Targeting cognition in schizophrenia through transcranial direct current stimulation: A systematic review and perspective.

Cognitive deficits are a fundamental feature of schizophrenia for which currently no effective treatments exist. This paper examines the possibility to use transcranial direct current stimulation (tDCS) to target cognitive deficits in schizophrenia as evidence from studies in healthy participants suggests that tDCS may improve cognitive functions and associated neural processes. We carried out a systematic review with the following search terms: 'tDCS', 'electric brain stimulation', 'schizophrenia', 'cognitive', 'cognition' until March 2019. 659 records were identified initially, 612 of which were excluded after abstract screening. The remaining 47 articles were assessed for eligibility based on our criteria and 26 studies were excluded. In addition, we compared several variables, such as online vs. offline-stimulation protocols, stimulation type and intensity on mediating positive vs. negative study outcomes. The majority of studies (n = 21) identified significant behavioural and neural effects on a range of cognitive functions (versus n = 11 with null results), including working memory, attention and social cognition. However, we could not identify tDCS parameters (electrode montage, stimulation protocol, type and intensity) that clearly mediated effects on cognitive deficits. There is preliminary evidence for the possibility that tDCS may improve cognitive deficits in schizophrenia. We discuss the rationale and strength of evidence for using tDCS for targeting cognitive deficits in schizophrenia as well as methodological issues and potential mechanisms of action.

Effects of single-pulse transcranial magnetic stimulation (TMS) on functional brain activity: a combined event-related TMS and evoked potential study.

OBJECTIVE: To further evaluate the potential of slew-rate limiting amplifiers to record electrophysiological signals in spite of concurrent transcranial magnetic stimulation (TMS), and to explore the effects of single-pulse TMS on electroencephalographic (EEG) correlates of functional brain activity. METHODS: Visual-evoked potentials (VEPs) to checkerboards were recorded in 7 right-handed subjects, while single-pulse TMS was applied to the occipital pole either at visual stimulus onset, during the build-up or at the expected peak of the early VEP component P1 (VIS&TMS). Timing of TMS was individually adjusted based on each subject's VEP-latency. A condition of TMS without concurrent visual stimulation (TMS(alone)) served for subtraction purposes (VIS&TMS minus TMS(alone)) to partial out TMS-related contaminations of the EEG signal. RESULTS: When TMS was applied at visual stimulus onset, VEPs (as calculated by subtraction) perfectly matched control VEPs to visual stimulation alone. TMS at around P1, in contrast, modified the targeted (P1) and the subsequent VEP component (N1), independently of whether TMS was given at build-up or peak. CONCLUSIONS: The retrieval of regular VEPs with concomitant TMS at visual stimulus onset suggests that the employed EEG system and subtraction procedure are suited for combined EEG-TMS studies. The VEP changes following TMS at around P1 provide direct clues on the temporal dynamics of TMS pulse effects on functional activity in the human brain. Our data suggest effects of relatively long duration (approximately 100 ms) when TMS is applied while functional neuronal activity evolves.

Face versus non-face object perception and the 'other-race' effect: a spatio-temporal event-related potential study.

OBJECTIVE: To investigate a modulation of the N170 face-sensitive component related to the perception of other-race (OR) and same-race (SR) faces, as well as differences in face and non-face object processing, by combining different methods of event-related potential (ERP) signal analysis. METHODS: Sixty-two channel ERPs were recorded in 12 Caucasian subjects presented with Caucasian and Asian faces along with non-face objects. Surface data were submitted to classical waveforms and ERP map topography analysis. Underlying brain sources were estimated with two inverse solutions (BESA and LORETA). RESULTS: The N170 face component was identical for both race faces. This component and its topography revealed a face specific pattern regardless of race. However, in this time period OR faces evoked significantly stronger medial occipital activity than SR faces. Moreover, in terms of maps, at around 170 ms face-specific activity significantly preceded non-face object activity by 25 ms. These ERP maps were followed by similar activation patterns across conditions around 190-300 ms, most likely reflecting the activation of visually derived semantic information. CONCLUSIONS: The N170 was not sensitive to the race of the faces. However, a possible pre-attentive process associated to the relatively stronger unfamiliarity for OR faces was found in medial occipital area. Moreover, our data provide further information on the time-course of face and non-face object processing.

Differential effects of low-frequency rTMS at the occipital pole on visual-induced alpha desynchronization and visual-evoked potentials.

