When is electrical cortical stimulation more likely to produce afterdischarges?

ObjectiveTo study when afterdischarges (ADs) are more likely to occur during cortical stimulation.MethodsWe examined 6250 electrical stimulation trials in 13 patients with subdural electrodes, studying whether AD occurrence during a trial was influenced by electrode pair stimulated or AD occurrence during the previous trial. In total 545 electrodes were stimulated, 119 frontal (pre-perirolandic), 289 perirolandic, 36 parietal (post-perirolandic), 95 temporal, and 6 occipital.ResultsWhen the same electrode pair was stimulated as the prior trial, 19% produced ADs compared to 5% of trials when a different electrodes pair was stimulated (p < 0.0001). When trials showed ADs, and the next trial stimulated the same electrode pair, ADs occurred in 46% of cases, compared to 13% of trials following trials without ADs (p < 0.0001). AD probability decreased with increased inter-trial interval length only when the prior trial was at the same electrode pair and had produced an AD (p = 0.001). AD probability increased with stimulation duration, whether the trial followed a trial with (p < 0.001) or without (p < 0.0001) an AD.ConclusionsADs were more likely to occur when an electrode pair showed ADs and was stimulated again, especially when stimulating after short inter-trial intervals or for longer duration.SignificanceWhen ADs occur, waiting about a minute before resuming stimulation might lessen the likelihood of AD recurrence.     

Detection of after-discharges during intraoperative functional brain mapping in awake brain tumor surgery using a novel high-density circular grid

ObjectiveTo evaluate intraoperative use of a novel high-density circular grid in detecting after-discharges (AD) on electrocorticography (ECoG) during functional brain mapping (FBM).MethodsFBM during glioma surgery (10/2016 to 5/2019) recorded ADs using a 22-channel circular grid compared to conventional strip electrodes. ADs were analyzed for detection, duration, amplitude, morphology, histology, direction, and clinical signs.ResultsThirty-two patients (mean age 54.2 years; r = 30–75) with glioma (WHO grade II-IV; 20 grade IV) had surgery. ADs during FBM were more likely in patients with wild-type as opposed to IDH-1 mutants (p < 0.0001) using more contacts compared with linear strip electrodes (p = 0.0001). More sensors tended to be involved in ADs detected by the circular grid vs strips (6.61 vs 3.43; p = 0.16) at lower stimulus intensity (3.14 mA vs 4.13 mA; p = 0.09). No difference in the number of cortical stimulations before resection was present (38.9 mA vs 47.9 mA; p = 0.26). ADs longer than 10 seconds were 32.5 seconds (circular grid) vs 58.4 (strips) (p = 0.12).ConclusionsHigh-density circular grids detect ADs in 360 degrees during FBM for glioma resection. Provocation of ADs was more likely in patients with wild-type than IDH-1 mutation.SignificanceCircular grids offer high-resolution ECoG during intraoperative FBM for detection of ADs.     

Optimizing parameters for terminating cortical afterdischarges with pulse stimulation

PURPOSE: We previously reported that brief pulses of electrical stimulation (BPSs) can terminate afterdischarges (ADs) during cortical stimulation. We investigated conditions under which BPS is more likely to suppress ADs. METHODS: We analyzed parameters altering BPS effectiveness on 200 ADs in seven patients with implanted subdural electrodes. RESULTS: The odds of BPSs stopping ADs was 8.6 times greater at primary sites (directly stimulated electrodes) than at secondary sites (adjacent electrodes) (p = 0.016). BPS applied within 4.5 s after onset of AD had 2 times greater odds of stopping ADs (p = 0.014). BPS applied when AD voltage was negative was 1.9 times more likely to stop ADs (p = 0.012). ADs with rhythmic pattern responded best (p < 0.0001). BPS stopped 100% of ADs not starting immediately after localization stimulus (LS) versus 29% of those starting immediately (p < 0.0001). CONCLUSIONS: BPS is more likely to terminate ADs at primary electrodes, if given early, if applied to the negative peak of the AD waveform, if AD has a rhythmic pattern, and if AD did not start immediately after LS.     

