- Research article
- Open access
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Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study
The Journal of Headache and Pain volume 17, Article number: 58 (2016)
Abstract
Background
Here, we aim to identify cortical electrofunctional correlates of responsiveness to short-lasting preventiveintervention with ketogenic diet (KD) in migraine.
Methods
Eighteen interictal migraineurs underwent visual (VEPs) and median nerve somatosensory (SSEPs) evokedpotentials before and after 1 month of KD during ketogenesis. We measured VEPs N1-P1 and SSEPs N20-P25 amplitudes respectively in six and in two sequential blocks of 100 sweeps as well as habituation as theslope of the linear regression between block 1 to 6 for VEPs or between 1 to 2 for SSEPs.
Results
After 1-month of KD, a significant reduction in the mean attack frequency and duration was observed (all P< 0.001). The KD did not change the 1st SSEP and VEP block of responses, but significantly inducednormalization of the interictally reduced VEPs and SSEPs (all p < 0.01) habituation during the subsequentblocks.
Conclusions
KD could restore normal EPs habituation curves during stimulus repetition without significantly changing theearly amplitude responses. Thus, we hypothesize that KD acts on habituation regulating the balancebetween excitation and inhibition at the cortical level.
Background
Migraine accounts for the highest headache-related disability of the primary headaches. Despite the great knowledge achieved on the pathophysiology of migraine, commonly available preventive treatments are effective in only about half of patients. Many have disabling and uncomfortable adverse effects. Pharmacological and non-pharmacological treatments that are more effective are very welcome [1–3]. In recent decades, specific dietetic interventions raised the interest of experts in the field of headaches. The evidence for an association between migraine, obesity [4, 5], and metabolic syndromes such as insulin resistance [6, 7] has supported this approach because they could be improved via specific dietary patterns.
We reported a case of a pair of overweighed twin sisters whose high-frequency migraine improved during a ketogenic diet (KD) that they followed to lose weight [8]. Their KD consists of a very low-calorie ketogenic diet (VLCKD) including a drastic restriction in carbohydrate and lipid intake that promotes fat metabolism and ketone body synthesis. After our initial accidental observation, we proved the clinical efficacy of VLCKD in a population of overweighed migraine patients. This was not related to diet-induced weight loss because the same improvement was not observed during a standard dietetic regimen [9]. According to the experimental observations in animal models, the underlying mechanisms of KD efficacy could be related to its ability to modulate cortical excitability [10, 11].
Time-locked cortical potentials evoked by a sensorial stimulation have been used frequently as a model to study migraine brain excitability. With these methods of clinical neurophysiology, researchers frequently observed a lack of cortical response habituation during any kind of stimulus repetition including visual and somatosensory [12, 13]. Habituation is a form of plastic learning and is a protective mechanism intended to limit cortical excitability. It prevents neuronal stress and excessive accumulation of metabolites such as lactate [14].
Here, in order to investigate if KD may exert its prophylactic effect regulating abnormal cortical information processing and excitability, we evaluated for the first time the influence of 1-month KD on habituation of visual and somatosensory cortical evoked potentials in a group of episodic migraineurs during the interictal phase.
Methods
Subjects
We initially enrolled 25 consecutive migraine patients who attended our headache centre. We discarded the recordings of seven patients who did not fulfil our primary inclusion criteria (see below). The final analysis set thus comprises a group of 18 migraine patients (14 without aura [MO, ICHD-III code 1.1], and four with aura [MA, ICHD-III code 1.2.1]) aged 19–54 years (mean 38.8 years). We took information on various clinical characteristics by collecting up to two-month headache diaries at the time of the screening visit. Patients had to indicate the duration of migraine history (years), attack frequency (n/month), and attack duration (hours). Of the enrolled migraineurs, we identified ten overweight patients (BMI ≥ 25, mean 28.6) and eight normal-weight patients (BMI < 25). For comparison, we included a group of 18 age- and gender- matched (one by one) healthy volunteers (HV, 16 women, mean age 38.8 years), with comparable BMI, we previously recruited among medical school students and healthcare professionals, who underwent both VEP and SSEP recordings.