Visual-induced alpha desynchronization (VID) and visual-evoked potentials (VEPs) characterize occipital activation in response to visual stimulation but their exact relationship is unclear. Here, we tested the hypothesis that VID and VEPs reflect different aspects of cortical activation. For this purpose, we determined whether VID and VEPs are differentially modulated by low-frequency repetitive transcranial magnetic stimulation (rTMS) over the occipital pole. Scalp EEG responses to visual stimuli (flashed either to the left or to the right visual field) were recorded for 8 min in six healthy subjects (1) before, (2) immediately following, and (3) 20 min after left occipital rTMS (1 Hz, 10 min). The parameters aimed to reduce cortical excitability beyond the end of the TMS train. In addition, simple reaction times to visual stimulation were recorded (left or right hand in separate blocks). In all subjects, VID was significantly and prominently reduced by rTMS (P = 0.0001). In contrast, rTMS failed to modulate early VEP components (P1/N1). A moderate effect was found on a late VEP component close to manual response onset (P = 0.014) but this effect was in the opposite direction to the VID change. All changes were restricted to the targeted left occipital cortex. The effects were present only after right visual field stimulation when a right hand response was required, were associated with a behavioral effect, and had washed out 20 min after rTMS. We conclude that VID and early VEPs represent different aspects of cortical activation. The findings that rTMS did not change early VEPs and selectively affected VID and late VEPs in conditions where the visual input must be transferred intrahemispherically for visuomotor integration (right visual field/right hand) are suggestive of rTMS interference with higher-order visual functions beyond visual input. This is consistent with the idea that alpha desynchronization serves an integrative role through a corticocortical "gating function."

Electric source imaging of human brain functions.

We review recent methodological advances in electromagnetic source imaging and present EEG data from our laboratory obtained by application of these methods. There are two principal steps in our analysis of multichannel electromagnetic recordings: (i) the determination of functionally relevant time periods in the ongoing electric activity and (ii) the localization of the sources in the brain that generate these activities recorded on the scalp. We propose a temporal segmentation of the time-varying activity, which is based on determination of changes in the topography of the electric fields, as an approach to the first step, and a distributed linear inverse solution based on realistic head models as an approach to the second step. Data from studies of visual motion perception, visuo-motor transfer, mental imagery, semantic decision, and cognitive interference illustrate that this analysis allows us to define the patterns of electric activity that are present at given time periods after stimulus presentation, as well as those time periods where significantly different patterns appear between different stimuli and tasks. The presented data show rapid and parallel activation of different areas within complex neuronal networks, including early activity of brain regions remote from the primary sensory areas. In addition, the data indicate information exchange between homologous areas of the two hemispheres in cases where unilateral stimulus presentation requires interhemispheric transfer.

Space-oriented segmentation and 3-dimensional source reconstruction of ictal EEG patterns.

OBJECTIVES: Characterization of the EEG pattern during the early phase of a seizure is crucial for identifying the epileptic focus. The purpose of the present investigation was to evaluate a method that divides ictal EEG activity into segments of relatively constant surface voltage distribution, and to provide a 3-dimensional localization of the activity during the different segments. METHODS: For each timepoint the electrical voltage distribution on the scalp (the voltage map) was determined from the digitized EEG recording. Through a spatial cluster analysis time sequences where the maps did not change much (segments) were identified, and a 3-dimensional source reconstruction of the activity corresponding to the different mean maps was performed using a distributed linear inverse solution algorithm. RESULTS: Segments dominating early in seizure development were identified, and source reconstruction of the EEG activity corresponding to the maps of these segments yielded results which were consistent with the results from invasive recordings. In some cases a sequence of consecutive segments was obtained, which might reflect ictal propagation. CONCLUSIONS: Segmentation of ictal EEG with subsequent 3-dimensional source reconstruction is a useful method to non-invasively determine the initiation and perhaps also the spread of epileptiform activity in patients with epileptic seizures.

The time course of semantic category processing in the cerebral hemispheres: an electrophysiological study.

