Short-term cortical synaptic depression/potentiation mechanisms in chronic migraine patients with or without medication overuse.

OBJECTIVE: To study the effects of trains of repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in patients with chronic migraine (CM) with or without medication overuse (MOH). SUBJECTS AND METHODS: Thirty-two patients (CM [n = 16]; MOH [n = 16]) and 16 healthy volunteers (HVs) underwent rTMS recording. Ten trains of 10 stimuli each (120% resting motor threshold) were applied over the left motor cortex at 1 Hz or 5 Hz in random order. The amplitude of motor evoked potential (MEP) was evaluated from electromyographic recording in the first dorsal interosseous muscle. The slope of the linear regression line for the 10 stimuli for each participant was calculated using normalized data. RESULTS: rTMS-1 Hz had a normal depressive effect on MEP amplitude in all groups. rTMS-5 Hz depressed instead of potentiating MEP amplitudes in MOH patients, with a significantly different response from that in HVs and CM patients. The slope of the linear regression of MEP amplitudes was negatively correlated with pain intensity in CM patients, and with the duration of overuse headache in MOH patients. CONCLUSIONS: This different plastic behaviour suggests that MOH and CM, despite exhibiting a similar clinical phenotype, have different neurophysiological learning processes, probably related to different pathophysiological mechanisms of migraine chronification.

Withdrawal from acute medication normalises short-term cortical synaptic potentiation in medication overuse headache.

OBJECTIVES: To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH). METHODS: Thirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication withdrawal program. Ten trains of 10 stimuli each (120% resting motor threshold) were delivered at 1 Hz or 5 Hz in two separate sessions in a randomised order. Motor evoked potential (MEP) amplitudes were measured from the right first dorsal interosseous muscle and the slope of the linear regression line from the first to the tenth stimuli was calculated for each participant. RESULTS: All subjects exhibited MEP amplitude inhibition in response to 1 Hz rTMS. Alternatively, the 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in patients with MOH. The physiological potentiating effect of 5 Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH. CONCLUSIONS: The results suggest that acute medication withdrawal normalises brain responses in patients with MOH. Clinical improvements after medication withdrawal may reflect the reversal of neurophysiological dysfunction. Accordingly, medication withdrawal should be offered to patients with MOH as early as possible in order to prevent the development of more pronounced alterations in brain plasticity.

Thalamo-cortical network activity between migraine attacks: Insights from MRI-based microstructural and functional resting-state network correlation analysis.

BACKGROUND: Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Here we were aimed to verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients between attacks. METHODS: Eighteen patients with untreated MO underwent 3 T MRI scans and were compared to a group of 19 healthy volunteers (HV). We used MRI to collect resting state data among two selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) and mean diffusivity (MD) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same subjects and correlated with resting state ICs Z-scores. RESULTS: In comparison to HV, in MO we found significant reduced functional connectivity between the default mode network and the visuo-spatial system. Both HV and migraine patients selected ICs Z-scores correlated negatively with FA values of the thalamus bilaterally. CONCLUSIONS: The present results are the first evidence supporting the hypothesis that an abnormal resting within networks connectivity associated with significant differences in baseline thalamic microstructure could contribute to interictal migraine pathophysiology.

Evidence for brain morphometric changes during the migraine cycle: a magnetic resonance-based morphometry study.

Neurophysiological investigations have demonstrated that there are unique fluctuations in the migraine brain functional activity between the ictal and interictal periods. Here we investigated the possibility that there are fluctuations over time also in whole brain morphometry of patients affected by episodic migraine without aura (MO).Twenty-four patients with untreated MO underwent 3T MRI scans during (n = 10) or between attacks (n = 14) and were compared to a group of 15 healthy volunteers (HVs). We then performed voxel-based-morphometry (VBM) analysis of structural T1-weighted MRI scans to determine if changes in brain structure were observed over the course of the migraine cycle.Interictally, MO patients had a significantly lower gray matter (GM) density within the right inferior parietal lobule, right temporal inferior gyrus, right superior temporal gyrus, and left temporal pole than did HVs. Ictally, GM density increased within the left temporal pole, bilateral insula, and right lenticular nuclei, but no areas exhibited decreased GM density.These morphometric GM changes between ictal and interictal phases suggest that abnormal structural plasticity may be an important mechanism of migraine pathology. Given the functional neuroanatomy of these areas, our findings suggest that migraine is a condition associated with global dysfunction of multisensory integration and memory processing.