The effectiveness of low-frequency stimulation for mapping cortical function

OBJECTIVE: To establish the efficacy and safety of low-frequency electrical stimulation for cortical brain mapping. METHODS: Cortical function was mapped using electrical stimulation in epilepsy patients with chronically implanted intracranial subdural electrodes. Contacts overlying motor, sensory, visual, and language cortex were stimulated at frequencies of 5, 10, and 50 Hz, using current levels ranging from 1 to 17.5 mA for 3-5 s. The current intensity and incidence at which functional alterations and afterdischarges (ADs) occurred were recorded. The modified McNemar test for nonindependent measures was used to analyze the data. RESULTS: 122 electrode contact pairs were electrically stimulated at least two different frequencies in 14 patients. Functional alterations were obtained at all stimulation frequencies (5, 10, and 50 Hz) at generally similar rates. The likelihood of producing an AD correlated with stimulation frequency, and lower-frequency stimulation was less likely to provoke an AD. Higher current intensity was required to induce both functional responses and ADs at low-frequency stimulation than high-frequency stimulation. While overall rates of producing functional changes were similar, differences in functional response with regard to frequency were noted at individual cortical sites. CONCLUSION: 5- and 10-Hz stimulation are as effective for mapping cortical function as 50-Hz stimulation and produce fewer ADs. We recommend that mapping of cortical function be started with 5-Hz-frequency stimulation. Higher frequencies should be used in suspect cortex if no symptoms or signs are produced with 5-Hz stimulation.     

Impairment of sensory-motor plasticity in mild Alzheimer’s disease

BackgroundPrimary motor cortex (M1) is relatively spared in the early stages of Alzheimer’s disease (AD).ObjectiveAim of the present study was to investigate whether abnormal M1 synaptic plasticity is present at an early stage of AD. We employed an electrophysiological protocol, named rapid paired associative stimulation (rPAS), involving repetitive transcranial magnetic stimulation (rTMS) paired with electrical stimulation of the contralateral median nerve, that modifies corticospinal excitability and short latency afferent inhibition (SAI).MethodsWe studied 10 patients with a diagnosis of probable mild AD according to the Mini Mental State Examination score (minimum 21) and 14 age-matched control subjects. Motor evoked potentials (MEP) amplitudes and short-afferent inhibition (SAI) were measured at baseline before and for up to 60 min after 5Hz-rPAS in abductor pollicis brevis (APB). rPAS consisted of 600 pairs of transcranial magnetic stimuli, at a rate of 5 Hz for 2 min, coupled with electrical median nerve stimulation preceding TMS over the contralateral M1 at an inter-stimulus interval of 25 ms.ResultsBaseline SAI was significantly reduced in AD patients. In the control subjects rPAS induced a significant increase in MEP amplitudes and a decrease of SAI in the APB muscle persistently for up to 1 h. Conversely 5Hz-rPAS did not induce any significant changes in MEP amplitudes and SAI in mild AD patients.ConclusionsSensory-motor plasticity is impaired in the motor cortex of AD at an early stage of the disease.     

Negative effects of chronic hemicerebellectomy of epileptiform after-discharges elicited by focal cortical stimulation in baboons (Papio papio).

The influence of chronic hemicerebellectomy on cortical epileptiform after-discharge (AD) induced by focal electrical stimulation was studied in the baboon. These preliminary results include 22 ADs elicited from motor cortex and 22 ADs elicited from premotor cortex before and after hemicerebellectomy. Only full-developed, generalized seizures with postictal silence were considered. EEG morphology, average duration and average current threshold were compared for each set of ictal events. No significant differences were found before and after hemicerebellectomy.     

Hypoperfusion Precedes Tau Deposition in the Entorhinal Cortex: A Retrospective Evaluation of ADNI-2 Data

