Prefrontal hemodynamic changes produced by anodal direct current stimulation

Abstract

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been investigated for the treatment of many neurological or neuropsychiatric disorders. Its main effect is to modulate the cortical excitability depending on the polarity of the current applied. However, understanding the mechanisms by which these modulations are induced and persist is still an open question. A possible marker indicating a change in cortical activity is the subsequent variation in regional blood flow and metabolism. These variations can be effectively monitored using functional near-infrared spectroscopy (fNIRS), which offers a noninvasive and portable measure of regional blood oxygenation state in cortical tissue. We studied healthy volunteers at rest and evaluated the changes in cortical oxygenation related to tDCS using fNIRS. Subjects were tested after active stimulation (12 subjects) and sham stimulation (10 subjects). Electrodes were applied at two prefrontal locations; stimulation lasted 10 min and fNIRS data were then collected for 20 min. The anodal stimulation induced a significant increase in oxyhemoglobin (HbO₂) concentration compared to sham stimulation. Additionally, the effect of active 10-min tDCS was localized in time and lasted up to 8–10 min after the end of the stimulation. The cathodal stimulation manifested instead a negligible effect. The changes induced by tDCS on HbO₂, as captured by fNIRS, agreed with the results of previous studies. Taken together, these results help clarify the mechanisms underlying the regional alterations induced by tDCS and validate the use of fNIRS as a possible noninvasive method to monitor the neuromodulation effect of tDCS.

Introduction

Application of transcranial direct current stimulation (tDCS) to the cortex has been shown to shift the membrane potential of superficial neurons in a de- or hyperpolarizing direction, and to modulate spontaneous neuronal activity as well as the processing of afferent signals (Paulus, 2004, Priori, 2003). If tDCS is continuously applied for 5 min or more, it can provoke sustained changes in neuronal firing rates that last for many hours after the current is switched off (Bindman et al., 1962). Consistent with animal data, in humans these changes in excitability also persist beyond the time of stimulation if tDCS is applied for several minutes and the after-effects can remain stable for an hour or more if tDCS is given for 9 min or longer (Lang et al., 2004, Nitsche et al., 2003, Nitsche and Paulus, 2001). tDCS modulates excitability in a polarity-specific manner. In humans, anodal polarization increases excitability measures of the motor and visual cortex (Edwards et al., 1993, Paulus, 2004). Cathodal stimulation produces opposite effects: excitability is reduced and some functions worsen (Been et al., 2007).

Changes in cortical excitability are associated with changes of the underlying cortical neuronal activity and with subsequent changes in the regional cerebral blood flow (rCBF). For this reason, it is conceivable that a measurable output of the after-effects of tDCS – virtually in any cortical area – could be obtained by measuring the rCBF. This aspect is not trivial, as so far it has been possible to measure the after-effects of tDCS only in the motor and visual cortex, where stimulation can be evaluated by motor evoked potentials and phosphene threshold to transcranial magnetic stimulation, respectively. However, it is not possible to assume that every different cortical area responds to tDCS in the same way. This is an important aspect as tDCS has been proposed as a possible neuromodulation treatment for many neurological and psychiatric disorders (Boggio et al., 2008, Monti et al., 2008, Ferrucci et al., 2008, Ohn et al., 2008, Nitsche et al., 2009). Both anodal and cathodal tDCS have been reported to increase the metabolism of the cortex underlying the stimulation electrodes (Lang et al., 2005). In the study by Lang et al. (2005), positron emission tomography (PET) was used to study brain metabolism of the cortex underlying the stimulation electrodes; however, PET is an invasive technique that cannot be repeated often in control subjects and patients.

The idea that regional cerebral blood flow could reflect neuronal activity began with the experiment by Roy and Sherrington (1890). Investigations on the energy metabolism of the human brain were limited by the fact that the brain within the skull is not easily accessible for performing experimental procedures and that the nervous tissue is composed of many different cell populations; additionally, more recent techniques for studying the metabolic state of the brain, such as single photon emission-computed tomography (SPECT), functional magnetic resonance (fMRI) and PET, are not easily applicable in any situation.

Some of the limitations encountered when using the aforementioned imaging technologies can be overcome by functional near-infrared spectroscopy (fNIRS). fNIRS is a noninvasive, repeatable method that allows for regional assessment of the oxygenation state of hemoglobin in tissue (Chance et al., 1993, Edwards et al., 1993, Paulus, 2004). fNIRS measures cerebral concentrations of oxyhemoglobin (HbO₂) and deoxyhemoglobin (HHb) by observing the absorption of near-infrared light. These parameters are expressed as μM variations from the baseline. Since HbO₂ and HHb have different absorption spectra in the visible and near-infrared wavelength ranges, spectroscopy techniques can be used to provide an index of blood oxygenation and hence oxygen delivery; thus, changes in HbO₂ and HHb concentration, as measured by near-infrared spectroscopy, could be considered a good index of rCBF variations. fNIRS can therefore provide metabolic information without invasive intervention and it is able to detect even small changes in the cerebral hemodynamic response to functional stimulation (Obrig et al., 1996). Several reports described the capability of fNIRS to measure the hemodynamic changes related to the human brain activities, such as motor, visual, auditory, language, and other cognitive functions (Edwards et al., 1993, Franceschini et al., 2003, Jasdzewski et al., 2003, Roland and Larsen, 1976, Sander et al., 1995, Tanosaki et al., 2001, Villringer et al., 1993, Williamson et al., 1996). Moreover fNIRS has been used to monitor rCBF modifications in physiological and pathological conditions with good results both in adults and in children (Cope and Delpy, 1988, Mehagnoul-Schipper et al., 2002, Obrig et al., 1996, Okada et al., 1993, Wyatt, 1994).

The purpose of this study was to investigate the relationship between the rCBF and neuronal activity modulated by tDCS. For this purpose, tDCS, with electrodes overlaying prefrontal cortex, was used to induce a change in neural activity and fNIRS was used to evaluate the hemodynamic changes in the same regions. More specifically, the anode was placed over the left prefrontal cortex and the cathode over the right one. This set up offers the opportunity to evaluate simultaneously the effect of anodal and cathodal stimulation over the underlying brain structures. We also analyzed the effects of a sham stimulation to rule out possible unspecific effects or arousal changes produced by the experimental procedures.