Using visual half-field presentations of words to the right (RVF) and to the left visual field (LVF), this study investigated the time course of the hemispheric involvement in the processing of semantic category information. Multi-channel event related brain potentials (ERPs) were recorded from 15 healthy subjects during a categorisation task of sequentially presented word pairs. Subjects had to judge mentally after the appearance of the second word whether the words of a pair were semantically related (SR) or not (SU). ERPs were computed, from 100 ms before the onset of the second word to 600 ms, for SR and SU conditions in the LVF and in the RVF separately. The temporal segmentation of ERP map series into sequences of quasi-stable map configurations revealed a total of seven segments in each visual field of which only the first five (S1-S5, appearing between 70 and 400 ms) showed different map configurations as a function of visual field but presented a similar temporal sequence in both visual fields. By contrast, of the last two segments (S6 and S7) which appeared between approximately 400 and approximately 600 ms, only S7 differentiated SR and SU conditions in terms of its duration. Source localisation analysis of the segments showed that following the initial activation of posterior brain regions as a function of the visual field of presentation, a common neural network was activated in the left hemisphere (LH) although the dynamics of activation varied as a function of visual field. Concerning the role of the right hemisphere (RH) in lexico-semantic processing, the results presented here appear to be compatible with a 'callosal relay model' and suggest that, in healthy subjects, information is transferred rapidly ( approximately 150 ms) from the RH to the language dominant-LH.

Intracranial Neurophysiological Correlates Related to the Processing of Faces.

Face perception and recognition is an intriguing ability, already present in neonates. Numerous studies in patients with brain lesions identified the temporo-occipital cortex as the crucial structure for this capacity. Analysis of electrical signals (EEG) inside the brain of patients implanted with intracranial electrodes for diagnostic purposes allows researchers to describe the temporal and spatial organization of responses to various aspects of face processing in human subjects. Several findings have emerged and appear relevant for cerebral organization in general: (1) Selective face responses were obtained from the basal temporo-occipital cortex at around 200 ms (N200); however, other structures such as the lateral temporal lobe and frontal cortex also participate in face recognition and perception tasks. (2) Each structure has a distinct "response profile"; that is, with respect to a given task certain structures respond strongly, others less or not at all. This profile might change with a different task, although the physical parameters of the stimuli remain the same. (3) The right hemispheric predominance of face processing, as suggested by patient data and studies in healthy volunteers, seemed to be restricted to its early stages (i.e., before 100-150 ms). (4) Recognition of faces might be associated with differential intracranial responses, despite an incorrect overt response, reflecting neurophysiological correlates of implicit memory. (5) The more the stimulus resembled a complete human face, the earlier and larger the N200 response was found, in particular over the basal temporobasal cortex. Analysis of electrical signals from intracranial electrodes might help to improve our understanding of the underlying physiological and anatomical constraints of cognitive processes.

Measuring the complexity of time series: an application to neurophysiological signals.

Measures of signal complexity can be used to distinguish neurophysiological activation from noise in those neuroimaging techniques where we record variations of brain activity with time, e.g., fMRI, EEG, ERP. In this paper we explore a recently developed approach to calculate a quantitative measure of deterministic signal complexity and information content: The Renyi number. The Renyi number is by definition an entropy, i.e., a classically used measure of disorder in physical systems, and is calculated in this paper over the basis of the time frequency representation (TFRs) of the measured signals. When calculated in this form, the Renyi entropy (RE) indirectly characterizes the complexity of a signal by providing an approximate counting of the number of separated elementary atoms that compose the time series in the time frequency plane. In this sense, this measure conforms closely to our visual notion of complexity since low complexity values are obtained for signals formed by a small number of "components". The most remarkable properties of this measure are twofold: 1) It does not rely on assumptions about the time series such as stationarity or gaussianity and 2) No model of the neural process under study is required, e.g., no hemodynamic response model for fMRI. The method is illustrated in this paper using fMRI, intracranial ERPs and intracranial potentials estimated from scalp recorded ERPs through an inverse solution (ELECTRA). The main theoretical and practical drawbacks of this measure, especially its dependence of the selected TFR, are discussed. Also the capability of this approach to produce, with less restrictive hypothesis, results comparable to those obtained with more standard methods but is emphasized.

Visually induced activity in human frontal motor areas during simple visuomotor performance.

Visuomotor tasks elicit neuronal activity in primate motor areas at relatively short latencies. Although this early activity embodies features of visual responses (short latency, stimulus-dependency), its sensory nature has been questioned. We investigated neural correlates of visuomotor performance in human motor areas using scalp and intracranial event-related potential measures. A simple visuomanual reaction-time task evoked early potentials at 133-145 ms post-stimulus which occurred much earlier than the motor potentials of the same region. The amplitude of the early potentials covaried with stimulus location and was independent of parameters of the motor response. Because of their timing, stimulus-dependency and characteristics of our behavioral task, the early potentials are suggested to reflect neuronal responses of sensory nature rather than processing related to pure motor aspects of the task.

