganization of vibrissal motor representation following severing and repair of the facial nerve in adult rats

This study examined the ability of adult rat motor cortex to reorganize its relationship with the somatic musculature following the severing and regeneration of a motor nerve. For this purpose experiments were performed on ten male albino rats where the facial nerve on one side was severed, sutured and allowed to regenerate for 6 months. Cortical motor output organization was assessed by mapping the vibrissal movement area extension and thresholds evoked by intracortical electrical stimulation in anesthetized rats. In all ten animals, the cortical output pattern of the motor cortex contralateral to the normal side was compared with that contralateral to the reinnervated side. After facial nerve reinnervation, the most notable differences in primary motor cortex (M1) output organization in the hemispheres contralateral to the reinnervated side were: (a) the area from which vibrissa movements could be evoked at low thresholds was smaller (mean 1.2+/-0.38 mm, range 0.75-1.75 mm), decreasing to 64.2% below those in hemispheres contralateral to the normal side (mean 3.4+/-0.52 mm, range 2.5-4 mm). The reorganized vibrissa area consisted of contiguous or discontinuous points shrunken to the medialmost portion of normal M1 vibrissal representation. (b) There was a clear medial extension of the forelimb representation, and a more modest lateral expansion of eye representation, into the vibrissa territory. The mean threshold required to evoke vibrissa movements was significantly higher in the hemispheres contralateral to the reinnervated side than in the other hemispheres (normal 23.9+/-9.7 microA vs reinnervated 37.8+/-11.9 microA; P< or =0.0001; t-test). The stimulation currents required to evoke other types of body movements were similar in the normal and reinnervated sides. Similar results were observed in all rats. In conclusion, these results indicate that motor nerve reinnervation is sufficient to produce long-lasting changes at a higher motor cortical level. This supports the notion that central supranuclear mechanisms may also be involved in the disorder of facial movements observed after facial nerve reinnervation.     

Quantifying the heritability of task-related brain activation and performance during the N-back working memory task: a twin fMRI study

Working memory-related brain activation has been widely studied, and impaired activation patterns have been reported for several psychiatric disorders. We investigated whether variation in N-back working memory brain activation is genetically influenced in 60 pairs of twins, (29 monozygotic (MZ), 31 dizygotic (DZ); mean age 24.4+/-1.7S.D.). Task-related brain response (BOLD percent signal difference of 2 minus 0-back) was measured in three regions of interest. Although statistical power was low due to the small sample size, for middle frontal gyrus, angular gyrus, and supramarginal gyrus, the MZ correlations were, in general, approximately twice those of the DZ pairs, with non-significant heritability estimates (14-30%) in the low-moderate range. Task performance was strongly influenced by genes (57-73%) and highly correlated with cognitive ability (0.44-0.55). This study, which will be expanded over the next 3 years, provides the first support that individual variation in working memory-related brain activation is to some extent influenced by genes.     

Neural substrates of manipulation in visuospatial working memory

The present study aimed to investigate in humans whether similar neuronal mechanisms underlie the manipulation and active processing of visual and visuospatial stimuli. Simultaneous and successive mental rotation and identity judgment of 2-D matrices and 3-D cube figures were contrasted using functional magnetic resonance imaging (fMRI). Results demonstrate that activation patterns during mental rotation with low working memory demands differ depending on stimulus type (2-D vs. 3-D). Comparison of simultaneous mental rotation of matrices and 3-D cubes resulted in activation of frontal as well as inferior and superior parietal cortices. The opposite contrast (mental rotation of 3-D cubes vs. 2-D matrices) yielded only frontal cortex activation. The findings also yield evidence for converging, overlapping activation patterns for 2-D and 3-D stimuli if working memory demands are increased. Results are discussed within the framework of current working memory models.     

Segregation of working memory functions within the dorsolateral prefrontal cortex

It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.     

Chemical neuromodulation of frontal-executive functions in humans and other animals

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.     

Information processing in long delay memory-guided saccades: further insights from TMS

The performance of memory-guided saccades with two different delays (3 s and 30 s of memorisation) was studied in eight subjects. Single pulse transcranial magnetic stimulation (TMS) was applied simultaneously over the left and right dorsolateral prefrontal cortex (DLPFC) 1 s after target presentation. In both delays, stimulation significantly increased the percentage of error in amplitude of memory-guided saccades. Furthermore, the interfering effect of TMS was significantly higher in the short delay compared to that of the long delay paradigm. The results are discussed in the context of a mixed model of spatial working memory control including two components: First, serial information processing with a predominant role of the DLPFC during the early period of memorisation and, second, parallel information processing, which is independent from the DLPFC, operating during longer delays.     