Ketogenic diet
Overweight patients received a 4-week low-carbohydrate (about 30 g/day carbohydrates), low-fat (fixed 15 g lipids), and normal protein (1.0–1.2 g/Kg of desired weight proteins) VLCKD diet (≤800 kcal) according to methods described elsewhere [8, 9]. This comprised five daily meals consisting of four protein shakes developed ad hoc as a protein supplement in KD (Ketoneural Protein Blend, Medi-Diet s.r.l., Aprilia, Italy), one daily meal of meat (up to 200 g) or fish (up to 350 g) accompanied by salad and nutraceutical integrators (Table 1). Further optional meals were allowed for non-sedentary subjects. Normal weight patients (BMI < 25) were administered a 4-week normo-caloric ketogenic dietary regimen (modified Atkins diet (MAD)) [15] consisting of low carbohydrate (about 15 g/day), normal/low protein (about 0.7 g/Kg/day, or less) and high fat (approximately little more than the weight of carbohydrates and proteins together) from meals prepared by common foods. These were supplemented with lipids in the form of a powder composed of medium chain triglycerides as well as omega-3 and long chain triglycerides (Ketoneural LipidiComplex, Medi-Diet s.r.l., Aprilia, Italy) with nutraceutical integrators (Table 1). For both groups, a daily urine dip stick test confirmed the presence of ketogenesis. Patients reported the stick results in a headache diary along with meals, daily weight, possible adverse events, or side effects. Patients had medical supervision and laboratory blood tests (alanine aminotransferase, aspartate aminotransferase, gamma glutamic transpeptidase, lactic dehydrogenase, alkaline phosphatase, bilirubin, blood urea nitrogen, and creatinine) at the start and the end of the 4-week KD.
The primary inclusion criterion was being attack-free for at least 3 days before and after the recording sessions as determined by collecting headache diaries and telephone or e-mail interviews. Exclusion criteria were regular medication intake (i.e. antibiotics, corticosteroids, antidepressants, benzodiazepines, prophylactic migraine drugs) except for contraceptive pills. Other exclusion criteria included failure to reach a best-corrected visual acuity of > 8/10, history of other neurological diseases, systemic hypertension, diabetes or other metabolic disorders, connective or autoimmune diseases, and any other type of primary or secondary headache. Female participants were always recorded mid-cycle. All study participants were naïve to the study procedure and received a complete description of the study and gave informed consent. The project was approved by the Ethics Committee of the “Sapienza” University of Rome, Polo Pontino.
Data acquisition
Visual-evoked potentials
Subjects were seated in an acoustically isolated room with dimmed lights in front of a TV monitor surrounded by a uniform luminance field of 5 cd/m2. To obtain a stable pupillary diameter, each subject was adapted to the ambient room light for 10 min before the Visual-evoked potentials (VEPs) recordings. The VEPs were elicited by right monocular stimulation. Visual stimuli consisted of full-field checkerboard patterns (contrast 80%, mean luminance 50 cd/m2) generated on a TV monitor. The reversal rate was 1.55 Hz (3.1 reversal per second). The single checks subtended a visual angle of 15 minutes at a viewing distance of 114 cm while the checkerboard subtended to 23°. Recordings were done with the best corrected visual acuity of > 8/10 at the viewing distance. Subjects were instructed to fixate with their right eye on a red dot in the middle of the screen with the contralateral eye covered by a patch to maintain stable fixation. The VEPs were recorded via the scalp through silver cup electrodes positioned at Oz (active electrode) and at the Fz (reference electrode, 10/20 system). A ground electrode was placed on the right forearm. Signals were amplified by Digitimer™ D360 pre-amplifiers (band-pass 0.05–2000 Hz, gain 1000) and recorded with a CED™ power 1401 device (Cambridge Electronic Design Ltd, Cambridge, UK). A total of 600 consecutive sweeps (each lasting 200 ms) were collected and sampled at 4000 Hz.
After applying a 100 Hz low-pass digital filter off-line, cortical responses were partitioned in six sequential blocks of 100 consisting of at least 95 artefact-free sweeps. Responses in each block were averaged off-line (“block averages”) using the Signal™ software package version 4.10 (CED Ltd).
