Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study

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.

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 1^st 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 (GABA_A) 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].

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.

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