Effects of neurocognitive enhancement therapy in schizophrenia: Normalisation of memory performance

Introduction. A preponderance of research indicates that cognitive function in schizophrenia can be improved through cognitive remediation. However, few studies have attempted to characterise the extent of improvement relative to nonpsychiatric controls.

Method. Cognitive performance on reaction time, digit recall, and word recall of 58 schizophrenia patients at baseline and after 6 months of cognitive remediation was compared to the performance on these tasks of 39 community controls. Schizophrenia patients participated in Neurocognitive Enhancement Therapy (NET) and received hierarchical training on the memory tasks, but not on the reaction time task, which was only administered at intake and follow‐up.

Results. The schizophrenia sample showed significantly poorer performances than the community control sample on all three tasks at baseline. NET led to significant improvements in performance on trained memory tasks, but not the untrained reaction time task. There was a significant increase in the proportion of schizophrenia patients who achieved normal range performance on the memory tasks.

Conclusions. 52% of schizophrenia patients who were impaired on at least one of the memory tasks normalised their performance on at least one of those tasks as a result of cognitive training. Results suggest that clinically meaningful improvement may be possible using cognitive remediation.     

tDCS selectively improves working memory in older adults with more education

Cognitive performance, including performance on working memory (WM) tasks declines with age. Changes in brain activations are one presumed contributor to WM decline in the healthy aging population. In particular, neuroimaging studies show that when older adults perform WM tasks there tends to be greater bilateral frontal activity than in younger adults. We hypothesized that stimulating the prefrontal cortex in healthy older adults would improve WM performance. To test this hypothesis we employed transcranial direct current stimulation (tDCS), a neurostimulation technique in which small amounts of electrical current are applied to the scalp with the intent of modulating the activity in underlying neurons. Across three testing sessions we applied sham stimulation or anodal tDCS to the left (F3) or right (F4) prefrontal cortex to healthy older adults as they performed trials of verbal and visual 2-back WM tasks. Surprisingly, tDCS was uniformly beneficial across site and WM task, but only in older adults with more education. In the less educated group, tDCS provided no benefit to verbal or visual WM performance. We interpret these findings as evidence for differential frontal recruitment as a function of strategy when older adults perform WM tasks.     

Effects of aging and working memory demands on prospective memory

The current study used event-related brain potentials (ERPs) to examine the effects of aging, increasing the working memory demands of the ongoing activity, and a prospective memory load on the neural correlates of prospective remembering and target recognition. The behavioral data revealed that the success of prospective memory was sensitive to working memory load in younger, but not older, adults and that a prospective memory load had a greater effect on the performance of older adults than that of younger adults. The ERP data revealed age-related differences in the neural correlates of the detection of prospective cues, post-retrieval processes that support prospective memory, and target recognition. Our results support the hypothesis that there are age-related differences in the ability to recruit preparatory attentional processes that underlie prospective memory, and demonstrate that younger and older adults may recruit somewhat different neural generators to support prospective memory and working memory.     

Variability in neuronal activity in primate cortex during working memory tasks

Persistent elevated neuronal activity has been identified as the neuronal correlate of working memory. It is generally assumed in the literature and in computational and theoretical models of working memory that memory-cell activity is stable and replicable; however, this assumption may be an artifact of the averaging of data collected across trials, and needs experimental verification. In this study, we introduce a classification scheme to characterize the firing frequency trends of cells recorded from the cortex of monkeys during performance of working memory tasks. We examine the frequency statistics and variability of firing during baseline and memory periods. We also study the behavior of cells on individual trials and across trials, and explore the stability of cellular firing during the memory period. We find that cells from different firing-trend classes possess markedly different statistics. We also find that individual cells show substantial variability in their firing behavior across trials, and that firing frequency also varies markedly over the course of a single trial. Finally, the average frequency distribution is wider, the magnitude of the frequency increases from baseline to memory smaller, and the magnitude of frequency decreases larger than is generally assumed. These results may serve as a guide in the evaluation of current theories of the cortical mechanisms of working memory.     