VEPs components were identified according to their latencies: N1 was the most negative peak between 60 and 90 ms, and P1 was the most positive peak following N1 between 80 and 120 ms. The N2 was the most negative peak following P1 between 125 and 150 ms (Fig. 2). We measured the peak-to-peak amplitude of the N1-P1 and P1-N2 complexes. Habituation was defined as the slope of the linear regression line for the 6 blocks [16].
Somatosensory-evoked potentials
Somatosensory evoked potentials (SSEPs) were elicited by electrical stimulation of the right median nerve at the wrist using a constant current square wave pulse (0.1 ms width, cathode positioned proximally) with a stimulus intensity set at 1.5 times the motor threshold; the repetition rate was 4.4 Hz. The 1st active electrode was placed over Erb’s point ipsilateral to the stimulus referenced to the contralateral side. The 2nd and 3rd recording electrodes were positioned over the 5th cervical spinous process (Cv5) and over the contralateral parietal area (C3′, 2 cm posterior to C3 in the international 10–20 system). Both were referenced to the Fz. The ground electrode was on the right arm. The SSEP signals were amplified and recorded with the same hardware/software electronic equipment as described above for VEPs recordings.
The subjects sat relaxed in a comfortable chair in a well-lit room with both eyes open during the recordings. They were asked to fix their attention on the stimulus-induced thumb movement. Five hundred consecutive sweeps of 50 ms, sampled at 5000 Hz, were collected.
After digital filtering of the signal between 0–450 Hz, the various SSEP components (N9, N13, N20, P25 and N33) were identified according to their respective latencies. We measured peak-to-peak amplitudes of the peripheral N9 (recorded under the active Erb’s point electrode), the cervical N13 component (recorded under the active Cv5 electrode), and the cortical N20-P25 and P25-N33 components (recorded under the active C3′ scalp electrode).
Thereafter, since a clear-cut habituation (or its lacking) already from the 2nd block of 100 averaged responses onwards was observed in previous studies by independent groups [17, 18], the first 200 evoked responses were partitioned in two sequential blocks of 100 responses (Fig. 3). Each block was averaged off-line (“block averages”) and analysed for N20-P25 amplitudes. Habituation was expressed as the slope of the linear regression line for the two blocks [18].
For both VEPs and SSEPs, the artefacts were automatically rejected using the Signal™ artefact rejection tool if the signal amplitude exceeded 90% of analogue-to-digital converter (ADC) range. The EP-signal was corrected off-line for DC-drifts.
Procedure
Somatosensory- and visual-evoked potential recordings were performed in random order during a single session including baseline (time 0) and 1-month after during the ketogenesis as verified through a ketone bodies urinary stick (ketur-test). This was performed on the same day of the recording session. All recordings were collected in the afternoon (between 02.00 and 6.00 p.m.) by the same investigators (D.D.L and C.D.L.) who were not involved in recruitment and inclusion of subjects. These investigators also did not meet the participants prior to the examination. All recordings were numbered anonymously and analysed blindly off-line by one investigator (M.B.), who was not blinded to the order of the blocks.
Statistical analysis
We used the Statistica for Windows (StatSoft Inc.) version 8.0 for all analyses. A Kolmogorov-Smirnov test showed that VEPs and SSEP components latencies and amplitudes had a normal distribution. A General Linear Model approach was used to analyse the “between-factor” × “within-factors” interaction effect. The between-subject factor was “group” or “time” (before vs. after KD) and within-subject factor was “blocks”. There were two models of repeated measure ANOVA (rm-ANOVA), one for VEPs and another for SSEP as well as univariate ANOVAs to investigate the interaction effect. Univariate results were analysed only if Wilks’ Lambda multivariate significance criterion was achieved. The sphericity of the covariance matrix was verified with the Mauchly Sphericity Test; in the case of violation of the sphericity assumption, the Greenhouse-Geisser (G-G) epsilon (ε) adjustment was used.
Sphericity cannot be evaluated for the second model of ANOVA (SSEP) because there were fewer than three levels of repeated measurement factors. In rm-ANOVA and ANOVA models, partial eta2 \( \left({\eta}_p^2\right) \) and observed power (op) were used as measures of effect size and power, respectively. In a third rm-ANOVA model, we used “type of KD” (normocaloric vs. hypocaloric) as the between-subject factor. The within-subject factor was “time” (before and after KD). These were used to evaluate the relative contribution of diet on neurophysiological results. To define which comparison(s) contributed to the major effects, post hoc tests were performed with a Tukey Honest Significant Difference (HSD) test.