Simple and complex vestibular responses induced by electrical cortical stimulation of the parietal cortex in humans.

The present study reports on a patient undergoing invasive monitoring for intractable epilepsy who experienced different vestibular sensations after electrical cortical stimulation of the inferior parietal lobule at the anterior part of the intraparietal sulcus. Types of vestibular response ranged from simple to complex sensations and depended on stimulation site and applied current. The findings suggest vestibular topography and hierarchical processing within the parietal vestibular cortex of humans.

Electrophysiological evidence for fast visual processing through the human koniocellular pathway when stimuli move.

There is increasing evidence from cellular recordings in primates and behavioral studies in humans that motion can be processed by other than the magnocellular (M) pathway and the cortical dorsal stream. Little is known about cortical processing of moving stimuli when the information is conveyed by the third retinogeniculocortical pathway - the so-called koniocellular (K) pathway. We addressed this issue in humans by studying the spatio-temporal dynamics of the brain electrical fields evoked by tritan (S-cone isolating) and luminance-defined moving stimuli. Tritan and luminance stimuli are presumably carried by the K and M pathways respectively. We found two time intervals where significant stimulus-specific electric fields were evoked: an early period between 40 and 75 ms after stimulus onset, and a later period between 175 and 240 ms. Some of these fields were identical for tritanand luminance-motion, suggesting that the processing of moving stimuli share common cortical substrates when mediated via K and M pathway input. However, tritan-motion stimuli also evoked unique electric fields that appeared earlier in time than the common motion-specific fields, indicating very fast activation of cortical areas specific to input through the K pathway. A distributed source localization procedure revealed simultaneous activation of striate and extrastriate areas even at the early processing stages, strongly suggesting a very fast activation of the visual cerebral network.

Location of the human frontal eye field as defined by electrical cortical stimulation: anatomical, functional and electrophysiological characteristics.

Electrical cortical stimulation of the human frontal gyri and the precentral gyrus has been shown to induce eye movements and it has classically been assumed that these stimulation-induced eye movements result from electrical interference with the human homologue of the monkey frontal eye field (FEF). However, amplitude of electrical current and induced type of eye movement, which are essential for the determination of eye fields in the monkey, have not been investigated systematically in man. We applied electrical cortical stimulation in the lateral frontal cortex in six epileptic patients. Sites whose stimulation resulted in eye movements were determined with respect to gyral and sulcal patterns, Talairach coordinates and neighboring functions as found by electrical cortical stimulation. Based on this approach, a restricted location of the electrically defined FEF is proposed within a larger oculomotor region on the posterior part of the middle frontal gyrus.

Temporal and spatial determination of EEG-seizure onset in the frequency domain.

OBJECTIVE: A quantitative analysis of scalp electric fields in patients suffering from pharmacoresistant temporal lobe epilepsy was performed in order to study the development of rhythmic ictal activities over time. METHODS: A method that calculates phase-corrected voltage maps in the frequency domain (FFT-approximation) was applied to ictal multichannel recordings in 10 epileptic patients. The onset of the ictally dominant frequency was determined and its temporal evolution over a time period of 46 s around the ictal EEG onset was studied. The analysis was completed by a linear inverse solution that estimated the sources of the dominant frequency. RESULTS: This method permitted the identification of an ictally dominant frequency which started on the average prior to the onset of initial EEG signs as determined by visual inspection. The frequency incremented during the evolution of the seizure in all patients. The linear inverse solution algorithm localized the source of this frequency to the brain region which was clinically determined as the site of seizure onset and whose resection rendered all patients seizure-free. CONCLUSIONS: Our data suggest that the constant increase of the ictally dominant frequency is related to the amount of temporal lobe tissue generating the ictal discharges. Frequential analysis of ictal electric fields can be reliably used to detect focal pathological activity early during seizure onset arising in deep structures such as the mesial temporal lobe.

Internally driven vs. externally cued movement selection: a study on the timing of brain activity.