Background and PurposeTau deposition in the entorhinal cortex is the earliest pathological feature of Alzheimer’s disease (AD). However, this feature has also been observed in cognitively normal (CN) individuals and those with mild cognitive impairment (MCI). The precise pathophysiology for the development of tau deposition remains unclear. We hypothesized that reduced cerebral perfusion is associated with the development of tau deposition.MethodsA subset of the Alzheimer’s Disease Neuroimaging Initiative data set was utilized. Included patients had undergone arterial spin labeling perfusion MRI along with [¹⁸F]flortaucipir tau PET at baseline, within 1 year of the MRI, and a follow-up at 6 years. The association between baseline cerebral blood flow (CBF) and the baseline and 6-year tau PET was assessed. Univariate and multivariate linear modeling was performed, with p<0.05 indicating significance.ResultsSignificant differences were found in the CBF between patients with AD and MCI, and CN individuals in the left entorhinal cortex (p=0.013), but not in the right entorhinal cortex (p=0.076). The difference in maximum standardized uptake value ratio between 6 years and baseline was significantly and inversely associated with the baseline mean CBF (p=0.042, R²=0.54) in the left entorhinal cortex but not the right entorhinal cortex. Linear modeling demonstrated that CBF predicted 6-year tau deposition (p=0.015, R²=0.11).ConclusionsThe results of this study suggest that a reduction in CBF at the entorhinal cortex precedes tau deposition. Further work is needed to understand the mechanism underlying tau deposition in aging and disease.     

Critical period plasticity of kitten visual cortex is not associated with enhanced susceptibility to electrical kindling

The goal of this study was to determine whether the use-dependent malleability of visual cortex functions which is particularly pronounced in 4-week-old kittens correlates with enhanced susceptibility to kindling. For that purpose the effects of high-frequency electrical stimulation were compared in the visual cortex of 4-week-old kittens and of adult cats. The striate cortex of one hemisphere was stimulated with a single train of pulses whose intensity was set just above the threshold for the elicitation of afterdischarges (ADs). In kittens the AD thresholds were consistently higher than in adults and with repeated stimulation, the ADs tended to disorganize, to decrease in amplitude and duration and to become more restricted to the site of stimulation after about 6 stimulations. In the adult, by contrast, the ADs remained well organized and constant in duration throughout 30 stimulations. They showed an increase in amplitude and spike frequency and spread with increasing consistency to the other hemisphere. No electrographic or behavioural signs of epileptic activity developed in kittens, while in adults ADs were on occasion followed by irregular spike activity associated with behavioural states resembling absences. We conclude that the visual cortex possesses powerful mechanisms to prevent the development of supracritical excitatory states, these mechanisms being more effective in the kitten than in the adult.     

Cortico-cortical evoked potential by single-pulse electrical stimulation is a generally safe procedure

ObjectiveCortico-cortical evoked potential (CCEP) by single-pulse electrical stimulation (SPES) is useful to investigate effective connectivity and cortical excitability. We aimed to clarify the safety of CCEPs.MethodsWe retrospectively analyzed 29 consecutive patients with intractable partial epilepsy undergoing chronic subdural grid implantation and CCEP recording. Repetitive SPES (1 Hz) was systematically applied to a pair of adjacent electrodes over almost all electrodes. We evaluated the incidences of afterdischarges (ADs) and clinical seizures.ResultsOut of 1283 electrode pairs, ADs and clinical seizures were observed in 12 and 5 pairs (0.94% and 0.39%, per electrode pair) in 7 and 3 patients (23.3% and 10.0%, per patient), respectively. Of the 18–82 pairs per patient, ADs and clinical seizures were induced in 0–4 and 0–3 pairs, respectively. Stimulating 4 SOZ (seizure onset zone) (2.5%) and 8 non-SOZ pairs (0.75%) resulted in ADs. We observed clinical seizures in stimulating 4 SOZ (2.5%) and 1 non-SOZ pair (0.09%). The incidence of clinical seizures varied significantly between SOZ and non-SOZ stimulations (p = 0.001), while the difference in AD incidence tended towards significance (p = 0.058).ConclusionAlthough caution should be taken in stimulating SOZ, CCEP is a safe procedure for presurgical evaluation.SignificanceCCEP is safe under the established protocol.     

Monoamines and seizures: microdialysis findings in locus ceruleus and amygdala before and during amygdala kindling

