PHARMACOLOGICALLY INDUCED AND STIMULUS EVOKED RHYTHMIC NEURONAL OSCILLATORY ACTIVITY IN THE PRIMARY MOTOR CORTEX IN VITRO N. YAMAWAKI, I. M. STANFORD, S. D. HALL AND G. L. WOODHALL* Biomedical Sciences, School of Life and Health Sciences, Aston Uni- versity, Aston Triangle, Birmingham B4 7ET, UK Abstract—Parkinson’s disease (PD) is associated with en- hanced synchronization of neuronal network activity in the beta (15–30 Hz) frequency band across several nuclei of the basal ganglia (BG). Deep brain stimulation of the subthalamic nucleus (STN) appears to reduce this pathological oscilla- tion, thereby alleviating PD symptoms. However, direct stim- ulation of primary motor cortex (M1) has recently been shown to be effective in reducing symptoms in PD, suggesting a role for cortex in patterning pathological rhythms. Here, we ex- amine the properties of M1 network oscillations in coronal slices taken from rat brain. Oscillations in the high beta frequency range (layer 5, 27.81.1 Hz, n6) were elicited by co-application of the glutamate receptor agonist kainic acid (400 nM) and muscarinic receptor agonist carbachol (50 M). Dual extracellular recordings, local application of tetrodo- toxin and recordings in M1 micro-sections indicate that the activity originates within deep layers V/VI. Beta oscillations were unaffected by specific AMPA receptor blockade, abol- ished by the GABA type A receptor (GABA A R) antagonist picrotoxin and the gap-junction blocker carbenoxolone, and modulated by pentobarbital and zolpidem indicating depen- dence on networks of GABAergic interneurons and electrical coupling. High frequency stimulation (HFS) at 125 Hz in su- perficial layers, designed to mimic transdural/transcranial stimulation, generated gamma oscillations in layers II and V (incidence 95%, 69.27.3 Hz, n17) with very fast oscillatory components (VFO; 100 –250 Hz). Stimulation at 4 Hz, how- ever, preferentially promoted theta activity (incidence 62.5%, 5.10.6 Hz, n15) that effected strong amplitude modulation of ongoing beta activity. Stimulation at 20 Hz evoked mixed theta and gamma responses. These data suggest that within M1, evoked theta, gamma and fast oscillations may coexist with and in some cases modulate pharmacologically induced beta oscillations. © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: basal ganglia, layer 5, interneuron network, deep brain stimulation. Neuronal oscillatory activity at beta (15–30 Hz) frequen- cies is observed in somatosensory, pre-motor, supplemen- tary and primary motor cortex (M1) and is associated with complex, sensory-motor behaviors such as wakefulness and alertness, visual and task orientated procedures (Mur- thy and Fetz, 1992; Donoghue et al., 1998). However, pathologically enhanced beta activity is associated with the loss of voluntary movement including akinesia/bradykine- sia, rigidity associated with Parkinson’s disease (PD) (Brown and Marsden, 1998). PD symptoms appear to be coincident with the loss of independent neuronal activity in both the cortex and the basal ganglia (BG). Thus, in the presence of normal dopaminergic drive, the activity of BG neurons is largely desynchronized. However, upon the loss of dopamine, in idiopathic PD and experimental mod- els of the disease, neurons of the subthalamic nucleus (STN), (internal and external) globus pallidus (GP) and substantia nigra pars reticulata (SNr), lose their indepen- dence and show increases in burst firing and synchroniza- tion of activity (Filion and Tremblay, 1991; Nini et al., 1995). This pathological activity favors oscillations with frequencies in either the beta range (20 Hz), which may exacerbate akinesia and bradykinesia (Brown and Mars- den, 1998; Levy et al., 2000) or the theta range (4 – 8 Hz), which appear phase-related to resting tremor (Bergman et al., 1994; Magnin et al., 2002). Pathological oscillations and motor symptoms may be suppressed by administra- tion of L-DOPA, which resets the pattern of activity in BG to one of tonic, uncorrelated firing (Brown et al., 2001), or by lesion or high-frequency (130 Hz) deep brain stimulation (DBS) of the STN (Bergman et al., 1994; Krack et al., 1998). In recent years, transdural stimulation of M1 in animal models of PD (Drouot et al., 2004) and in some groups of PD patients (e.g. Pagni et al., 2003) and transcranial mag- netic stimulation (TMS) (Lefaucheur et al., 2004) of the same region have been shown to improve motor impair- ments, opening the possibility of non-invasive therapeutic approaches. As the STN receives direct monosynaptic projections from M1 in a somatotopic manner (Nambu et al., 1996), the cortico-subthalamic ‘hyperdirect’ pathway is the fastest way for transfer of both physiological (Nambu et al., 2002) and pathological (Paz et al., 2005) information. Further- more, the rationale for non-invasive interventions has been substantiated by recent experimental data which implicate the cortico-subthalamic pathway in patterning pathological activities leading to inappropriate burst firing and neuronal synchronization in BG nuclei (Magill et al., 2001, 2004). *Corresponding author. Tel: +44-121-204-3995; fax: +44-121-204- 3696. E-mail address: G.L.Woodhall@aston.ac.uk (G. Woodhall). Abbreviations: aCSF, artificial cerebrospinal fluid; AMPAR, AMPA type glutamate receptor; BG, basal ganglia; CCh, carbachol; GABA A R, GABA type A receptor; IPSPs, inhibitory postsynaptic potentials; KA, kainic acid; KAR, kainate-type glutamate receptor; M1, primary motor cortex; PD, Parkinson’s disease; STN, subthalamic nucleus; TMS, transcranial magnetic stimulation. Neuroscience 151 (2008) 386 –395 0306-4522/08$32.00+0.00 © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2007.10.021 386