Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory

How the cerebellum is involved in the practice and proficiency of non-motor functions is still unclear. We tested whether transcranial direct current stimulation (tDCS) over the cerebellum (cerebellar tDCS) induces after-effects on the practice-dependent increase in the proficiency of a working memory (WM) task (Sternberg test) in 13 healthy subjects. We also assessed the effects of cerebellar tDCS on visual evoked potentials (VEPs) in four subjects and compared the effects of cerebellar tDCS on the Sternberg test with those elicited by tDCS delivered over the prefrontal cortex in five subjects. Our experiments showed that anodal or cathodal tDCS over the cerebellum impaired the practice-dependent improvement in the reaction times in a WM task. Because tDCS delivered over the prefrontal cortex induced an immediate change in the WM task but left the practice-dependent proficiency unchanged, the effects of cerebellar tDCS are structure-specific. Cerebellar tDCS left VEPs unaffected, its effect on the Sternberg task therefore seems unlikely to arise from visual system involvement. In conclusion, tDCS over the cerebellum specifically impairs the practice-dependent proficiency increase in verbal WM.     

Visual working memory revealed by repetitive transcranial magnetic stimulation

We evaluated whether repetitive transcranial magnetic stimulation (rTMS) could be utilized for studying the hemispheric lateralization and anatomical localization of the cortical areas of the visual system that are concerned with object-related visual working memory. In eight normal volunteers, visual working memory was tested during rTMS delivery over nine regions in each hemisphere. Visual working memory was significantly disturbed by rTMS over the right hemisphere compared with the left (P<0.05). The disturbance in visual working memory by rTMS was significant over the right inferior frontal (F8), inferior temporal (T8), and middle parietal (P4) areas compared with the control region (P<0.05). This study suggests that visual working memory is lateralized to the right hemisphere and localized in the right inferior frontal, inferior temporal, and middle-parietal areas. As a non-invasive tool, rTMS may be useful for the functional localization of the working memory system.     

Transcranial magnetic stimulation of left prefrontal cortex impairs working memory.

OBJECTIVES: Several lines of evidence suggest that the prefrontal cortex is involved in working memory. Our goal was to determine whether transient functional disruption of the dorsolateral prefrontal cortex (DLPFC) would impair performance in a sequential-letter working memory task. METHODS: Subjects were shown sequences of letters and asked to state whether the letter just displayed was the same as the one presented 3-back. Single-pulse transcranial magnetic stimulation (TMS) was applied over the DLPFC between letter presentations. RESULTS: TMS applied over the left DLPFC resulted in increased errors relative to no TMS controls. TMS over the right DLPFC did not alter working memory performance. CONCLUSION: Our results indicate that the left prefrontal cortex has a crucial role in at least one type of working memory.     

Bilateral parieto-frontal network for verbal working memory: an interference approach using repetitive transcranial magnetic stimulation (rTMS)

Verbal working memory has been attributed to a left-dominant neuronal network, including parietal, temporal and prefrontal cortical areas. The current study was designed to evaluate the contribution of these brain regions to verbal working memory processes and to assess possible hemispheric asymmetry. The effect of repetitive transcranial stimulation (rTMS) on performance in a verbal working memory task both during, and after an rTMS train (110% of individual motor threshold, 4 Hz) over nine different scalp locations was studied [bilateral middle frontal gyrus (MFG), bilateral supramarginal gyrus (SMG), bilateral inferior parietal cortex (IP) and three different midline control sites]. Significant performance deterioration was observed during rTMS over the left and right MFG and left and right IP. There was no consistent interference effect across subjects over the left or right SMG and the three different midline control sites. The interference effect with the given stimulation parameters did not last beyond the rTMS train itself. The data provide evidence for a symmetrical, bilateral parieto-frontal verbal working memory network. The data are discussed with respect to the competing ideas of a parieto-frontal central executive network vs. a network that processes the inherent semantic and object features of the visually presented verbal stimuli in parallel.     