Brain imaging studies in man and single cell recordings in monkey have suggested that medial supplementary motor areas (SMA) and lateral pre-motor areas (PMA) are functionally dissociated concerning their involvement in internally driven and externally cued movements. This dichotomy, however, seems to be relative rather than absolute. Here, we searched for further evidence of relative differences and aimed to determine by what aspect of brain activity (duration, strength, or both) these might be accounted for. Event-related potentials (ERPs) were recorded while healthy, right-handed subjects selected one of three possible right hand digit movements based either on 'internal' choice or 'external' cues. The results obtained from ERP mapping suggest that movement selection evokes the same electrical brain activity patterns in terms of surface potential configurations in the same order and at the same strength independent of the selection mode. These identical configurations, however, differed in their duration. Combined with the results of a distributed source localization procedure, our data are suggestive of longer lasting activity in SMA during the 'internal' and longer lasting activity in PMA during the 'external' condition. Our results confirm previous findings in showing that SMA and PMA are distinctively involved in the two tasks and that this functional dichotomy is relative rather than absolute but indicate that such a dissociation can result from differences in duration rather than pure strength of activation.

Evidence for interhemispheric motor-level transfer in a simple reaction time task: an EEG study.

Simple visuomanual reaction time tasks require interhemispheric communication when stimuli are presented in the hemifield opposite the responding hand. Although confirmed in many studies, it is still a matter of debate when, at what functional level and at what site this interhemispheric transfer takes place. To address these questions, we recorded event-related potentials (ERPs) in 12 healthy subjects performing such a task and analyzed the data using techniques based on topographic ERP map characteristics. A method which has proved useful for associating ERP map configurations of different time periods with functional states of the brain was supplemented by a source localization procedure. The results suggest that transfer occurs late in time, on a functional motor level and at frontal sites, at least for left-to-right interhemispheric direction of transfer.

Visual activity in the human frontal eye field.

Although visual information processing in the monkey frontal eye field (FEF) has been well demonstrated, the contribution of its human homologue to vision is still unknown. Here we report a study of intracranial visual evoked potentials (VEPs) recorded from the human FEF which was identified by electrical cortical stimulation. Electrical stimulations and EEG recordings were carried out via subdural grid electrodes placed over the frontal cortex in three epileptic patients. Evoked eye movements were mainly horizontal and always directed to the hemispace contralateral to the stimulation site. Intracranial VEPs showed responses predominately to stimuli in the contralateral visual field. Our findings demonstrate a close relationship between the direction of the electrically elicited eye movements and the visual stimulus location which predominantly leads to neural responses in the FEF. These findings provide evidence for the functional role of the human FEF in the analysis of visual stimuli from the contralateral visual field as well as in the generation of eye movements towards these conspicuous targets.

Activation of the human brain by monetary reward.

With the purpose of studying neural activation associated with reward processing in humans, we measured regional cerebral blood flow in 10 right-handed healthy subjects performing a delayed go-no go task in two different reinforcement conditions. Correct responses were either rewarded by money or a simple "ok' reinforcer. Behaviour rewarded by money, as compared with the "ok' reinforcement, was most significantly associated with activation of dorsolateral and orbital frontal cortex and also involved the midbrain and thalamus. These results may reflect the processing of reward information, although arousal effects cannot be completely excluded. It is suggested that the observed foci are implicated in the assessment of consequences in goal-directed behaviour which agrees with research in non-human primates.

What is the role of the corpus callosum in intermanual transfer of motor skills? A study of three cases with callosal pathology.

Intermanual transfer for a skilled motor task was studied in two patients with total callosal agenesis, and one with an acquired partial callosal lesion and clinical evidence for disturbed transfer of motor signals. Patients had to draw meaningless figures with one upper extremity (original learning, OL) and to reproduce their mirror-reversals thereafter with the other side (transfer learning, TL). Both directions of intermanual transfer were tested in two conditions, that is, between either proximal or distal muscle groups. Transfer was evaluated by comparing OL and TL performance at the same effector. The main variable of interest was movement time during the first eight trials of OL and TL. All three patients displayed a significant benefit for transfer from the dominant to the non-dominant hand but not vice versa during proximal motor activity. When compared with the performance of healthy subjects tested in almost identical conditions in a previously reported study, the proximal transfer behavior was found to be similar for all patients and the normal group. Although patients exhibited no significant benefit for distal transfer, their non-dominant-to-dominant distal transfer was above the normal range. The similar transfer pattern of the patients and healthy subjects when using proximal musculature suggests that proximal transfer may be subserved by identical extracallosal pathways, most probably by the ipsilaterally descending motor systems. Since non-dominant-to-dominant distal transfer was found to be disadvantageous in healthy subjects, the patients' relative superiority in this condition may reflect missing callosal influences of an inhibitory nature.