Paired-sample t tests were used to compare the clinical data before vs. after KD. P values less than 0.05 were considered to indicate statistical significance.
Results
Clinical characteristics
The clinical characteristics of migraine patients before and after 1-month of KD are displayed in Table 2 and Fig. 1. This figure also shows that there was a significant reduction in attack frequency (from 4.4 ± 2.7 to 1.3 ± 1.1 attacks/month, t = 4.70, p < 0.001) and attack duration (from 50.7 ± 26.9 to 15.8 ± 20.1 hours, t = 5.43, p < 0.001) after 1-month duration KD.
Basic neurophysiological parameters
Assessable VEP and SSEP recordings were obtained from all subjects participating in the study (Figs. 2 and 3). On grand-average the VEP (N1, P1, and N2, Table 3) and SSEP (N9, N13, N20, P25, and N33, Table 4) latencies and their corresponding amplitudes (VEP N1-P1 and P1-N2; SSEP N9, N13, N20-P25, and P25-N33) were not significantly different between migraineurs and healthy volunteers (P > 0.05).
Before KD short-term intervention, the migraine patients lacked habituation in response to both visual and somatosensory repetitive stimulations. In fact, in the rm-ANOVA model with VEP N1-P1 or SSEP N20-P25 peak-peak amplitudes as dependent variable, multivariate test was significant for the “group” × “blocks” interaction effect (Wilks’ Lambda = 0.711, F5,30 = 5.395, p = 0.001 for VEP; Wilks’ Lambda = 0.838, F5,30 = 6.593, p = 0.015 for SSEP). The linear regression slope of VEP (N1-P1) and SSEP (N20-P25) amplitudes over all blocks differed significantly between the two groups (F1,34 = 27.029, p < 0.0001 for VEP; F1,34 = 6.613, p = 0.015 for SSEP). By contrast, in the rm-ANOVA model with VEP P1-N2 peak-peak amplitude as dependent variable, multivariate test was not significant for the “group” × “blocks” interaction effect (Wilks’ Lambda = 0.918, F5,30 = 0.538, p = 0.746).
Dietetic intervention effects
On grand-average the VEP (N1, P1, and N2, Table 3) and SSEP (N9, N13, N20, P25, and N33, Table 4) latencies and their corresponding amplitudes (VEP N1-P1 and P1-N2; SSEP N9, N13, N20-P25, and P25-N33) were not significantly different before and after KD in migraineurs overall and in both KD regimen groups (P > 0.05).
In the rm-ANOVA model using VEP N1-P1 peak-peak block amplitude as dependent variable, the multivariate test was significant for the “time” × “blocks” interaction effect (Wilks’ Lambda = 0.631, F5,30 = 3.27, p = 0.019). The univariate rm-ANOVAs for N1-P1 peak-peak amplitudes confirmed the significant interaction factor effect (F5,170 = 2.71, ε = 0.79, p = 0.033, partial η2 = 0.078, op = 0.81) observed at the multivariate test. The linear regression N1-P1 slope of VEP amplitudes over all blocks differed significantly between before and after KD (F1,34 = 8.92, p = 0.005, partial η2 = 0.208, op = 0.83; raw data are shown in Fig. 4).
In the rm-ANOVA model using VEP P1-N2 peak-peak block amplitude as dependent variable, multivariate test was not significant for the “time” × “blocks” interaction effect (Wilks’ Lambda = 0.971, F5,30 = 0.180, p = 0.968).
In the rm-ANOVA model using SSEP N20-P25 peak-peak block amplitude as the dependent variable, the multivariate test was significant for the “time” × “blocks” interaction effect (Wilks’ Lambda = 0.711, F5,30 = 13.83, p = 0.0007). The univariate rm-ANOVAs for N20-P25 peak-peak amplitude confirmed the significant interaction factor effect (F1,34 = 13.83, p = 0.0007, partial η2 = 0.289, op = 0.95) observed at the multivariate test. The linear regression N20-P25 slope of SSEP amplitudes over the two blocks differed significantly between the before and after KD (F1,34 = 13.83, p = 0.0007, partial η2 = 0.289, op = 0.95; raw data are shown in Fig. 4).
