A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs

DOI: https://doi.org/10.1186/s12883- 019- 1351- 1

Abstract-Summary We aim to prove if the KD-related changes of cortical excitability are primarily due to cerebral cortex activity or are modulated by the brainstem.

384

2 Mechanisms

Through the stimulation of the right supraorbital division of the trigeminal nerve, we concurrently interictally recorded the nociceptive blink reflex (nBR) and the pain-related evoked potentials (PREP) in 18 migraineurs patients without aura before and after 1-month on KD, while in metabolic ketosis.

nBR and PREP reflect distinct brain structures activation: the brainstem and the

cerebral cortex respectively.

KD significantly normalized the interictal PREP habituation (pre: + 1.8, post:

− 9.1, p = 0.012), while nBR deficit of habituation did not change.

The positive clinical effects we observed in a population of migraineurs by a 1-month KD treatment coexists with a normalization at the cortical level, not in the brainstem, of the typical interictal deficit of habituation.

These findings suggest that the cerebral cortex may be the primary site of

KD-related modulation.

Extended: nBR and PREP recordings were simultaneously recorded during a single session including baseline (time 0) and 1-month after, during metabolic keto- sis (> 0.5 mmol/l), as verified through urine ketone testing (Ketur Test), on the same day of the recording session.

These findings suggest that the cerebral cortex may be the primary site of

KD-related modulation.

Background Aiming to understand mechanisms of KD clinical efficacy in migraine, we analysed the changes in cortical evoked potentials (EPs) in response to repeated visual and somatosensorial stimuli before and after 1-month on KD, during metabolic ketosis, and we observed a normalization of the baseline interictal deficit of habituation for both sensory modalities [624].

Whether the primary mechanism of action of KD in improving clinical and neu- rophysiological effects of migraine is solely based on alteration of activity in the cerebral cortex or the monoaminergic modulation of the nociceptive brainstem tri- geminal system, which has been shown to play a pivotal role in the ignition of the migraine attack [625], remains to be determined.

To do so, we simultaneously recorded nociceptive blink reflex (nBR) and cortical pain-related evoked potentials (PREP) elicited by the same supraorbital painful stimuli [626–628] before and during metabolic ketosis induced by KD, in a group of patients with episodic migraine without aura, between attacks.

Methods The Simultaneous recording of nociceptive Blink Reflex (nBR) and Pain-Related Evoked Potentials (PREP) was performed in all subjects enrolled according to methods described elsewhere [627].

Habituation of the nBR R2 component and of the N-P PREP amplitude were defined as the slope of the linear regression (calculated using the SLOPE function in Microsoft Excel) of the R2 AUC and of the N-P PREP amplitude between the first and the second blocks of recordings.

nBR and PREP recordings were simultaneously recorded during a single session including baseline (time 0) and 1-month after, during metabolic ketosis (>0.5

2.4 Lifestyle

385

mmol/l), as verified through urine ketone testing (Ketur Test), on the same day of the recording session.

Pearson’s correlation test was used to search for correlations among nBR and PREP slopes and clinical variables (duration of migraine history [years], attack fre- quency [n/month], attack duration [h/month], intensity of migraine headache [0–10], and migraine severity [0–3]).

Results With controls, 1st R2 component AUC was significantly lower in migraine on both homolateral (F1,34 = 18.682, p = 0.0001) and contralateral sides (F1,34 = 7.792, p = 0.008), while 1st N-P PREP amplitude block did not differ between groups (F1,34 = 2.194, p = 0.148).

In the rm-ANOVA model with nBR R2 AUC (homolateral) or N-P peak-peak amplitudes as dependent variable, multivariate test was significant for the “group” × “blocks” interaction effect (F1,34 = 11.973, p = 0.001 for nBR R2 homolateral; F1,34 = 9.420, p = 0.004 for PREP), but this was not the case in the model with nBR R2 AUC contralateral to the stimulated side (F1,34 = 3.456, p = 0.07).

Discussion The most relevant finding of our study is that the response to trigeminal PREP habituates during the KD, while the simultaneous recording of nBR elicited by the same trigeminal nociceptive stimuli does not habituate.

The described dissociation of habituation between PREP and nBR during meta- bolic ketosis reflects the different origins of the elicited responses to the repetitive nociceptive stimuli: the origin of PREP signal, although partially influenced by the brainstem, originates from cortical activity, whereas nBR is a pure brainstem response, not influenced by cortical activity.

We propose as a possible neural mechanism by which metabolic ketosis induces an increase in BDNF release which in turn normalizes the basic interictal PREP lack of habituation and prevents migraine.

We observed that the genetic polymorphism of the MAOA (predicting for mono- aminergic dysfunctions) was also able to affect the habituation of PREP, potentially by influencing the brainstem processing of stimuli before their projections to corti- cal structures [629].

Conclusions Our study confirms that in migraineurs on a ketogenic diet, the typical interictal deficit of habituation of evoked responses to repeated electric painful trigeminal stimuli can normalize, but only at cortical levels (as measured by the recording of PREPs), not in the brainstem (studied by the nBR analysis).

These findings suggest that the cerebral cortex may be the primary site of

KD-related modulation.

Acknowledgement A machine generated summary based on the work of Di Lorenzo, Cherubino; Coppola, Gianluca; Bracaglia, Martina; Di Lenola, Davide; Sirianni, Giulio;

386

2 Mechanisms

Rossi, Paolo; Di Lorenzo, Giorgio; Parisi, Vincenzo; Serrao, Mariano; Cervenka, Mackenzie C.; Pierelli, Francesco2019 in BMC Neurology

The association between dietary tryptophan intake and migraine