Cerebellar contributions to verbal working memory: beyond cognitive theory

Neuropsychological findings together with recent advances in neuroanatomical and neuroimaging techniques have spurred the investigation of cerebellar contributions to cognition. One cognitive process that has been the focus of much research is working memory, in particular its verbal component. Influenced by Baddeley’s cognitive theory of working memory, cerebellar activation during verbal working memory tasks has been predominantly attributed to the cerebellum’s involvement in an articulatory rehearsal network. Recent neuroimaging and neuropsychological findings are inconsistent with a simple motor view of the cerebellum’s function in verbal working memory. The present article examines these findings and their implications for an articulatory rehearsal proposal of cerebellar function. Moving beyond cognitive theory, we propose two alternative explanations for cerebellar involvement in verbal working memory: Error-driven adjustment and internal timing. These general theories of cerebellar function have been successfully adapted from the motor literature to explain cognitive functions of the cerebellum. We argue that these theories may also provide a useful framework to understand the non-motor contributions of the cerebellum to verbal working memory.     

Time-dependent hierarchical organization of spatial working memory: a transcranial magnetic stimulation study

The performance of memory-guided saccades with two different delays (3 and 30 s of memorization) was studied in seven healthy subjects. Double-pulse transcranial magnetic stimulation (dTMS) with an interstimulus interval of 100 ms was applied over the right dorsolateral prefrontal cortex (DLPFC) early (1 s after target presentation) and late (28 s after target presentation). Early stimulation significantly increased in both delays the percentage of error in amplitude (PEA) of contralateral memory-guided saccades compared to the control experiment without stimulation. dTMS applied late in the delay had no significant effect on PEA. Furthermore, we found a significantly smaller effect of early stimulation in the long-delay paradigm. These results suggest a time-dependent hierarchical organization of the spatial working memory with a functional dominance of DLPFC during the early memorization, independent from the memorization delay. For a long memorization delay, however, working memory seems to have an additional, DLPFC-independent component.     

Rapid-rate transcranial magnetic stimulation of animal auditory cortex impairs short-term but not long-term memory formation

Bilateral rapid-rate transcranial magnetic stimulation (rTMS) of gerbil auditory cortex with a miniature coil device was used to study short-term and long-term effects on discrimination learning of frequency-modulated tones. We found previously that directional discrimination of frequency modulation (rising vs. falling) relies on auditory cortex processing and that formation of its memory depends on local protein synthesis. Here we show that, during training over 5 days, certain rTMS regimes contingent on training had differential effects on the time course of learning. When rTMS was applied several times per day, i.e. four blocks of 5 min rTMS each followed 5 min later by a 3-min training block and 15-min intervals between these blocks (experiment A), animals reached a high discrimination performance more slowly over 5 days than did controls. When rTMS preceded only the first two of four training blocks (experiment B), or when prolonged rTMS (20 min) preceded only the first block, or when blocks of experiment A had longer intervals (experiments C and D), no significant day-to-day effects were found. However, in experiment A, and to some extent in experiment B, rTMS reduced the within-session discrimination performance. Nevertheless the animals learned, as demonstrated by a higher performance the next day. Thus, our results indicate that rTMS treatments accumulate over a day but not strongly over successive days. We suggest that rTMS of sensory cortex, as used in our study, affects short-term memory but not long-term memory formation.     

Using transcranial direct current stimulation to improve verbal working memory: A detailed review of the methodology

Introduction: Transcranial direct current stimulation (tDCS) is a noninvasive electrical brain stimulation technique that has been used extensively over prefrontal cortex in an effort to enhance verbal working memory (WM). However, inconsistent and contradictory outcomes from similar stimulation protocols have created a strong need to examine methodologies in greater detail. This review undertook an in-depth look at both positive and negative prefrontal tDCS–WM findings in adult populations to shed light on methodological parameters that may be driving the inconsistent outcomes in the literature.