We used microdialysis to determine extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) before and during a 1-day amygdala kindling paradigm. Subjects were young cats (<1 year old; n=8; 6 female, 2 male). Consecutive 5-min samples (2 microl/min infusion rate) were obtained from left amygdala and ipsilateral locus ceruleus complex (LC) under 3 experimental conditions lasting 1-h each (n=12 samples per cat per condition): (1) just before amygdala stimulation (baseline), (2) during focal afterdischarge (AD) and (3) during generalized AD. ADs were elicited by electrical stimulation applied to establish thresholds immediately before dialysate collection as well as during each sample collected in focal vs. generalized AD conditions. Sample concentrations were time-adjusted to correspond with sleep vs. waking state and/or focal vs. generalized ADs. Seizure activity was indexed by AD threshold (mA) and duration (s) as well as number and duration of specific clinically evident (behavioral) seizure manifestations. Main results were: (1) Lower baseline concentrations (fmoles per sample) of NE, DA and 5-HT correlated with subsequent increases in duration of focal and generalized AD as well as number of behavioral seizure correlates. (2) When compared to baseline levels, NE, DA and 5-HT concentrations significantly increased only in amygdala during focal AD and in both amygdala and LC during generalized AD. (3) NE and 5-HT concentrations were higher than DA at both collection sites and were selectively associated with increased wakefulness throughout the study.     

Differential expression of immediate early genes in the hippocampus in the kindling model of epilepsy.

Kindling is a phenomenon in which brief afterdischarges (ADs) evoked by periodic electrical stimulation of the brain eventually result in generalized clonic motor seizures. Once present, the enhanced sensitivity to electrical stimulation is lifelong. The mechanism by which brief ADs produce this long-lasting effect may involve a change in gene expression. To begin to investigate changes in gene expression that occur during kindling, we used in situ hybridization histochemistry to examine the time course of expression of mRNAs of the immediate early genes (IEGs) c-fos, c-jun, NGFI-A, and c-myc within the dorsal hippocampus of rats following a kindling AD. Three principal findings resulted from this study. First, the expression of all mRNAs except c-myc was significantly increased (P less than 0.05) within discrete neuronal populations. Second, the time course of expression of the IEGs differed markedly within the same neuronal population. Third, for a given IEG, the time course and anatomic pattern of expression were strikingly different among different neuronal populations of the hippocampus. The prolonged and distinctly different patterns of IEG expression suggest that target genes are differentially regulated in these neuronal populations for prolonged periods following a kindling AD.     

Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat

Abstract

Improving functional recovery following cerebral strokes in humans will likely involve augmenting brain plasticity. This study examined skilled forelimb behavior, neocortical evoked potentials, and movement thresholds to assess cortical electrical stimulation concurrent with rehabilitative forelimb usage following a focal ischemic insult. Adult rats were trained on a task that required skilled usage of both forelimbs. They then underwent an acute focal ischemic insult to the caudal forelimb area of sensorimotor cortex contralateral to their preferred forelimb. During the same procedure, they also received a stimulation electrode over the infarct area and two depth electrodes anterior to the lesion to record evoked potentials. One week following the surgery, rats received cortical stimulation during performance of the skilled task. Evoked potentials and movement thresholds were also determined. Functional assessment revealed that cortical stimulation resulted in superior performance compared to the no stimulation group, and this was initially due to a shift in forelimb preference. Cortical stimulation also resulted in enhanced evoked potentials and a reduction in the amount of current required to elicit a movement, in a stimulation frequency dependent manner. This study suggests that cortical stimulation, concurrent with rehabilitative training, results in better forelimb usage that may be due to augmented synaptic plasticity.     

Rapid,Dose-Dependent Enhancement of Cerebral Blood Flow by transcranial AC Stimulation in Mouse

BackgroundTranscranial electrical stimulation at an appropriate dose may demonstrate intracranial effects, including neuronal stimulation and cerebral blood flow responses.ObjectiveWe performed in vivo experiments on mouse cortex using transcranial alternating current [AC] stimulation to assess whether cerebral blood flow can be reliably altered by extracranial stimulation.MethodsWe performed transcranial AC electrical stimulation transversely across the closed skull in anesthetized mice, measuring transcranial cerebral blood flow with a laser Doppler probe and intracranial electrical responses as endpoint biomarkers. We calculated a stimulation dose–response function between intracranial electric field and cerebral blood flow.ResultsStimulation at electric field amplitudes of 5–20 mV/mm at 10–20 Hz rapidly increased cerebral blood flow (within 100 ms), which then quickly decreased with no residual effects. The time to peak and blood flow shape varied with stimulation intensity and duration, showing a linear correlation between stimulation dose and peak blood flow increase. Neither afterdischarges nor spreading depression occurred from this level of stimulation.ConclusionsExtracranial stimulation amplitudes sufficient to evoke reliable blood flow changes require electric field strengths higher than what is tolerable in unanesthetized humans (<1 mV/mm), but less than electroconvulsive therapy levels (>40 mV/mm). However, anesthesia effects, spontaneous blood flow fluctuations, and sampling error may accentuate the apparent field strength needed for enhanced blood flow. The translation to a human dose–response function to augment cerebral blood flow (i.e., in stroke recovery) will require significant modification, potentially to pericranial, focused, multi-electrode application or intracranial stimulation.     

