The authors have declared that no competing interests exist.
Conceived and designed the experiments: RB DB. Performed the experiments: EM LB AJ RB DB. Analyzed the data: EM LB. Contributed reagents/materials/analysis tools: LB. Wrote the paper: EM RB DB.
The hypothalamus has been implicated in migraine based on the manifestation of autonomic symptoms with the disease, as well as neuroimaging evidence of hypothalamic activation during attacks. Our objective was to determine functional connectivity (FC) changes between the hypothalamus and the rest of the brain in migraine patients vs. control subjects. This study uses fMRI (functional magnetic resonance imaging) to acquire resting state scans in 12 interictal migraine patients and 12 healthy matched controls. Hypothalamic connectivity seeds were anatomically defined based on high-resolution structural scans, and FC was assessed in the resting state scans. Migraine patients had increased hypothalamic FC with a number of brain regions involved in regulation of autonomic functions, including the locus coeruleus, caudate, parahippocampal gyrus, cerebellum, and the temporal pole. Stronger functional connections between the hypothalamus and brain areas that regulate sympathetic and parasympathetic functions may explain some of the hypothalamic-mediated autonomic symptoms that accompany or precede migraine attacks.
Migraine, a common neurological disorder, is characterized by episodic headache attacks, and is frequently accompanied by nausea, vomiting, hunger, yawning, thirst, photophobia, phonophobia, and/or sleep disorders
By regulating many sympathetic and parasympathetic responses, the hypothalamus is thought to heavily involved in physiological functions such as food ingestion, energy balance, stress, circadian rhythms, arousal, and autonomic responses to pain. The central role of the hypothalamus in regulating autonomic functions and homeostasis suggests that it may underlie some autonomic symptoms associated with migraine
While the hypothalamus appears to be an important structure in migraine, imaging studies have yet to explicitly evaluate whether the hypothalamus has altered functional processing during the interictal state. One approach is to evaluate changes in functional connectivity of this structure in patients compared with healthy controls. In fMRI, functional connectivity (FC) is defined as temporal correlations between spatially remote neurophysiological events or functional interactions
Using fMRI, we recorded blood oxygen level dependent (BOLD) signal fluctuations during resting state in 12 episodic migraine patients and 12 healthy age- and gender-matched control subjects.
This study was approved by the McLean Hospital Institutional Review Board, and met the scientific and ethical guidelines for human research of the Helsinki Accord (
Episodic migraine patients (9 females, 3 males; 31·7±7·6 years old;
Age | Sex | Freq | Onset | Side | Pain w/o med | Pain w/med | Medications | |
M1 | 31.9 | M | 1/mo | 15 yrs | B | 9 | 4 | Acetaminophen, Ibuprofen |
M2 | 49 | F | 5/mo | 39 yrs | U | 10 | 0 | Sumatriptan, Lisinopril |
M3 | 36.3 | F | 1/mo | 33 yrs | L | 10 | 9 | Aspirin, Acetaminophen, Ibuprofen |
M4 | 24.8 | F | 7–8/mo | 8 yrs | B | 8 | 4 | Amitriptyline, Atenolol, Acetaminophen, Naproxen, Rizatriptan |
M5 | 22.9 | F | 3–4/mo | 7 yrs | B | 10 | 7 | Acetaminophen, Ibuprofen |
M6 | 25.7 | F | 3–4/mo | 7 yrs | B | 10 | 10 | Ibuprofen |
M7 | 32.1 | F | 2–4/mo | 21 yrs | U | 7 | 6 | None |
M8 | 37.6 | M | 2/mo | 32 yrs | R | 10 | 9 | None |
M9 | 24.6 | F | 1/mo | 4 yrs | L | 10 | 6 | Acetaminophen |
M10 | 26.8 | M | 5/mo | 3 yrs | B | 5–6 | N/A | None |
M11 | 38.8 | F | 2/mo | 28 yrs | U | 9–10 | 4 | Ibuprofen, Midrin |
M12 | 30.2 | F | 1–3/mo | 8 yrs | R | 7 | 7 | Rizatriptan |
H1 | 32.2 | M | – | – | – | – | – | – |
H2 | 27.9 | F | – | – | – | – | – | – |
H3 | 24.5 | F | – | – | – | – | – | – |
H4 | 23.3 | F | – | – | – | – | – | – |
H5 | 36.9 | F | – | – | – | – | – | – |
H6 | 26.4 | F | – | – | – | – | – | – |
H7 | 38 | M | – | – | – | – | – | – |
H8 | 30.8 | F | – | – | – | – | – | – |
H9 | 24.3 | M | – | – | – | – | – | – |
H10 | 31.6 | F | – | – | – | – | – | – |
H11 | 36.3 | M | – | – | – | – | – | – |
H12 | 49 | F | – | – | – | – | – | – |
Subjects verbally rated the pain intensity of their average migraine as a 5 or higher on a 0–10 scale, with 10 being the most intense pain imaginable. For those patients taking daily medications (e.g., preventive as opposed to acute medications to abort the attack), patients abstained from taking their migraine medications for one dosing interval prior to their scheduled scan session. Age- and gender-matched healthy subjects (8 females, 4 males; 31·7±7·2 years old) were also tested. Gender-matching was not exact, as the control group had one more male (and one less female) than the patient group.