Method: To facilitate comprehension of the protocols employed in each study and aid between-study comparisons, we illustrated study design alongside key findings. To aid clinical translation, we reviewed separately by population (healthy young adults versus WM impaired) performance changes during stimulation (online) versus following stimulation (offline), which offers more therapeutic promise.

Results: Our dissection of the literature highlighted design factors that are likely adding unnecessary noise and obscuring outcomes. Of note, a major blind spot in the literature relates to cognitive factors, including influential characteristics pertaining to the details of the WM test used to assess tDCS effects and participant characteristics that influence WM abilities and the organization of WM in the brain, and can impact the efficacy of tDCS–WM protocols through complex interactions.

Conclusions: By attending to both cognitive- and tDCS-related factors in the design phase of the study, future researchers can reduce unintended variation that may obscure positive outcomes or lead to spurious results, thereby advancing the field forward toward developing more effective tDCS–WM protocols.     

Dorsolateral prefrontal cortex, working memory and episodic memory processes: insight through transcranial magnetic stimulation techniques

The ability to recall and recognize facts we experienced in the past is based on a complex mechanism in which several cerebral regions are implicated. Neuroimaging and lesion studies agree in identifying the frontal lobe as a crucial structure for memory processes, and in particular for working memory and episodic memory and their relationships. Furthermore, with the introduction of transcranial magnetic stimulation (TMS) a new way was proposed to investigate the relationships between brain correlates, memory functions and behavior. The aim of this review is to present the main findings that have emerged from experiments which used the TMS technique for memory analysis. They mainly focused on the role of the dorsolateral prefrontal cortex in memory process. Furthermore, we present state-of-the-art evidence supporting a possible use of TMS in the clinic. Specifically we focus on the treatment of memory deficits in depression and anxiety disorders.     

Left temporoparietal transcranial magnetic stimulation in treatment-resistant schizophrenia with verbal hallucinations

Left temporoparietal repetitive transcranial magnetic stimulation (rTMS) reportedly diminishes verbal hallucinations. A 21-year-old schizophrenic man, who had killed his mother in the belief that she was a demon, failed to respond to combined treatment with a variety of antipsychotic agents. His persistent hallucinations consisted of two voices (God and the Devil). As an adjunct to continued antipsychotic medication, the patient received a course of rTMS: 10 sessions of 1-Hz stimulations near Wernicke's area. After rTMS, the patient's hallucinations grew less intrusive and he no longer required isolation. Although the improvement could be a delayed effect of medication, further trials of rTMS in cases of this type appear justified.     

Short duration transcranial direct current stimulation (tDCS) modulates verbal memory

Transcranial direct current stimulation (tDCS) is a noninvasive method of modulating cortical excitability. The aim of this study was to investigate the effects of short-duration tDCS (1.6 seconds per trial) on memory performance, and whether the effects were affected by stimulation administered early or late in a trial. Participants memorize words under anodal and cathodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) in two separate sessions in no-stimulation, early stimulation, and late stimulation trials. Early stimulation occurred during word presentation, whereas late stimulation occurred after word presentation. Early anodal tDCS led to significantly better accuracy and speed in a subsequent recognition test compared to anodal late or no-stimulation conditions. Early cathodal tDCS, on the other hand, led to significantly worse accuracy and speed in a subsequent recognition test?compared with cathodal late or no-stimulation conditions. The results of this study suggest that short-duration tDCS can modulate memory performance and highlight the importance of period of stimulation.     

