Satu K. Jääskeläinen

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)

A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.

Sensory dysfunction in burning mouth syndrome

&NA; Our preliminary observations on a small group of burning mouth syndrome (BMS) patients indicated a change in the non‐nociceptive, tactile sensory function in BMS and provided evidence for the hypothesis of a neuropathic etiology of BMS. In the present clinical study on a group of 52 BMS patients, we used quantitative sensory tests (QST) in addition to the blink reflex (BR) recordings in order to gain further insight into the neural mechanisms of BMS pain. Based on electrophysiologic findings, the BMS patients could be grouped into four different categories: (1) The results of the BR were suggestive of brainstem pathology or peripheral trigeminal neuropathy in ten (19%) patients. In most of the cases, the abnormalities in the BR seemed to represent subclinical changes of the trigeminal system. (2) Increased excitability of the BR was found in the form of deficient habituation of the R2 component of the BR in 11 (21%) of the patients. Two of these patients also showed signs of warm allodynia in QST. (3) One or more of the sensory thresholds were abnormal indicating thin fiber dysfunction in altogether 35 patients (76%) out of the 46 tested with QST. Thirty‐three of these patients showed signs of hypoesthesia. (4) There were only five patients with normal findings in both tests. The present findings with strong evidence for neuropathic background in BMS will hopefully provide insights for new therapeutic strategies.

Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography.

Background The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis. Methods Using H215O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC50, or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 &mgr;g/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation. Results Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36–53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7–16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62–70%, with minor further effects. In the SPM analysis of the “awake to 1 MAC/EC50” step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices. Conclusions Both anesthetic agents caused a global reduction of rCBF (propofol > sevoflurane) at the 1 MAC/EC50 level. The effect was maintained at higher propofol concentrations, whereas 2 MAC sevoflurane caused noticeable flow redistribution. Despite the marked global changes, SPM analysis enabled detailed localization of regions with the greatest relative decreases.

Role of the dopaminergic system in chronic pain -- a fluorodopa-PET study.

&NA; Recent data from animal experiments suggest an important role for the basal ganglia in the processing and sensorimotor gating of nociceptive information. However, very little is known about their possible participation in human pain. Because of our previous finding of increased excitability of the blink reflex (a brainstem reflex under dopaminergic inhibitory control) in some burning mouth syndrome (BMS) patients, we have studied the dopaminergic function of the striatum (putamen and caudatus) of BMS patients with positron emission tomography (PET). 6‐[18F]fluorodopa (FDOPA) PET scans were done on ten BMS patients and 14 healthy control subjects. The presynaptic dopaminergic function was significantly decreased in the right putamen (20%, P=0.04) of the BMS patients compared to control subjects. On the left side, the FDOPA uptake was decreased by 17% (P=0.08). The mean FDOPA uptake was not significantly changed in the caudate nucleus of the patients. The finding of decreased striatal FDOPA uptake in the putamen supports our previous neurophysiological observations indicating decreased dopaminergic inhibition in BMS patients. The present result provides direct evidence of the involvement of the nigrostriatal dopaminergic system in pain for the first time in a clinical pain condition.

Striatal dopamine D1 and D2 receptors in burning mouth syndrome

&NA; Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C‐NNC 756 and 11C‐raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C‐NNC 756 did not differ between patients and controls. In a voxel‐level analysis, the uptake of 11C‐raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P‐value 0.038 at cluster‐level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64±0.04 vs. 0.69±0.04, P=0.01) and 6.4 % lower in the left putamen (0.65±0.05 vs. 0.70±0.05, P=0.05) when compared to controls. Increased 11C‐raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients.

Abnormalities of the blink reflex in burning mouth syndrome.

&NA; To our knowledge, this is the first report on pain‐related abnormalities of the eye blink reflex (BR) in a clinical pain patient population. The objective of this study was to evaluate the possible neuropathic mechanisms underlying the burning mouth syndrome (BMS), by means of objective electrophysiological examination of the trigemino‐facial system. We studied the BR with stimulation of the supraorbital nerve (SON) with particular emphasis on the occurrence of the pain‐related ultralate R3 components, and the habituation response of the R2 components. The subjects consisted of eleven BMS patients and 10 healthy control subjects. All patients underwent thorough clinical oral and neurological examinations. The motor function of the trigeminal nerve was assessed with a jaw reflex recording, and a needle‐EMG examination of the facial and masticatory muscles was performed in the patients with abnormalities in the BR recordings. The jaw reflexes, the latencies of the BR components, and the needle‐EMG examinations were normal in all patients. As a group, the BMS patients had statistically significantly higher stimulus thresholds for the tactile R1 components of the BR compared with the control subjects. With non‐noxious stimulation, the BMS patients showed more frequently pain‐related R3 components (11/22 SONs) compared with the controls (3/20 SONs). In addition, four BMS patients had abnormal habituation of the R2 components. In two of these patients, the findings were segmental (i.e., unilateral), coinciding with the side of the subjective BM symptoms. The abnormalities of the BR tests appeared to be related to longer disease duration. Our results suggest a possible pathologic involvement of the nervous system in chronic BMS.

Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep

Background: Dexmedetomidine, a selective α2‐adrenoceptor agonist, induces a unique, sleep‐like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep‐promoting pathways.

Altered dopamine D2 receptor binding in atypical facial pain.

&NA; Animal studies suggest that the dopaminergic system plays a role in central pain modulation. We have previously demonstrated with positron emission tomography (PET) that striatal dopaminergic hypofunction may be involved in the burning mouth syndrome. The aim of the present study was to evaluate the nigrostriatal dopaminergic system in patients with atypical facial pain using PET. In seven patients with atypical facial pain, striatal presynaptic dopaminergic function was assessed with [18F]FDOPA and dopamine D1 and D2 receptor availabilities with [11C]NNC 756 and [11C]raclopride, respectively. The results were compared with those of healthy controls. A quantitative region‐of‐interest analysis showed that the uptakes of [18F]FDOPA and [11C]NNC 756 did not differ between patients and controls. There was a tendency of increased D2 receptor availability in the left putamen (P=0.056), and the D1/D2 ratio in the putamen was decreased bilaterally by 7.7% (P=0.002) in patients when compared to controls. In a voxel‐based analysis, the uptake of [11C]raclopride was increased in the left putamen (P=0.025). In conclusion, the increase in D2 receptor availability in the left putamen and the decrease in D1/D2 ratio imply that alterations in the striatal dopaminergic system as evaluated by PET may be involved in chronic orofacial pain conditions.

Pathophysiology of primary burning mouth syndrome

Primary burning mouth syndrome (BMS) is severe, disabling and chronic intraoral pain condition for which no local or systemic cause can be found and clinical examination is normal. It mostly affects elderly citizens, especially postmenopausal women with prevalence up to 12-18%. In addition to spontaneous burning pain, patients may complain of taste alterations. Recent neurophysiologic, psychophysical, neuropathological, and functional imaging studies have elucidated that several neuropathic mechanisms, mostly subclinical, act at different levels of the neuraxis and contribute to the pathophysiology of primary BMS. Demonstration of loss of small diameter nerve fibres in the tongue epithelium explains thermal hypoesthesia and increase in taste detection thresholds found in quantitative sensory testing. As in neuropathic pain, decreased brain activation to heat stimuli has been demonstrated with fMRI in BMS patients. However, it seems that the clinical diagnosis of primary BMS encompasses at least three distinct, subclinical neuropathic pain states that may overlap in individual patients. The first subgroup (50-65%) is characterized by peripheral small diameter fibre neuropathy of intraoral mucosa. The second subgroup (20-25%) consists of patients with subclinical lingual, mandibular, or trigeminal system pathology that can be dissected with careful neurophysiologic examination but is clinically indistinguishable from the other two subgroups. The third subgroup (20-40%) fits the concept of central pain that may be related to hypofunction of dopaminergic neurons in the basal ganglia. The neurogenic factors acting in these subgroups differ, and will require different treatment strategies. In the future, with proper use of diagnostic tests, BMS patients may benefit from interventions specifically targeted at the underlying pathophysiological mechanisms.

Neurophysiologic and quantitative sensory testing in the diagnosis of trigeminal neuropathy and neuropathic pain.

&NA; This study investigated the utility of neurophysiologic examination and thermal quantitative sensory testing (QST) in the diagnosis of trigeminal neuropathy and neuropathic pain. Fifty‐eight patients (14 men), 34 with sensory deficit within the inferior alveolar nerve (IAN) and 24 within the lingual nerve (LN) distribution, were included. Twenty‐six patients (45%) reported neuropathic pain. Patients underwent blink reflex (BR) test and thermal QST; sensory neurography was done to the IAN patients. Results of clinical sensory testing were available from the charts of 48 patients revealing abnormal findings in 77% of the IAN and in 94% of the LN patients. The BR test was abnormal in 41%, neurography in 96%, and QST in 91% of the IAN patients. In the LN group, BR was abnormal in 33%, and QST in 100% of the patients tested. Neurophysiologic tests and QST verified the subjective sensory alteration in all but 2 IAN patients, both with old injuries, and 4 LN patients who did not undergo QST. When abnormal, thermal QST showed elevation of warm and cold detection thresholds (hypo/anesthesia), hypoalgesia was less marked, and heat allodynia was only occasionally present. Contralateral thermal hypoesthesia after unilateral injury was found in 14 patients. It was associated with the occurrence of neuropathic pain (P=0.016). Axonal Aβ afferent damage was less severe in the IAN patients with pain than in those without pain (P=0.012). Neurophysiologic tests and thermal QST provide sensitive tools for accurate diagnosis of trigeminal neuropathy and study of pathophysiological features characteristic to human neuropathic pain.