In the rm-ANOVA model with VEP N1-P1 or SSEP N20-P25 amplitude slope (before or after KD) as the dependent variable, the multivariate test was not significant for the “time” × “type of KD” interaction effect (Wilks’ Lambda = 0.711, F1,16 = 1.13, p = 0.304; Wilks’ Lambda = 0.881, F1,16 = 2.17, p = 0.160, respectively). Nevertheless, in both KD regimen groups (normo- and hypo- caloric), the baseline attack frequency, attack duration, and BMI were significantly reduced after a month of diet (Table 2).
Discussion
This study confirms our previous clinical finding that migraine features significantly improve in terms of attack frequency and duration during a month of ketogenic diet [8, 9]. Moreover, this study also confirms that before KD short-term interventions, the migraine patients lacked habituation in response to visual (VEP N1-P1 slope: + 0.09) and somatosensory (SSEP N20-P25 slope: + 0.32) repetitive stimulations [19, 20].
The most striking finding is that KD could significantly normalize the habituation deficit on evoked potentials as long as migraine clinical features improved. This was a general behavioural cortical process in response to KD because it was independent from the stimulus modality inducing the lack of habituatory effect. Moreover, our neurophysiological findings were independent from loss of weight because both patients who followed normo-caloric and those who followed hypo-caloric regimen habituate normally during KD.
Various mechanisms might underlie these findings. Most of these are borrowed from the clinical and experimental studies performed in epilepsy. These include induction of neural plasticity, changes in cortical excitability and enhancement in energetic metabolism.
Habituation, i.e. the “response decrement as a result of repeated stimulation” is a basic form of learning and memory [21]. Such changes in behavioural response offers insight into the adaptive short- and long- term plasticity mechanisms that correspond to changes in neuronal excitability. These include a decrease in evoked potential amplitudes that further depend on the underlying genetic load [22–24].
Interestingly, in animal models, KD seems to precisely affect synaptic plasticity and cortical excitability. In freely behavioural rats, a ketogenic diet—although not significantly altering baseline excitability—did reduce the magnitude of long-term potentiation plastic mechanisms in the hippocampal dentate gyrus [11, 25]. Our results seem to be in perfect agreement with those provided by the animal models. While we did not find significant differences in term of initial baseline excitability as reflected in the non-significant changes in 1st block VEP and SSEP amplitudes, we did observe that KD reduced the interictal-evoked potential amplitude potentiation and normalized the response. This is not unusual. Indeed, in a habituation paradigm, early and late responses may behave differently because they are regulated by different mechanisms. In fact, according to the dual-process theory, facilitation/sensitization (increasing response) competes with habituation (decreasing response) to determine the final behavioural outcome. Facilitation occurs at the beginning of the stimulus session and accounts for the initial transitory increase in response amplitude. Habituation occurs throughout the recording session and accounts for the delayed response decrease [26]. Therefore, our results suggest that KD selectively affects delayed habituation by reducing migraineurs’ cortical hyperresponsivity. This avoids any influence on the initial facilitatory mechanism.
Reduced potentiation/hyperresponsivity mechanisms in ketogenic diet-fed rats [11, 25] is consistent with a general modulation of cortical excitability. This was confirmed by the observation that KD is a useful tool in controlling childhood seizures [27, 28]. In hippocampal in vitro seizures models, KD feeding limited epileptic activity in several portions of the hippocampus by promoting ATP-sensitive K+ channel activity that is implicated in plasma membrane excitability and in regulation of aerobic metabolism [29–31]. Both augmentation of fast GABAergic (GABAA) neurotransmission and decreased probability of excitatory neurotransmitter release from presynaptic neurons have been implicated in the anticonvulsivant actions of the KD [32, 33]. In fact, elevated concentrations of KBs have been reported to increase and maintain synaptosomal GABA contents at a higher value [34] and increase the intracellular concentration [35] and cause presynaptic input reduction of glutamate [31]. In healthy humans, KD is associated with a significant enhancement of intracortical inhibition as measured with transcranial magnetic stimulation [10]. These experimental observations are of particular interest in migraine because we have previously reported that the migraineurs’ brains are characterized by an imbalance between excitation and inhibition in the sensory cortices [36]. In particular, distinct cortical inhibitory mechanism, the so-called lateral inhibition, were reported to be impaired interictally in the visual [20] and somatosensory [37] cortices of migraine patients. This impairment may contribute to the interictal propensity to lack EP amplitude habituation [20]. Further evidence for defective inhibitory mechanisms in the visual cortex of migraine with and without aura patients came also from studies using paired-pulse suppression of visual evoked potentials [38, 39]. We hypothesize that KD works by heightening GABAergic and diminishing excitatory activities. This may have forced the delayed reduction of VEP and SSEP amplitudes and restored normal habituatory behaviour.