Effect of olfactory bulb kindling on evoked potentials in the pyriform cortex

The potential evoked in the pyriform cortex by single-pulse stimulation of the olfactory bulb was examined before and after single and repeated elicitation of an epileptiform afterdischarge produced by stimulation of the olfactory bulb. A single afterdischarge (AD) produced a rapid (i.e. within 5 min) increase in the amplitude of an early surface-negative wave and duration of a later surface-positive wave. These effects persisted at least 48–72 h. Repeated elicitation of ADs resulted in kindling. A large increase in the amplitude of a later surface-negative wave (approximately 25 ms latency) occurred during kindling. This wave remained significantly elevated for at least 72 h after the last AD. Long-term potentiation of the early surface-negative wave was produced by kindling or two focal ADs. A short-term effect which was consistently observed following a focal or generalized AD was a prolongation of a late surface-positive wave. These effects are discussed in relation to long-term potentiation, postseizure inhibition, and kindling development.     

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.     

Accelerated intermittent theta-burst stimulation broadly ameliorates symptoms and cognition in Alzheimer's disease: A randomized controlled trial

BackgroundDeficits in associative memory (AM) are the earliest and most prominent feature of Alzheimer's disease (AD) and demonstrate a clear cause of distress for patients and their families.ObjectiveThe present study aimed to determine AM enhancements following accelerated intermittent theta-burst stimulation (iTBS) in patients with AD.MethodsIn a randomized, double-blind, sham-controlled design, iTBS was administered to the left dorsolateral prefrontal cortex (DLPFC) of patients with AD for 14 days. Measurements included AM (primary outcome) and a comprehensive neuropsychological battery. Patients were evaluated at baseline, following the intervention (week 2), and 8 weeks after treatment cessation (week 10).ResultsSixty patients with AD were initially enrolled; 47 completed the trial. The active group displayed greater AM improvements compared with the sham group at week 2 (P = 0.003), which was sustained at week 10. Furthermore, higher Mini-Mental State Examination (MMSE) scores at baseline were associated with greater AM improvements at weeks 2 and 10. For the independent iTBS group, this correlation predicted improvements in AM (P < 0.001) and identified treatment responders with 92% accuracy. Most of the neuropsychological tests were markedly improved in the active group. In particular, the Montreal Cognitive Assessment and MMSE in the active group increased by 2.8 and 2.3 points, respectively, at week 2, while there was no marked change in the sham group.ConclusionIn the present study, accelerated iTBS of the DLPFC demonstrated an effective and well-tolerated complementary treatment for patients with AD, especially for individuals with relatively high MMSE scores.     

Task-free electrocorticography frequency mapping of the motor cortex

ObjectiveElectrocortical stimulation mapping (ESM) is the current gold standard for functional mapping of the eloquent cortex prior to epilepsy surgery. The procedure is, however, time-consuming and quite demanding for patients. Electrocorticography frequency mapping (ECoG mapping) has been suggested as an adjunct method. Here, we investigated whether it is possible to perform mapping of motor regions using ECoG data of spontaneous movements.MethodsUsing the video registration of seven epilepsy patients who underwent electrocorticography and ESM, we selected periods of spontaneous hand and arm movements and periods of rest. Frequency analysis was performed, and electrodes showing a significant change in power (4–7, 8–14, 15–25, 26–45 or 65–95 Hz) were compared with those being identified as relevant for hand and/or arm movement by ESM.ResultsAll frequency bands showed a high specificity (>0.80), and the 65–95 Hz frequency band additionally had a high sensitivity (0.82) for identifying ESM positive electrodes.ConclusionsOur data show a good match between ECoG mapping of spontaneous movements and ESM data.SignificanceThe accurate match suggests that ECoG mapping of the motor cortex using spontaneous movements may be a valuable complement to ESM, especially when other options requiring patient cooperation fail.     