Cerebellar dysfunction in progressive supranuclear palsy: A transcranial magnetic stimulation study

Progressive supranuclear palsy (PSP) rarely shows cerebellar signs and symptoms even though the cerebellar dentate nuclei are involved pathologically. This study evaluates cerebellar function using transcranial magnetic stimulation (TMS) to determine whether subclinical cerebellar involvement is present in PSP patients. We studied 11 patients with PSP, 11 patients with Parkinson's disease (PD), and 10 age‐matched controls. Patients were examined with their usual medications and in their relative on state. Motor evoked potentials (MEPs) were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, which we call cerebellar inhibition (CBI). Interstimulus intervals (ISIs) of 4 to 8 ms were used, and the time course of CBI was analyzed. The CBI was reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state. Although the CBI in their off state should be examined in future studies, the results described herein suggest that Purkinje cells or the dentato–thalamo–cortical pathway assessed by CBI is involved in PSP. Our results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients. © 2010 Movement Disorder Society     

Improved object recognition memory using post-encoding repetitive transcranial magnetic stimulation

BackgroundBrain stimulation is known to affect canonical pathways and proteins involved in memory. However, there are conflicting results on the ability of brain stimulation to improve to memory, which may be due to variations in timing of stimulation.HypothesisWe hypothesized that repetitive transcranial magnetic stimulation (rTMS) given following a learning task and within the time period before retrieval could help improve memory.MethodsWe implanted male B6129SF2/J mice (n = 32) with a cranial attachment to secure the rTMS coil so that the mice could be given consistent stimulation to the frontal area whilst freely moving. Mice then underwent the object recognition test sampling phase and given treatment +3, +24, +48 h following the test. Treatment consisted of 10 min 10 Hz rTMS stimulation (TMS, n = 10), sham treatment (SHAM, n = 11) or a control group which did not do the behavior test or receive rTMS (CONTROL n = 11). At +72 h mice were tested for their exploration of the novel vs familiar object.ResultsAt 72-h's, only the mice which received rTMS had greater exploration of the novel object than the familiar object. We further show that promoting synaptic GluR2 and maintaining synaptic connections in the perirhinal cortex and hippocampal CA1 are important for this effect. In addition, we found evidence that these changes were linked to CAMKII and CREB pathways in hippocampal neurons.ConclusionBy linking the known biological effects of rTMS to memory pathways we provide evidence that rTMS is effective in improving memory when given during the consolidation and maintenance phases.     

Cerebellar transcranial magnetic stimulation: The role of coil type from distinct manufacturers

BackgroundStimulating the cerebellum with transcranial magnetic stimulation is often perceived as uncomfortable. No study has systematically tested which coil design can effectively trigger a cerebellar response with the least discomfort.ObjectiveTo determine the relationship between perceived discomfort and effectiveness of cerebellar stimulation using different coils: MagStim (70 mm, 110 mm-coated, 110-uncoated), MagVenture and Deymed.MethodsUsing the cerebellar-brain inhibition (CBI) protocol, we conducted a CBI recruitment curve with respect to each participant’s maximum tolerated-stimulus intensity (MTI) to assess how effective each coil was at activating the cerebellum.ResultsOnly the Deymed double-cone coil elicited CBI at low intensities (−20% MTI). At the MTI, the MagStim (110 mm coated/uncoated) and Deymed coils produced reliable CBI, whereas no CBI was found with the MagVenture coil.Conclusions: The Deymed double-cone coil was most effective at cerebellar stimulation at tolerable intensities. These results can guide coil selection and stimulation parameters when designing cerebellar TMS studies.     

Repetitive transcranial magnetic stimulation of Broca's area affects verbal responses to gesture observation

The aim of the present study was to determine whether Broca's area is involved in translating some aspects of arm gesture representations into mouth articulation gestures. In Experiment 1, we applied low-frequency repetitive transcranial magnetic stimulation over Broca's area and over the symmetrical loci of the right hemisphere of participants responding verbally to communicative spoken words, to gestures, or to the simultaneous presentation of the two signals. We performed also sham stimulation over the left stimulation loci. In Experiment 2, we performed the same stimulations as in Experiment 1 to participants responding with words congruent and incongruent with gestures. After sham stimulation voicing parameters were enhanced when responding to communicative spoken words or to gestures as compared to a control condition of word reading. This effect increased when participants responded to the simultaneous presentation of both communicative signals. In contrast, voicing was interfered when the verbal responses were incongruent with gestures. The left stimulation neither induced enhancement on voicing parameters of words congruent with gestures nor interference on words incongruent with gestures. We interpreted the enhancement of the verbal response to gesturing in terms of intention to interact directly. Consequently, we proposed that Broca's area is involved in the process of translating into speech aspects concerning the social intention coded by the gesture. Moreover, we discussed the results in terms of evolution to support the theory [Corballis, M. C. (2002). From hand to mouth: The origins of language. Princeton, NJ: Princeton University Press] proposing spoken language as evolved from an ancient communication system using arm gestures.     