Another possible mechanism of KD is the restoration of normal EP habituation via potentiation of mitochondrial energy metabolism. The KD may induce a strengthened mitochondrial metabolism and biogenesis [40] and improve energy production throughout the oxidative respiratory complex [41]. This leads to a more efficient synaptic transmission and plasticity [42, 43]. This is of obvious relevance because neuronal excitability depends on energy metabolism and because convergent data from various laboratories have shown that brain oxidative metabolism, mitochondrial functioning, and energetic production are significantly reduced in the brain of migraineurs between attacks [44–46].
This mitochondrial dysfunction in migraine causes anaerobic metabolites (e.g. lactate) to increase in the brain. In healthy humans during sustained visual stimulation, the increasing habituation of evoked potentials coincides with a decrease in cortical lactate levels [47]. Migraineurs show the opposite effect during continuous visual stimulation [45]. This is of interest because the elevation of cerebral lactate concentration is a common finding in patients with mitochondrial dysfunction [48]. Consequently, we speculate that the KD regimen may dampen the excessive brain lactate accumulation produced during sensory habituation deficit because KD improves mitochondrial metabolism. This favours the restoration of a normal reducing response, i.e. habituation.
Finally, we have shown that VEP and SSEP amplitudes habituate normally following KD irrespective of the type of KD (normo-caloric or hypo-caloric). Because the different diets were assigned according to the baseline weight, this implies that neither the pre-diet BMI nor the amount of lipids and calories related to the diet seem to influence the outcome of neurophysiological measures. Moreover, baseline clinical and neurophysiological variables were not significantly different between subgroups (see Tables 2 and 3). Therefore, these observations favour the hypothesis that the switch from glucose to KBs as an energetic substrate in patients’ brain could play a relevant role in changing their interictal abnormal information processing.
As with all studies, our findings need to be considered with our study limitations. First, the number of patients and the period of observation are too small to generalize our results, although our cohort was sufficient to disclose the same behavioural phenomenon in response to KD using two different stimulus modality. The issue of low number of patients is particularly true for the analysis of the subgroups of patients who underwent normo- or hypo-caloric ketogenic dietetic regimens. Future studies should attempt to clarify the possible cortical effects of different ketogenic dietetic regimens in a larger cohort of patients. Moreover, we acknowledge as a limitation of the present study the lack of inclusion of a patients control group staying on the waiting-list not undergoing the dietetic intervention in order to control for effects of repeated measurements at the neurophysiological level and for unpredictable spontaneous clinical improvement. However, this point should not consider to be detrimental since a recent study in migraine proved that, at least for the visual modality, evoked potential amplitude habituation has a sufficient repeatability over an average test-retest time interval of 60 days [49], and because we previously proved that only 1-month KD, but not a standard diet, was clinically effective in a population of migraine patients [9].
Another shortcoming of our study is that we cannot exclude the possibility that other mechanisms not related to the ketogenesis could account for the results we have observed. For instance, other possibilities are that KD induces effects by promoting hypoglycaemia, lack of fluctuations of insulin blood levels, or by lowering the activity of the so-called nutrient-integrating pathways that sense and respond to fluctuations in nutrient levels [50].
Conclusions
In conclusion, our study proves that in migraineurs KBs has central nervous system effects in parallel with clinical improvement. In our migraine patients who were characterized by a baseline increasing of VEP and SSEP amplitude responses during repetitive stimulation (deficit of habituation), this dietetic intervention was followed by a significant EPs amplitude decrement (habituation).