Influence of rTMS over the left primary motor cortex on initiation and performance of a simple movement executed with the contralateral arm in healthy volunteers.

Repetitive transcranial magnetic stimulation (rTMS) affects cortical excitability according to the frequency of stimulation. Few data are available on the influence of rTMS applied over the primary motor cortex (M1) on motor performances in healthy volunteers. The aim of this study was to determine, through kinematic analysis, whether rTMS over the left M1 changes initiation and performance of movement executed with the contralateral arm. Nine healthy males completed a set of motor tasks, consisting of a single-joint rapid movement between two objects performed under three different behavioral conditions (self-initiated; externally triggered known, during which the subject could see where the target was positioned in advance; externally triggered unknown, during which the subject could not see where the target was positioned until he reached it). The tasks were performed in a randomized order in three different sessions, with a seven-day interval between each session: (1) without stimulation (baseline); (2) immediately after 1-Hz rTMS; (3) immediately after 10-Hz rTMS. We measured reaction time, movement time, calculated as the sum of the time taken to reach the target from movement onset (T1) and that taken to reach the target to movement termination (T2), acceleration and deceleration time on the velocity profile, as well as the ratio between them, and maximum speed and maximum acceleration. Reaction time, movement time, and T2 significantly increased after 1-Hz rTMS and decreased after 10-Hz rTMS, while the other parameters remained unchanged. Our results suggest that rTMS may modify both initiation and performance of a voluntary movement.

Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism.

BACKGROUND: Medication overuse headache (MOH) is a disabling health problem. Convincing evidence attributes a pathophysiologic role to central sensitization. By recording somatosensory evoked potentials (SSEPs) in patients with MOH, we observed increased sensitization and deficient habituation to repetitive sensory stimuli consistent with drug overuse. The renin-angiotensin system in the brain seems to play a relevant role in neural plasticity and dependence behavior. We therefore sought differences in SSEP sensitization and habituation in patients with MOH who underwent angiotensin converting enzyme (ACE) I/D polymorphism analysis. METHODS: We recorded median-nerve SSEPs (two blocks of 100 sweeps) in 43 patients with MOH. We measured N20-P25 amplitudes, and assessed sensitization using the first block amplitudes, and habituation using amplitude changes between the two sequential blocks. According to their genotype, subjects were divided into three groups: "D/D", "D/I" and "I/I" carriers. RESULTS: The habituation slope of the two SSEP block amplitudes was significantly increased in the D/D subgroup (n = 16) with respect to that of the I/I subgroup (n = 6), with the D/I subgroup (n = 21) falling in between. In D/D carriers, the habituation slope correlated positively with the duration of the overuse headache, and the first SSEP block amplitudes, a measure of sensitization, increased in strict relationship with the type of overused medication in the MOH patients overall and in the D/D subgroup; this was not so in the D/I and I/I subgroups. CONCLUSION: In patients with MOH, the homozygote D/D ACE polymorphism influences habituation and sensitization to repeated sensory stimuli in strict relationship with medication overuse. We suggest that angiotensin peptides influence neuronal mechanisms of plasticity by interacting with central monoaminergic synaptic transmission.

Recurrent leukoencephalopathy in a cocaine abuser.

We report the case of a cocaine abuser who presented two consecutive episodes of acute leukoencephalopathy, documented by serial MRI, with favourable outcome. Clinical findings and brain imaging led to the diagnosis of cocaine-induced toxic leukoencephalopathy and other possible mimickers have been excluded on the basis of clinical assessment. The patient's unexpected recovery on neurological and neuropsychological examination, despite initially severe neurological symptoms, is striking and differs from more common reports of a rapid progression to death. Of note, case presented in the peculiar form of recurrent episodes of acute leukoencephalopathy, with favourable outcome, which, to our knowledge, has not been described yet. We speculate about the aetiology of this condition, which is still poorly understood.