Imaging was conducted using a 3T Siemens Tim Trio scanner with a quadrature head coil. T1-weighted structural images were acquired using a 3D magnetization-prepared rapid gradient echo sequence (MPRAGE - 128 1.3 mm-thick slices with an in-plane resolution of 1 mm (256×256)). For functional resting state scans, a Gradient Echo (GE) echo planar imaging (EPI) sequence with TE/TR = 30/2000 was performed, with three hundred volumes captured for each scan. Each functional scan consisted of 34 slices oriented in an oblique plane to match the brainstem axis. Slices were 4.0 mm thick with an in-plane resolution of 3.5 mm (64×64). During these resting state scans, subjects were instructed to stay awake and to keep their eyes open.
Functional imaging datasets were processed and analyzed using scripts within FSL (FMRIB’s Software Library,
The hypothalamus was identified for each subject based on anatomical landmarks in the MPRAGE as described previously (
Anatomical boundaries for each subject were based on Saleem et al., 2007 (see Methods for details).
First-level functional connectivity analysis of single subject data was performed using FMRI Expert Analysis Tool using FMRIB’s Improved Linear Model (FEAT FILM) Version 6.00 with local autocorrelation correction
Group functional connectivity maps were generated by fMRI expert analysis tool (FEAT) fMRIB’s Local Analysis of Mixed Effects (FLAME). A mixed effects contrast analysis was performed to compare migraine vs. control group functional connectivity. Statistical parametric maps were thresholded using Gaussian Mixture Modeling (GMM)
Twelve patients and twelve matched healthy controls were successfully scanned. All patients were had episodic migraine without aura. None were on preventive medications (
A mixed effects contrast analysis was performed to compare migraine vs. control group functional connectivity showed significant differences in a number of areas (details below).
Widespread differences in hypothalamic functional connectivity were detected in migraine patients vs. healthy control subjects. The majority of these differences occurred in brain regions related to sympathetic and/or parasympathetic nervous system processing, with migraine patients showing greater functional connectivity with these structures (
Functional connectivity contrast maps were thresholded at a posterior probability of p>0.5 using GMM. Contrast maps overlay the standard MNI152 whole-brain atlas. PNS = parasympathetic nervous system, SNS = sympathetic nervous system. In reference to coordinates, x = sagittal (posterior-anterior, from left to right of the image), y = coronal (right-left), and z = axial planes (right-left).