Cerebral blood flow identifies responders to transcranial magnetic stimulation in auditory verbal hallucinations

Auditory hallucinations comprise a critical domain of psychopathology in schizophrenia. Repetitive transcranial magnetic stimulation (TMS) has shown promise as an intervention with both positive and negative reports. The aim of this study was to test resting-brain perfusion before treatment as a possible biological marker of response to repetitive TMS. Twenty-four medicated patients underwent resting-brain perfusion magnetic resonance imaging with arterial spin labeling (ASL) before 10 days of repetitive TMS treatment. Response was defined as a reduction in the hallucination change scale of at least 50%. Responders (n=9) were robustly differentiated from nonresponders (n=15) to repetitive TMS by the higher regional cerebral blood flow (CBF) in the left superior temporal gyrus (STG) (P<0.05, corrected) before treatment. Resting-brain perfusion in the left STG predicted the response to repetitive TMS in this study sample, suggesting this parameter as a possible bio-marker of response in patients with schizophrenia and auditory hallucinations. Being noninvasive and relatively easy to use, resting perfusion measurement before treatment might be a clinically relevant way to identify possible responders and nonresponders to repetitive TMS.     

Acute neuroimmune stimulation impairs verbal memory in adults: A PET brain imaging study

Psychiatric and neurologic disorders are often characterized by both neuroinflammation and cognitive dysfunction. To date, however, the relationship between neuroinflammation and cognitive dysfunction remains understudied in humans. Preclinical research indicates that experimental induction of neuroinflammation reliably impairs memory processes. In this paradigm development study, we translated those robust preclinical findings to humans using positron emission tomography (PET) imaging with [¹¹C]PBR28, a marker of microglia, and lipopolysaccharide (LPS), a potent neuroimmune stimulus. In a sample of 18 healthy adults, we extended our previous findings that LPS administration increased whole-brain [¹¹C]PBR28 availability by 31–50%, demonstrating a robust neuroimmune response (Cohen’s ds > 1.6). We now show that LPS specifically impaired verbal learning and recall, hippocampal memory processes, by 11% and 22%, respectively (Cohen’s ds > 0.9), but did not alter attention, motor, or executive processes. The LPS-induced increase in [¹¹C]PBR28 binding was correlated with significantly greater decrements in verbal learning performance in the hippocampus (r = −0.52, p = .028), putamen (r = −0.50, p = .04), and thalamus (r = −0.55, p = .02). This experimental paradigm may be useful in investigating mechanistic relationships between neuroinflammatory signaling and cognitive dysfunction in psychiatric and neurologic disorders. It may also provide a direct approach to evaluate medications designed to rescue cognitive deficits associated with neuroinflammatory dysfunction.     

Effect of repetitive transcranial magnetic stimulation on rate of memory acquisition

Repetitive transcranial magnetic stimulation (rTMS) may temporarily accelerate knowledge acquisition by neural networks, possibly by promoting rapid Hebbian learning. The authors tested this hypothesis in 20 normal subjects by comparing the impact of 25 minutes of high-frequency left dorsolateral prefrontal rTMS with that of sham rTMS on subsequent knowledge acquisition in several procedural and declarative memory domains. No significant group effects, positive or negative, were noted for any memory acquisition test, but prefrontal rTMS did reduce motor evoked potential threshold.