Neuroprotective effect of melatonin on soluble Aβ1–42-induced cortical neurodegeneration via Reelin–Dab1 signaling pathway

Objective: Soluble Aβ_1–42 oligomers play a vital role in the development and pathogenesis of Alzheimer’s disease (AD). Melatonin could delay the progress of AD through multiple mechanisms. Reelin–Dab1 signaling plays an important role in AD, including neuronal function and synaptic plasticity. However, whether melatonin could exert its neuroprotective function against soluble Aβ_1–42-induced neurotoxicity during AD development through regulating Reelin–Dab1 signaling remains poorly understood.

Methods: AD rat model was established by soluble Aβ_1–42 repeated intracerebroventricular injection. Using immunohistochemistry and Western blot analyses, the effect of melatonin on synaptic plasticity, neuritic degeneration, and astrocyte activation was investigated in cerebral cortex. Meanwhile, the expression of Reelin and Dab1 was also examined in cerebral cortex. In our in vitro study, Reelin–Dab1 signaling was inhibited by Reelin antibody, and neuroprotective effect of melatonin against Aβ_1–42 was further determined.

Results: Melatonin ameliorated the neurotoxiciy and astrocyte activation induced by Aβ_1–42 in the cerebral cortex. Melatonin also blocked the reduction in Reelin and Dab1 expression induced by Aβ_1–42. Using in vitro study, Reelin inactivation completely abolished the protective effect of melatonin against Aβ_1–42-induced neurotoxicity.

Discussion: Melatonin might play its neuroprotective role against Aβ_1–42 through mediating Reelin–Dab1 signaling pathway. Melatonin could be a safe and remarkable therapeutic candidate for AD and other aged-associated neurodegenerative diseases.     

Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer's disease

BackgroundAlthough single or multiple sessions of transcranial direct current stimulation (tDCS) on the prefrontal cortex over a few weeks improved cognition in patients with Alzheimer's disease (AD), effects of repeated tDCS over longer period and underlying neural correlates remain to be elucidated.ObjectiveThis study investigated changes in cognitive performances and regional cerebral metabolic rate for glucose (rCMRglc) after administration of prefrontal tDCS over 6 months in early AD patients.MethodsPatients with early AD were randomized to receive either active (n = 11) or sham tDCS (n = 7) over the dorsolateral prefrontal cortex (DLPFC) at home every day for 6 months (anode F3/cathode F4, 2 mA for 30 min). All patients underwent neuropsychological tests and brain ¹⁸F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) scans at baseline and 6-month follow-up. Changes in cognitive performances and rCMRglc were compared between the two groups.ResultsCompared to sham tDCS, active tDCS improved global cognition measured with Mini-Mental State Examination (p for interaction = 0.02) and language function assessed by Boston Naming Test (p for interaction = 0.04), but not delayed recall performance. In addition, active tDCS prevented decreases in executive function at a marginal level (p for interaction < 0.10). rCMRglc in the left middle/inferior temporal gyrus was preserved in the active group, but decreased in the sham group (p for interaction < 0.001).ConclusionsDaily tDCS over the DLPFC for 6 months may improve or stabilize cognition and rCMRglc in AD patients, suggesting the therapeutic potential of repeated at-home tDCS.     

The release of β-endorphin and the neuropeptide-receptor mismatch in the brain

Microprobes bearing immobilized antibodies to the carboxy-terminus of β-endorphin were used to study the release of β-endorphin in the urethane anaesthetized rat following electrical stimulation of the ipsilateral arcuate nucleus. The microprobes were inserted through the cerebral hemisphere, the superior colliculus and the midbrain periaqueductal grey. Since such microprobes detect extracellular molecules along their entire length they give information on the persistence and spread of compounds following release. Little immunoreactive-β-endorphin was detected in the areas of brain sampled during electrical stimulation of arcuate nucleus but a remarkable spread throughout the midbrain and cerebral cortex occurred within 30 min of the cessation of stimulation. The results suggest that although β-endorphin-containing fibres are absent in many parts of the brain, this neuropeptide can access receptors in these sites and it is not necessary for release to be directly adjacent to opiate receptors. As such it is important evidence supporting the hypothesis of volume transmission as a means of neuronal communication. The results also suggest that an important mechanism of the transport of β-endorphin is the cerebrospinal fluid.