Neural correlates of decision making with explicit information about probabilities and incentives in elderly healthy subjects

Recent functional neuroimaging and lesion studies demonstrate the involvement of the orbitofrontal/ventromedial prefrontal cortex as a key structure in decision making processes. This region seems to be particularly crucial when contingencies between options and consequences are unknown but have to be learned by the use of feedback following previous decisions (decision making under ambiguity). However, little is known about the neural correlates of decision making under risk conditions in which information about probabilities and potential outcomes is given. In the present study, we used functional magnetic resonance imaging to measure blood-oxygenation-level-dependent (BOLD) responses in 12 subjects during a decision making task. This task provided explicit information about probabilities and associated potential incentives. The responses were compared to BOLD signals in a control condition without information about incentives. In contrast to previous decision making studies, we completely removed the outcome phase following a decision to exclude the potential influence of feedback previously received on current decisions. The results indicate that the integration of information about probabilities and incentives leads to activations within the dorsolateral prefrontal cortex, the posterior parietal lobe, the anterior cingulate and the right lingual gyrus. We assume that this pattern of activation is due to the involvement of executive functions, conflict detection mechanisms and arithmetic operations during the deliberation phase of decisional processes that are based on explicit information.     

Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation

We studied the effect of repetitive transcranial magnetic stimulation (rTMS) on changes in regional cerebral blood flow (rCBF) as revealed by positron emission tomography (PET) while subjects performed a 2-back verbal working memory (WM) task. rTMS to the right or left dorsolateral prefrontal cortex (DLPFC), but not to the midline frontal cortex, significantly worsened performance in the WM task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. These results for the first time demonstrate the ability of rTMS to produce temporary functional lesions in elements of a neuronal network thus changing its distributed activations and resulting in behavioral consequences.     

Working memory as an emergent property of the mind and brain

Cognitive neuroscience research on working memory has been largely motivated by a standard model that arose from the melding of psychological theory with neuroscience data. Among the tenets of this standard model are that working memory functions arise from the operation of specialized systems that act as buffers for the storage and manipulation of information, and that frontal cortex (particularly prefrontal cortex) is a critical neural substrate for these specialized systems. However, the standard model has been a victim of its own success, and can no longer accommodate many of the empirical findings of studies that it has motivated. An alternative is proposed: Working memory functions arise through the coordinated recruitment, via attention, of brain systems that have evolved to accomplish sensory-, representation-, and action-related functions. Evidence from behavioral, neuropsychological, electrophysiological, and neuroimaging studies, from monkeys and humans, is considered, as is the question of how to interpret delay-period activity in the prefrontal cortex.     

Distinctions between orthographic long-term memory and working memory

Research in the cognitive and neural sciences has long posited a distinction between the long-term memory (LTM) storage of information and the short-term buffering of information that is being actively manipulated in working memory (WM). This basic type of distinction has been posited in a variety of domains, including written language production—spelling. In the domain of spelling, the primary source of empirical evidence regarding this distinction has been cognitive neuropsychological studies reporting deficits selectively affecting what the cognitive neuropsychological literature has referred to as the orthographic lexicon (LTM) or the graphemic buffer (WM). Recent papers have reexamined several of the hallmark characteristics of impairment affecting the graphemic buffer, with implications for our understanding of the nature of the orthographic LTM and WM systems. In this paper, we present a detailed case series study of 4 individuals with acquired spelling deficits and report evidence from both error types and factors influencing error rates that support the traditional distinction between these cognitive systems involved in spelling. In addition, we report evidence indicating possible interaction between these systems, which is consistent with a variety of recent findings in research on spelling.     

Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory

Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex that can be more pronounced than cortical modulation induced by transcranial magnetic stimulation, but there are no studies that have evaluated the effects of tDCS on working memory. Our aim was to determine whether anodal transcranial direct current stimulation, which enhances brain cortical excitability and activity, would modify performance in a sequential-letter working memory task when administered to the dorsolateral prefrontal cortex (DLPFC). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Our results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. This accuracy enhancement during active stimulation cannot be accounted for by slowed responses, as response times were not changed by stimulation. Our results indicate that left prefrontal anodal stimulation leads to an enhancement of working memory performance. Furthermore, this effect depends on the stimulation polarity and is specific to the site of stimulation. This result may be helpful to develop future interventions aiming at clinical benefits.Felipe Fregni and Paulo S. Boggio contributed equally to this work.     