We have hypothesized that several interacting mechanisms may be at work in the clinical and neurophysiological actions of the KD. Future works will clarify whether cerebral cortex is the primary site of KD-related changes or if the latter are the expression of its ability to modulate subcortical structures including the brainstem and thalamus. In turn, these may cause abnormal cortical activation.
Abbreviations
BMI, body mass index; HSD, tukey honest significant difference; KD, ketogenic diet; MAD, atkins modified diet; rm-ANOVA, repeated measure ANOVA; SSEPs, somatosensory evoked potentials; VEPs, visual evoked potentials; VLCKD, very low-calorie ketogenic diet
References
Rossi P, Di Lorenzo G, Malpezzi MG et al (2005) Prevalence, pattern and predictors of use of complementary and alternative medicine (CAM) in migraine patients attending a headache clinic in Italy. Cephalalgia 25:493–506
Rossi P, Torelli P, Di Lorenzo C et al (2008) Use of complementary and alternative medicine by patients with cluster headache: results of a multi-centre headache clinic survey. Complement Ther Med 16:220–227
Coppola G, Di Lorenzo C, Serrao M et al (2015) Pathophysiological targets for non-pharmacological treatment of migraine. Cephalalgia. doi:10.1177/0333102415620908
Bigal ME, Lipton RB (2006) Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology 67:252–257
Chai N, Scher AI, Moghekar A et al (2014) Obesity and headache: part I--a systematic review of the epidemiology of obesity and headache. Headache 54:219–234
Rainero I, Limone P, Ferrero M et al (2005) Insulin sensitivity is impaired in patients with migraine. Cephalalgia 25:593–597
Cavestro C, Rosatello A, Micca G et al (2007) Insulin metabolism is altered in migraineurs: a new pathogenic mechanism for migraine? Headache 47:1436–1442
Di Lorenzo C, Currà A, Sirianni G et al (2013) Diet transiently improves migraine in two twin sisters: possible role of ketogenesis? Funct Neurol 28:305–308
Di Lorenzo C, Coppola G, Sirianni G et al (2015) Migraine improvement during short lasting ketogenesis: a proof-of-concept study. Eur J Neurol 22:170–177
Cantello R, Varrasi C, Tarletti R et al (2007) Ketogenic diet: electrophysiological effects on the normal human cortex. Epilepsia 48:1756–1763
Blaise JH, Ruskin DN, Koranda JL, Masino SA (2015) Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. Physiol Rep 3:e12411
Coppola G, Di Lorenzo C, Schoenen J, Pierelli F (2013) Habituation and sensitization in primary headaches. J Headache Pain 14:65
Magis D, Vigano A, Sava S et al (2013) Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia 33:526–539
Schoenen J (1996) Deficient habituation of evoked cortical potentials in migraine: a link between brain biology, behavior and trigeminovascular activation? Biomed Pharmacother = Biomédecine pharmacothérapie 50:71–78
McDonald, McDonald L (1998) The Ketogenic Diet. Austin, Texas: Lyle McDonald
Coppola G, Bracaglia M, Di Lenola D et al (2015) Visual evoked potentials in subgroups of migraine with aura patients. J Headache Pain 16:92
Ozkul Y, Uckardes A (2002) Median nerve somatosensory evoked potentials in migraine. Eur J Neurol 9:227–232
Coppola G, Iacovelli E, Bracaglia M et al (2013) Electrophysiological correlates of episodic migraine chronification: evidence for thalamic involvement. J Headache Pain 14:76
Coppola G, Currà A, Di Lorenzo C et al (2010) Abnormal cortical responses to somatosensory stimulation in medication-overuse headache. BMC Neurol 10:126
Coppola G, Parisi V, Di Lorenzo C et al (2013) Lateral inhibition in visual cortex of migraine patients between attacks. J Headache Pain 14:20
Harris JD (1943) Habituatory response decrement in the intact organism. Psychol Bull 40:385–422
Di Lorenzo C, Coppola G, Currà A et al (2012) Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism. Cephalalgia 32:1189–1197
Di Lorenzo C, Di Lorenzo G, Daverio A et al (2012) The Val66Met polymorphism of the BDNF gene influences trigeminal pain-related evoked responses. J Pain 13:866–873
Di Lorenzo C, Daverio A, Pasqualetti P et al (2014) The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses. Eur J Neurosci 39:501–507
Koranda JL, Ruskin DN, Masino SA, Blaise JH (2011) A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. J Neurophysiol 106:662–666