Brain Region | Lat. | z-stat | X | Y | Z | Vol (cm3) |
PrCG | R | 3.0019 | 6 | −32 | 72 | 0.35 |
MFG | R | 2.8577 | 44 | 22 | 44 | 0.41 |
SPL/SMG | L | 2.8535 | −46 | −44 | 58 | 0.34 |
ITG | L | 3.7500 | −50 | 0 | −38 | 0.31 |
Planum Polare | R | 3.6963 | 46 | −4 | −16 | 0.66 |
TmP | L | 3.6501 | −36 | 6 | −22 | 0.41 |
MTG | L | 3.1737 | −58 | −10 | −26 | 0.46 |
L | 2.9026 | −58 | −12 | −14 | 0.73 | |
PHG | L | 3.1445 | −22 | −16 | −28 | 0.42 |
L | 2.8751 | −22 | −12 | −34 | 0.33 | |
STG | L | 3.1319 | −62 | −30 | 0 | 0.76 |
Hippocampus | R | 3.0327 | 44 | −16 | −24 | 0.3 |
L | 2.9341 | −48 | −22 | −22 | 0.46 | |
Caudate | L | 2.8124 | −16 | −4 | 24 | 0.5 |
Nucleus coeruleus | R | 3.4440 | 8 | −34 | −26 | 0.58 |
PN | L | 3.5626 | −8 | −24 | −42 | 0.59 |
R | 2.9397 | 8 | −20 | −40 | 0.79 | |
R | 3.0793 | 6 | −26 | −42 | 0.54 | |
Cr I/II | L | 3.3418 | −40 | −50 | −48 | 0.85 |
V | L | 3.2582 | −12 | −50 | −14 | 0.78 |
R | 3.2184 | 14 | −46 | −16 | 0.52 | |
R | 3.1642 | 12 | −52 | −20 | 1.19 | |
R | 3.0691 | 6 | −60 | −22 | 0.86 | |
L | 2.8326 | −10 | −60 | −8 | 0.45 | |
Verm VIIIa/VIIIb | L | 3.2080 | −2 | −62 | −36 | 0.33 |
Dentate nucleus | L | 3.1411 | −24 | −50 | −34 | 0.36 |
IX | R | 3.0394 | 8 | −46 | −46 | 0.43 |
V/VI | R | 2.8944 | 12 | −58 | −18 | 0.35 |
Migraineurs showed enhanced functional connectivity with the hypothalamus in subcortical structures and throughout the temporal lobe (
Brain Region | Lat. | z-stat | X | Y | Z | Vol (cm3) |
PrCG | R | 3.9425 | 48 | 4 | 34 | 1.34 |
R | 3.872 | 24 | −10 | 60 | 0.42 | |
FrPole | L | 3.8249 | −40 | 38 | 16 | 0.41 |
L | 3.6729 | −34 | 44 | 20 | 0.58 | |
L | 3.6329 | −28 | 38 | 28 | 0.44 | |
ParaCG | L | 3.2542 | −4 | 40 | 32 | 0.34 |
SFG | R | 2.9452 | 18 | −2 | 64 | 0.32 |
Fusiform G | R | 4.2019 | 16 | −78 | −12 | 0.46 |
Lingual G | L | 3.7044 | −4 | −84 | 0 | 0.43 |
L | 3.3314 | 4 | −86 | −8 | 0.31 |
This study found that interictal migraineurs have enhanced functional connectivity (FC) between the hypothalamus and brain structures related to autonomic function. Enhanced connectivity was observed to overlap with central representations of autonomic nervous system function, which has recently been characterized in a neuroimaging meta-analysis
In migraineurs, the hypothalamus demonstrated increased functional connectivity with sympathetic nervous system structures, such as the parahippocampal gyrus and cerebellar Crus I and II. The hypothalamus is structurally connected to the hippocampus through the fornix
Migraineurs also showed increased hypothalamic connectivity with parasympathetic nervous system structures, including the temporal pole, superior temporal gyrus, and cerebellar lobules V and VI. Structural connectivity between these areas and the hypothalamus has been established previously
Structures related to both sympathetic and parasympathetic processing, such as the locus coeruleus (LC), also exhibited increased hypothalamic connectivity. The LC is the largest noradrenergic nucleus in the brain. Through heavy innervation of multiple forebrain regions including the hypothalamus
Another structure showing altered hypothalamic FC that is implicated in sympathetic and parasympathetic function is the caudate nucleus. Efferent connections between the hypothalamus and the caudate have been shown in tracing studies in the rat
The data indicates decreased functional connectivity with a number of brain regions of migraineurs vs. healthy controls (
The study did not differentiate between migraine patients with and without aura. Migraine with aura is a more aggressive disease, at least based on observed brain changes
While the resting state connectivity data suggests that the hypothalamus has widespread influence on autonomic nervous system structures in migraine patients, it does not necessarily indicate that the hypothalamus has a central role in generating migraines. The connectivity results are correlative, and the inference of functional impact is based on previous studies. However, the results do indicate that changes in hypothalamic connectivity are a central feature in migraine patients, and may be responsible for the manifestation of autonomic symptoms. While other autonomic brain systems must clearly play a role in migraine, only those areas noted in the results showed differences between healthy subjects and controls for the resting state data acquired. Thus, measures of hypothalamic hyperactivity to a stressor (e.g., heat or a migraine attack) or measures of hypothalamic hormones would contribute to our understanding of the structure in the migraine condition.
We thank Lauren Nutile and Gabi Barmettler for recruiting, scheduling and scanning patients and Nasim Maleki for helping with imaging. We would like to thank Rosanna Veggeberg for her help retrieving patient records.