Interfering with working memory in humans

The interference method transcranial magnetic stimulation has to be seen as a complimentary tool to the other noninvasive correlational techniques such as positron emission tomography, functional magnetic resonance imaging or electroencephalography in cognitive neuroscience. However, the combination of two methods e.g. transcranial magnetic stimulation and positron emission tomography seems to be the strongest approach to validate or postulate new hypotheses. In this review several studies using transcranial magnetic stimulation to disentangle working memory functions are presented. The conclusion is drawn that there exists a superordinated amodal central executive within the dorsolateral prefrontal cortex strongly connected with modality specific areas mainly within the prefrontal cortex.     

The role of the rat prelimbic/infralimbic cortex in working memory: not involved in the short-term maintenance but in monitoring and processing functions

Contrary to human and primate, working memory in the rodent is usually considered as a simple short term memory buffer and mainly investigated using delayed response paradigms. The aim of the present study was to further investigate the role of the rat prelimbic/infralimbic cortex in different spatial delayed tasks in order to dissociate its involvement in temporary storage from other information processes, such as behavioral flexibility and attention. In experiment 1 rats were trained in a standard elimination win-shift task in a radial-arm maze after which a 1-min delay was inserted mid trial. Prelimbic/infralimbic lesions induced only a transient disruption of performance following introduction of the delay. In experiment 2, rats were trained directly in a win-shift task with a 5-min delay that was subsequently extended to 30 min. Prelimbic/infralimbic lesions did not significantly affect behavior. Nevertheless, transient disruptions of performance (correlated with lesion extent) were noted repeatedly in lesioned rats when sets of interfering events were presented. The present findings indicate that prelimbic/infralimbic cortex is not directly involved in the short term maintenance of specific information but is implicated when changes, such as sudden introduction of a delay or exposure to unexpected interfering events, alter the initial situation. It appears that working memory in rodents should be considered, as in humans and primates, to encompass both storage and monitoring functions. The present results along with previous ones strongly suggest that prelimbic/infralimbic cortex is not involved in the temporary on-line storage but rather in the control of information required to prospectively organize the ongoing action.     

A functional magnetic resonance imaging study of the effects of pergolide, a dopamine receptor agonist, on component processes of working memory

Working memory is an important cognitive process dependent on a network of prefrontal and posterior cortical regions. In this study we tested the effects of the mixed D1-D2 dopamine receptor agonist pergolide on component processes of human working memory using functional magnetic resonance imaging (fMRI). An event-related trial design allowed separation of the effects on encoding, maintenance, and retrieval processes. Subjects were tested with spatial and object memoranda to investigate modality-specific effects of dopaminergic stimulation. We also measured baseline working memory capacity as previous studies have shown that effects of dopamine agonists vary with working memory span. Pergolide improved reaction time for high-span subjects and impaired reaction time for low-span subjects. This span-dependent change in behavior was accompanied by span-dependent changes in delay-related activity in the premotor cortex. We also found evidence for modality-specific effects of pergolide only during the response period. Pergolide increased activity for spatial memoranda and decreased activity for object memoranda in task-related regions including the prefrontal and parietal cortices.     

Using arterial spin labeling perfusion MRI to explore how midazolam produces anterograde amnesia

While our previous work suggests that the midazolam-induced memory impairment results from the inhibition of new association formation, little is known about the neural correlates underlying these effects beyond the effects of GABA agonists on the brain. We used arterial spin-labeling perfusion MRI to measure cerebral blood flow changes associated with the effects of midazolam on ability to learn arbitrary word-pairs. Using a double-blind, within-subject cross-over design, subjects studied word-pairs for a later cued-recall test while they were scanned. Lists of different word-pairs were studied both before and after an injection of either saline or midazolam. As expected, recall was severely impaired under midazolam. The contrast of MRI signal before and after midazolam administration revealed a decrease in CBF in the left dorsolateral prefrontal cortex (DLPFC), left cingulate gyrus and left posterior cingulate gyrus/precuneus. These effects were observed even after controlling for any effect of injection. A strong correlation between the midazolam-induced changes in neural activity and memory performance was found in the left DLPFC. These findings provide converging evidence that this region plays a critical role in the formation of new associations and that low functioning of this region is associated with anterograde amnesia.