Groves PM, Thompson RF (1970) Habituation: a dual-process theory. Psychol Rev 77:419–450
Wheless JW (2008) History of the ketogenic diet. Epilepsia 8:3–5
Klein P, Tyrlikova I, Mathews GC (2014) Dietary treatment in adults with refractory epilepsy: a review. Neurology 83:1978–1985
Stafstrom CE, Wang C, Jensen FE (1999) Electrophysiological observations in hippocampal slices from rats treated with the ketogenic diet. Dev Neurosci 21:393–399
Bough KJ, Schwartzkroin PA, Rho JM (2003) Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo. Epilepsia 44:752–760
Kawamura M, Ruskin DN, Geiger JD et al (2014) Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res 55:2254–2260
Nylen K, Velazquez JL, Likhodii SS et al (2008) A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exp Neurol 210:449–457
Simeone TA, Samson KK, Matthews SA, Simeone KA (2014) In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv 1.1α knockout mice. Epilepsia 55:e44–e49
Erecińska M, Nelson D, Daikhin Y, Yudkoff M (1996) Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J Neurochem 67:2325–2334
Sato K, Kashiwaya Y, Keon CA et al (1995) Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 9:651–658
Coppola G, Pierelli F, Schoenen J (2007) Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 27:1427–1439
Coppola G, Bracaglia M, Di Lenola D et al (2016) Lateral inhibition in the somatosensory cortex during and between migraine without aura attacks: correlations with thalamocortical activity and clinical features. Cephalalgia 36:568–578
Höffken O, Stude P, Lenz M et al (2009) Visual paired-pulse stimulation reveals enhanced visual cortex excitability in migraineurs. Eur J Neurosci 30:714–720
Strigaro G, Cerino A, Falletta L et al (2015) Impaired visual inhibition in migraine with aura. Clin Neurophysiol 126:1988–1993
Bough KJ, Wetherington J, Hassel B et al (2006) Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 60:223–235
Maalouf M, Sullivan PG, Davis L et al (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145:256–264
Bough K (2008) Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. Epilepsia 8:91–93
Kim DO, Vallejo J, Rho JM (2010) Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem 114:130–141
Barbiroli B, Montagna P, Cortelli P et al (1992) Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology 42:1209–1214
Sándor P, Dydak U, Schoenen J et al (2005) MR-spectroscopic imaging during visual stimulation in subgroups of migraine with aura. Cephalalgia 25:507–518
Di Lorenzo C, Pierelli F, Coppola G et al (2009) Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs. Neurology 72:1588–1594
Sappey-Marinier D, Calabrese G, Fein G et al (1992) Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab 12:584–592
Jackson MJ, Schaefer JA, Johnson MA et al (1995) Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain 118:339–357
Ambrosini A, Coppola G, Iezzi E et al (2016) Reliability and repeatability of testing visual evoked potential habituation in migraine: A blinded case–control study. Cephalalgia. doi:10.1177/0333102416648656
Kossoff EH, Hartman AL (2012) Ketogenic diets: new advances for metabolism-based therapies. Curr Opin Neurol 25:173–178
Acknowledgment
Funding for the present study was supported by an Academic grant from the Sapienza University of Rome. The Italian Ministry of Health supported the contribution of the Don Carlo Gnocchi Onlus Foundation in this paper. The contribution of the G.B. Bietti Foundation in this paper was supported by Ministry of Health and Fondazione Roma.
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CDL and made substantial contributions to interpretation of data as well as in drafting the manuscript. ME, GS, PR and GDL were implied in the interpretation of data as well as in drafting the manuscript; MS, VP, and FP gave critical revision of the manuscript for important intellectual content. MB, CDL, and DDL were implied in recording and analyzing data. All authors read and approved the final manuscript.
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Di Lorenzo, C., Coppola, G., Bracaglia, M. et al. Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain 17, 58 (2016). https://doi.org/10.1186/s10194-016-0650-9
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DOI: https://doi.org/10.1186/s10194-016-0650-9